Amantadine, Oseltamivir and Zanamivir for the Prophylaxis of Influenza (Including a Review of Existing Guidance No

Health Technology Assessment 2009; Vol. 13: No. 11

Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation

P Tappenden, R Jackson, K Cooper, A Rees, E Simpson, R Read and K Nicholson

February 2009 DOI: 10.3310/hta13110

Health Technology Assessment NIHR HTA Programme www.hta.ac.uk HTA

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P Tappenden,1* R Jackson,1 K Cooper,1 A Rees,1 E Simpson,1 R Read2 and K Nicholson3

1University of Sheffield, School of Health and Related Research (ScHARR), UK 2Department of Infectious Diseases, University of Sheffield, UK 3Department of Infectious Diseases, University of Leicester, UK

*Corresponding author

Declared competing interests of authors: none

Published February 2009 DOI: 10.3310/hta13110

This report should be referenced as follows: Tappenden P, Jackson R, Cooper K, Rees A, Simpson E, Read R, et al. Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation. Health Technol Assess 2009; 13(11). Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta Medica/EMBASE, Science Citation Index Expanded (SciSearch) and Current Contents/Clinical Medicine. NIHR Health Technology Assessment Programme

he Health Technology Assessment (HTA) Programme, part of the National Institute for Health TResearch (NIHR), was set up in 1993. It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. ‘Health technologies’ are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care. The research findings from the HTA Programme directly influence decision-making bodies such as the National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee (NSC). HTA findings also help to improve the quality of clinical practice in the NHS indirectly in that they form a key component of the ‘National Knowledge Service’. The HTA Programme is needs led in that it fills gaps in the evidence needed by the NHS. There are three routes to the start of projects. First is the commissioned route. Suggestions for research are actively sought from people working in the NHS, from the public and consumer groups and from professional bodies such as royal colleges and NHS trusts. These suggestions are carefully prioritised by panels of independent experts (including NHS service users). The HTA Programme then commissions the research by competitive tender. Second, the HTA Programme provides grants for clinical trials for researchers who identify research questions. These are assessed for importance to patients and the NHS, and scientific rigour. Third, through its Technology Assessment Report (TAR) call-off contract, the HTA Programme commissions bespoke reports, principally for NICE, but also for other policy-makers. TARs bring together evidence on the value of specific technologies. Some HTA research projects, including TARs, may take only months, others need several years. They can cost from as little as £40,000 to over £1 million, and may involve synthesising existing evidence, undertaking a trial, or other research collecting new data to answer a research problem. The final reports from HTA projects are peer reviewed by a number of independent expert referees before publication in the widely read journal series Health Technology Assessment. Criteria for inclusion in the HTA journal series Reports are published in the HTA journal series if (1) they have resulted from work for the HTA Programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors. Reviews in Health Technology Assessment are termed ‘systematic’ when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others.

The research reported in this issue of the journal was commissioned and funded by the HTA Programme on behalf of NICE as project number 07/35/01. The protocol was agreed in October 2007. The assessment report began editorial review in February 2008 and was accepted for publication in July 2008. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme or the Department of Health. Editor-in-Chief: Professor Tom Walley Series Editors: Dr Aileen Clarke, Dr Peter Davidson, Dr Chris Hyde, Dr John Powell, Dr Rob Riemsma and Professor Ken Stein ISSN 1366-5278 © 2009 Queen’s Printer and Controller of HMSO This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NCCHTA, Alpha House, Enterprise Road, Southampton Science Park, Chilworth, Southampton SO16 7NS, UK. Published by Prepress Projects Ltd, Perth, Scotland (www.prepress-projects.co.uk), on behalf of NCCHTA. Printed on acid-free paper in the UK by the Charlesworth Group. T DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Abstract Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation P Tappenden,1* R Jackson,1 K Cooper,1 A Rees,1 E Simpson,1 R Read2 and K Nicholson3

*Corresponding author

Objectives: To evaluate the clinical effectiveness 95% CI 0.02–1.72). For post-exposure prophylaxis, and incremental cost-effectiveness of amantadine, data on the use of amantadine were again limited: in oseltamivir and zanamivir for seasonal and post- adolescents an RR of 0.10 (95% CI 0.03–0.34) was exposure prophylaxis of influenza. reported for the prevention of SLCI. Oseltamivir was Data sources: A MEDLINE search strategy was used effective in households of mixed composition (RR and searches were carried out in July 2007. 0.19, 95% CI 0.08–0.45). The efficacy of zanamivir in Review methods: An independent health economic post-exposure prophylaxis within households was also model was developed based on a review of existing reported (RR 0.21, 95% CI 0.13–0.33). Interventions cost-effectiveness models and clinical advice. The model appeared to be well tolerated. Limited evidence was draws together a broad spectrum of evidence relating available for the effectiveness of the interventions in to the costs and consequences associated with influenza preventing complications and hospitalisation and in and its prevention. Where direct evidence concerning minimising length of illness and time to return to normal the effectiveness of prophylaxis within specific model activities. No clinical effectiveness data were identified subgroups was lacking, the model uses estimates from for health-related quality of life or mortality outcomes. mixed subgroups or extrapolates from other mutually With the exception of at-risk children, the incremental exclusive subgroups. cost–utility of seasonal influenza prophylaxis is expected Results: Twenty-six published references relating to 22 to be in the range £38,000–£428,000 per QALY gained randomised controlled trials (RCTs) were included in the (depending on subgroup). The cost-effectiveness clinical effectiveness review, along with one unpublished ratios for oseltamivir and zanamivir as post-exposure report. Eight, six and nine RCTs were included for prophylaxis are expected to be below £30,000 per amantadine, oseltamivir and zanamivir respectively. QALY gained in healthy children, at-risk children, healthy The study quality was variable and gaps in the evidence elderly and at-risk elderly individuals. Despite favourable base limited the assessment of the clinical effectiveness clinical efficacy estimates, the incorporation of recent of the interventions. For seasonal prophylaxis, there evidence of viral resistance to amantadine led to it being was limited evidence for the efficacy of amantadine in dominated in every economic comparison. preventing symptomatic, laboratory-confirmed influenza Conclusions: All three interventions showed some (SLCI) in healthy adults [relative risk (RR) 0.40, 95% efficacy for seasonal and post-exposure prophylaxis. confidence interval (CI) 0.08–2.03]. Oseltamivir was However, weaknesses and gaps in the clinical evidence effective in preventing SLCI, particularly when used in base are directly relevant to the interpretation of at-risk elderly subjects (RR 0.08, 95% CI 0.01–0.63). the health economic model and rendered the use of The preventative efficacy of zanamivir was most notable advanced statistical analyses inappropriate. These data in at-risk adults and adolescents (RR 0.17, 95% CI 0.07– limitations should be borne in mind in interpreting the 0.44), and healthy and at-risk elderly subjects (RR 0.20, findings of the review.

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DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Contents

Glossary and list of abbreviations ...... vii 7 Conclusions ...... 137 Conclusions on the clinical effectiveness of Executive summary ...... ix influenza prophylaxis ...... 137 Conclusions on the cost-effectiveness of 1 Background ...... 1 influenza prophylaxis ...... 137 Description of health problem ...... 1 Recommendations for research ...... 139 Current service provision ...... 5 Description of technology under Acknowledgements ...... 141 assessment ...... 6 References ...... 143 2 Definition of the decision problem ...... 15 Decision problem ...... 15 Appendix 1 Literature search strategies .... 149 Overall aims and objectives of assessment . 15 Appendix 2 Quality assessment ...... 151 3 Assessment of clinical effectiveness ...... 17 Methods for reviewing effectiveness ...... 17 Appendix 3 Study quality characteristics for Results ...... 19 amantadine prophylaxis trials ...... 153

4 Assessment of cost-effectiveness ...... 43 Appendix 4 Study quality characteristics for Systematic review of existing cost-effectiveness oseltamivir prophylaxis trials ...... 157 evidence ...... 43 Independent economic assessment ...... 61 Appendix 5 Study quality characteristics for Cost-effectiveness results ...... 84 zanamivir prophylaxis trials ...... 159 Budget impact analysis ...... 102 Appendix 6 Studies excluded after close 5 Assessment of factors relevant to the NHS scrutiny with rationale ...... 161 and other parties ...... 127 Use of amantadine for Parkinson’s disease Appendix 7 List of all model and herpes zoster virus ...... 127 parameters ...... 163 Herd immunity ...... 127 Additional support in using antivirals ...... 127 Appendix 8 Cost-effectiveness acceptability Prescribing patterns for influenza curves (base-case analysis) ...... 223 prophylaxis ...... 127 Impact on primary care ...... 128 Appendix 9 Cost-effectiveness acceptability Involvement of pharmacist in use of powder curves (incorporating proposed price reduction for oral suspension ...... 128 for zanamivir) ...... 235

6 Discussion ...... 129 Health Technology Assessment reports Statement of principal findings ...... 129 published to date ...... 247 Strengths and limitations of the assessment ...... 132 Health Technology Assessment Uncertainties ...... 133 Programme ...... 265

DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Glossary and list of abbreviations

Glossary

Attack rate A cumulative incidence rate from influenza; treatment typically lasts 7–10 in a population over time, such as in the days following presumed exposure circumstances of an epidemic Protective efficacy 1 minus the RR value, Dominated (simple) Where a given treatment expressed as a percentage alternative is less effective and more expensive than its comparator Relative risk (RR) Ratio of the probability of an event occurring in an exposed group relative Dominated (extended) The state when a to a non-exposed or control group strategy under study is both less effective and more costly than a linear combination of Seasonal prophylaxis Prophylaxis initiated two other strategies with which it is mutually in response to known circulation of influenza exclusive within the community; treatment typically lasts for 6 weeks Meta-analysis A statistical method by which the results of a number of studies are pooled to Symptomatic, laboratory-confirmed give a combined summary statistic influenza Cases of influenza in which illness is clinically confirmed according to presence Post-exposure prophylaxis Prophylaxis of symptoms indicative of influenza and with initiated in response to close contact of an evidence of infection by the influenza virus, as individual with another suspected as suffering determined by laboratory methods

List of abbreviations

A&E accident and emergency EISS European Influenza Surveillance Scheme ARI acute respiratory illness EQ-5D EuroQol-5D BNF British National Formulary GI gastrointestinal CEAC cost-effectiveness acceptability curve GP general practitioner

CI confidence interval GPRD General Practice Research Database CNS central nervous system GSK GlaxoSmithKline COPD chronic obstructive pulmonary disease HAI haemagglutination inhibition assay continued vii

HPA Health Protection Agency PE protective efficacy

HRG Health-care Resource Group PSSRU Personal Social Services Research Unit HRQoL health-related quality of life Px prophylaxis HTA Health Technology Assessment QALY quality-adjusted life-year

HUI Health Utilities Index QUOROM quality of reporting of meta- analyses ICER incremental cost- effectiveness ratio RCGP Royal College of General Practitioners ICU intensive care unit RCT randomised controlled trial ILI influenza-like illness RR relative risk ITT intention-to-treat RSV respiratory syncytial virus ITU intensive therapy unit SAVE simulating anti-influenza MVH Measurement and Valuation value and effectiveness of Health SE standard error NAMCS National Ambulatory Medical Care Survey SLCI symptomatic, laboratory- confirmed influenza NI neuraminidase inhibitor SPC Summary of Product NICE National Institute for Health Characteristics and Clinical Excellence TTO time trade-off ONS Office for National Statistics VAS visual analogue scale PCR polymerase chain reaction WHO World Health Organization

All abbreviations that have been used in this report are listed here unless the abbreviation is well known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only in figures/tables/appendices, in which case the abbreviation is defined in the figure legend or in the notes at the end of the table.

viii DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Executive summary

Background effectiveness of seasonal prophylaxis using amantadine in adults assumed to be the same in Influenza is an acute, febrile illness caused children and elderly individuals). Cost-effectiveness by infection of the respiratory system by the estimates are presented according to subgroups influenza virus. The illness is usually self-limiting distinguished by age, risk status and vaccination in otherwise healthy people. In individuals status. For the purposes of the model, ‘at-risk’ is considered to be at high risk, such as those aged defined as the presence of an underlying medical over 65 years or having concomitant disease, it condition; this definition may not necessarily carries the risk of increased morbidity, potentially coincide with Department of Health definitions serious complications and mortality. A Health of target groups for vaccination (for example, Technology Assessment of amantadine, oseltamivir an otherwise healthy adult working in a hospital and zanamivir for the prophylaxis of influenza setting may be eligible for influenza vaccination). was reported earlier by Turner and colleagues. Since that review, the marketing authorisation for zanamivir has been extended to include Results intervention in the prophylaxis of influenza as Clinical effectiveness well as in its treatment. This report presents an updated assessment of new and existing evidence Twenty-six published references relating to 22 for the clinical effectiveness and cost-effectiveness randomised controlled trials (RCTs) were included of amantadine, oseltamivir and zanamivir in the in the clinical effectiveness review. An additional prevention of influenza. unpublished report was included in the assessment, giving a total of 23 RCTs. Eight, six and nine RCTs were included for amantadine, oseltamivir and Objectives zanamivir respectively. The quality of the studies identified was highly variable and gaps in the To evaluate the clinical effectiveness of amantadine, evidence base limited the assessment of the clinical oseltamivir and zanamivir in seasonal and post- effectiveness of the interventions across population exposure prophylaxis against influenza and to subgroups and settings. estimate the incremental cost-effectiveness of the above interventions in comparison with each other Seasonal prophylaxis and no prophylaxis. Evidence for the use of amantadine in prophylaxis was very limited and drawn from older research of relatively poor quality. Evidence was presented for Methods its efficacy in preventing symptomatic, laboratory- confirmed influenza (SLCI) in seasonal prophylaxis A systematic review was undertaken and an in healthy adults [relative risk (RR) = 0.40, independent health economic model developed, 95% confidence interval (95% CI) 0.08–2.03]. based on a detailed review of existing cost- Oseltamivir was effective in preventing SLCI, effectiveness models together with ongoing particularly when used in seasonal prophylaxis clinical advice. The model draws together a broad in at-risk elderly subjects (RR = 0.08, 95% CI spectrum of evidence relating to the costs and 0.01–0.63). The preventative efficacy of zanamivir consequences associated with influenza and its in seasonal prophylaxis was most notable in at- prevention. Importantly, where direct evidence risk adults and adolescents (RR = 0.17, 95% CI concerning the effectiveness of prophylaxis within 0.07–0.44) and healthy and at-risk elderly subjects specific model subgroups is lacking, the model (RR = 0.20, 95% CI 0.02–1.72) uses effectiveness estimates from mixed subgroups (e.g. effectiveness of oseltamivir and zanamivir as Post-exposure prophylaxis post-exposure prophylaxis taken from studies of Again, very few data were available for the use households of mixed composition) or extrapolates of amantadine in post-exposure prophylaxis from other mutually exclusive subgroups (e.g. and were taken from older research of lower ix

quality. A relative risk of 0.10 (95% CI 0.03–0.34) willingness to pay threshold of £30,000 per QALY for the prevention of SLCI in adolescents by gained, the probability that no prophylaxis is post-exposure prophylaxis with amantadine optimal is close to 1.0. was reported. Oseltamivir was effective in post- exposure prophylaxis within households of mixed In at-risk adults composition (RR = 0.19, 95% CI 0.08–0.45), Based on the current list price for zanamivir, both and the efficacy of zanamivir in post-exposure amantadine and zanamivir are ruled out of the prophylaxis within households was also reported analysis. The incremental cost-effectiveness of (RR = 0.21, 95% CI 0.13–0.33). Interventions oseltamivir versus no prophylaxis is expected to be appeared to be well tolerated, with a relatively low greater than £64,000 per QALY gained. Assuming occurrence of subjects experiencing drug-related a willingness to pay threshold of £30,000 per adverse events and withdrawals. Very limited QALY gained, the probability that no prophylaxis evidence was available for their effectiveness in is optimal is close to 1.0. When the proposed preventing complications and hospitalisations and price reduction for zanamivir is incorporated, in minimising length of illness and time to return the incremental cost-effectiveness of zanamivir to normal activities. No data were identified for versus no prophylaxis is expected to be around health-related quality of life or mortality outcomes. £53,000 per QALY gained in unvaccinated at-risk adults and £157,000 in previously vaccinated at- Cost-effectiveness risk adults. The incremental cost-effectiveness of Seasonal prophylaxis oseltamivir is likely to be around £108,000 per In healthy children QALY gained in unvaccinated at-risk adults and around £314,000 in previously vaccinated at-risk Amantadine and zanamivir as seasonal prophylaxis adults. Assuming a willingness to pay threshold of are expected to be dominated or extendedly £30,000 per QALY gained, the probability that no dominated. The incremental cost-effectiveness prophylaxis is optimal is expected to be 0.99 or of oseltamivir versus no prophylaxis is expected higher. to be greater than £44,000 per quality-adjusted life-year (QALY) gained. Assuming a willingness In healthy elderly to pay threshold of £30,000 per QALY gained, Amantadine and zanamivir are expected to the probability that no prophylaxis is optimal is be dominated or extendedly dominated. The expected to be around 0.97. incremental cost-effectiveness of oseltamivir versus no prophylaxis in healthy elderly individuals is In at-risk children expected to be greater than £50,000 per QALY Amantadine and zanamivir as seasonal prophylaxis gained. Assuming a willingness to pay threshold are expected to be dominated or extendedly of £30,000 per QALY gained, the probability that dominated. The incremental cost-effectiveness of no prophylaxis is optimal is expected to be close to oseltamivir versus no prophylaxis is expected to be 1.0. around £17,000 per QALY gained for unvaccinated at-risk children, and in previously vaccinated In at-risk elderly at-risk children greater than £50,000 per QALY Amantadine and zanamivir are expected to be gained. Assuming a willingness to pay threshold extendedly dominated. The incremental cost- of £20,000 per QALY gained, the probability effectiveness of oseltamivir versus no prophylaxis that oseltamivir is optimal in unvaccinated at-risk in at-risk elderly individuals is expected to be children is expected to be approximately 0.70, greater than £38,000 per QALY gained. Assuming and assuming a threshold of £30,000 per QALY a willingness to pay threshold of £30,000 per QALY gained, the equivalent probability is around gained, the probability that no prophylaxis is 0.94. For previously vaccinated at-risk children, optimal is expected to be around 0.77 or higher. the probability that no prophylaxis is optimal at £30,000 per QALY gained is 0.97 or higher. Simple sensitivity analysis suggests that the cost- effectiveness of seasonal prophylaxis is sensitive to In healthy adults assumptions regarding the influenza attack rate, Amantadine and zanamivir as seasonal prophylaxis the level of resistance against oseltamivir, vaccine are expected to be dominated or extendedly efficacy, the threshold used to describe when dominated. The incremental cost-effectiveness influenza is circulating in the community, the risk of oseltamivir versus no prophylaxis is expected of hospitalisation in uncomplicated cases, and the to be greater than £148,000 per QALY gained, discount rate. x irrespective of vaccination status. Assuming a DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Post-exposure prophylaxis equivalent figures are expected to be 0.26 and 0.65 In healthy children respectively. Amantadine and oseltamivir as post-exposure prophylaxis are expected to be dominated or For at-risk children under the age of 5 years, the extendedly dominated. For unvaccinated healthy incremental cost-effectiveness of oseltamivir versus children, the incremental cost-effectiveness of no prophylaxis is expected to be around £9000 and zanamivir post-exposure prophylaxis versus no £29,000 per QALY gained for unvaccinated and prophylaxis is expected to be £19,000–£23,000 vaccinated at-risk children respectively. per QALY gained, depending on the list price for zanamivir, and for vaccinated healthy children In healthy adults at least £59,000 per QALY gained. Based on the Amantadine and zanamivir prophylaxis are current list price for zanamivir, the probability expected to be dominated or extendedly that zanamivir is optimal in unvaccinated healthy dominated. For unvaccinated healthy adults, the children is expected to be 0.15 and 0.45 at incremental cost-effectiveness of oseltamivir post- willingness to pay thresholds of £20,000 and exposure prophylaxis versus no prophylaxis is £30,000 per QALY gained respectively. When the expected to be around £34,000 per QALY gained, proposed price reduction is incorporated, the and for previously vaccinated healthy adults around equivalent figures are expected to be 0.47 and £104,000 per QALY gained. The probability that 0.79 respectively. For the vaccinated subgroup, oseltamivir is optimal in unvaccinated otherwise the probability that no prophylaxis is optimal at a healthy adults is expected to be around 0 and 0.19 threshold of £30,000 per QALY gained is expected at willingness to pay thresholds of £20,000 and to be close to 1.0. £30,000 per QALY gained respectively, and for healthy adults who have previously been vaccinated For children under the age of 5 years, oseltamivir close to zero at a threshold of £30,000 per QALY is the only licensed antiviral prophylaxis. The gained. incremental cost-effectiveness of oseltamivir versus no prophylaxis is expected to be around £24,000 In at-risk adults and £74,000 per QALY gained in unvaccinated and Amantadine and zanamivir prophylaxis are vaccinated groups respectively. expected to be dominated or extendedly dominated. For unvaccinated at-risk adults, the In at-risk children incremental cost-effectiveness of oseltamivir Amantadine and oseltamivir as post-exposure post-exposure prophylaxis versus no prophylaxis prophylaxis are expected to be dominated or is around £13,000 per QALY gained, and for extendedly dominated. For unvaccinated at-risk previously vaccinated at-risk adults around £44,000 children, the incremental cost-effectiveness of per QALY gained. Based on the current list price zanamivir post-exposure prophylaxis versus no for zanamivir, the probability that oseltamivir is prophylaxis is expected to be around £8000 per optimal in unvaccinated at-risk adults is expected QALY gained at the current list price, and around to be 0.89 and 0.84 at willingness to pay thresholds £6000 per QALY gained when the proposed price of £20,000 and £30,000 per QALY gained reduction for zanamivir is assumed. For vaccinated respectively. The probability that oseltamivir is at-risk children, the equivalent figures are expected optimal in previously vaccinated at-risk adults is to be around £28,000 and £23,000 respectively. below 0.05. Based on its current list price, the probability that zanamivir is optimal in unvaccinated at- In healthy elderly risk children is expected to be 0.67 and 0.73 at Amantadine and zanamivir prophylaxis are willingness to pay thresholds of £20,000 and expected to be dominated or extendedly £30,000 per QALY gained respectively. When dominated. For unvaccinated healthy elderly the proposed price reduction is included in the individuals, the incremental cost-effectiveness of analysis, the probability that zanamivir is optimal oseltamivir post-exposure prophylaxis versus no is expected to be 0.85 at both thresholds. Based on prophylaxis is expected to be around £11,000 the current list price for zanamivir, the probability per QALY gained, and for previously vaccinated that it is optimal in vaccinated at-risk children healthy elderly individuals around £28,000 per is expected to be 0.08 and 0.31 at willingness QALY gained. Based on the current list price to pay thresholds of £20,000 and £30,000 per for zanamivir, the probability that oseltamivir is QALY gained respectively. When the proposed optimal in unvaccinated healthy elderly individuals price reduction is included in the analysis, the is expected to be 0.87 and 0.82 at willingness to xi

pay thresholds of £20,000 and £30,000 per QALY account in the cost-effectiveness analysis. Although gained respectively. For previously vaccinated the base case assumes oseltamivir resistance to be healthy elderly individuals, the equivalent figures zero, multiple sensitivity analyses were undertaken are expected to be 0.09 and 0.50 respectively. in order to assess the impact of variation in levels of resistance amongst influenza strains to the In at-risk elderly interventions under study. It should be noted Amantadine and zanamivir as post-exposure that in the 2 weeks preceding completion of this prophylaxis are expected to be dominated report, the Health Protection Agency issued a press or extendedly dominated. For unvaccinated release stating that approximately 5% (8/162) of at-risk elderly individuals, the incremental H1N1 influenza tested isolates were resistant to cost-effectiveness of oseltamivir post-exposure oseltamivir. Further research is required to assess prophylaxis versus no prophylaxis is expected the impact of this resistance. Sensitivity analysis to be around £8000 per QALY gained, and for suggests that low levels of resistance are likely to vaccinated at-risk elderly individuals around have a minor impact upon the cost-effectiveness of £22,000 per QALY gained. Based on its current list oseltamivir. However, increasing levels of resistance price, the probability that oseltamivir is optimal could dramatically influence the conclusions of the in unvaccinated at-risk elderly individuals is economic analysis. It is centrally important that the expected to be around 0.83 and 0.77 at willingness results of the economic analysis are interpreted in to pay thresholds of £20,000 and £30,000 per the light of current levels of influenza activity and QALY gained. For vaccinated at-risk elderly resistance. individuals, the equivalent figures are 0.35 and 0.78 respectively. A number of uncertainties are apparent within the evidence base, including variation in the The simple sensitivity analysis suggests that the quality of trials in terms of internal and external cost-effectiveness of post-exposure prophylaxis is validity, study design and clarity of reporting. The sensitive to assumptions regarding the influenza absence of head-to-head RCTs meant that a direct attack rate, the level of resistance against comparison of the effectiveness of the interventions oseltamivir, and the comparative efficacy of was not possible. These weaknesses are directly oseltamivir and zanamivir, the efficacy of influenza relevant to the interpretation of the health vaccination, multiple prescribing of prophylaxis economic model results and rendered the use of to contact cases, the risk of hospitalisation in more advanced statistical analyses inappropriate. uncomplicated cases, and the discount rate. A central area of uncertainty is the paucity of robust preference-based valuations of the impact of influenza and influenza prophylaxis on health- Discussion and conclusions related quality of life.

The clinical effectiveness data used in the cost- Several areas warrant further research: effectiveness modelling was limited for a number of population subgroups. This must be borne in mind • additional RCTs of influenza prophylaxis in in the interpretation of the findings. Additional subgroups for which data are currently lacking consideration should be given to the occurrence of • RCTs in which the follow-up period extends adverse events attributable to amantadine and the beyond the duration of prophylaxis issue of resistance to antivirals among influenza • head-to-head RCTs in which the clinical isolates, which, although not directly reflected effectiveness of the interventions in different within the trials identified for inclusion, are factors subgroups is directly compared that may have an important influence on the • quality of life studies to inform future economic effectiveness of antiviral prophylaxis in clinical decision modelling practice. Variation in the levels of resistance to • further research concerning the incidence and antivirals among influenza isolates was taken into management of complications of influenza.

xii DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Chapter 1 Background

Description of 65 years, infants beyond the age when maternally- health problem derived antibodies provide protection (and those with congenital abnormalities) and individuals Influenza is a highly contagious, acute febrile with co-morbidities such as chronic respiratory respiratory infection caused by the influenza virus. disease [including asthma and chronic obstructive Cases typically occur in a seasonal pattern, with pulmonary disease (COPD)], cardiovascular localised epidemics during the winter months. disease, chronic renal disease, diabetes mellitus or Illness is generally self-limiting but bacterial immunosuppression.2 complications may arise. Such complications can be life threatening in nature, particularly in the Complications of influenza are often respiratory; elderly and in individuals with co-morbidities. these include primary viral pneumonia, secondary Worldwide pandemics of influenza may occur bacterial pneumonia, bronchitis, bronchiolitis in when a major new subtype arises, often originating children, exacerbations of asthma and chronic from avian influenza. Circumstances of pandemic respiratory disease and otitis media. Additionally, influenza and avian influenza are beyond the scope influenza can cause a range of non-respiratory of this review. symptoms and complications, including febrile convulsions, toxic shock syndrome, Reye syndrome, Symptoms encephalopathy, transverse myelitis, pericarditis and myocarditis. Some of these complications may Common symptoms of influenza include require hospitalisation and can be life threatening, respiratory symptoms such as sneezing, runny especially in the elderly or those with underlying nose, cough, sore throat and coryza, and systemic disease.1,2 symptoms such as fever, malaise, myalgia, chills and headache. There may also be gastrointestinal The presence of complications increases the risk (GI) symptoms such as nausea, vomiting and of mortality due to influenza. The mortality risk diarrhoea. The duration of the acute illness is is highest in individuals who are elderly or have usually around 3–4 days, but cough and malaise co-morbidities. Estimates of deaths each year in may persist for 1–2 weeks. It is also possible for the UK that are thought to be caused by influenza individuals to be asymptomatic while infected with range from 12,000 to 13,800.3,4,5 The UK epidemic the influenza virus.1,2 of 1989–90 was estimated to have caused in excess of 29,000 deaths.1 The symptoms of influenza can also arise from a number of other infectious diseases, known The influenza virus as influenza-like illnesses (ILIs). These can be caused by adenoviruses, rhinovirus, respiratory Influenza is an orthomyxovirus, comprising a lipid syncytial virus, parainfluenza virus and bacterial membrane surrounding a matrix protein shell infections. Confirmation of influenza infection and a core consisting of seven or eight ribonucleic requires laboratory methods such as viral culture or acid (RNA)–nucleoprotein complexes. There are serological examination of antibody titres. three serotypes of influenza virus – influenza A, B and C – which differ in their core proteins. Prognosis, complications Influenza A and B are responsible for nearly and mortality all influenza-associated clinical illnesses. The influenza virus contains two surface glycoproteins, Influenza infection can cause unpleasant symptoms which act as powerful antigens: haemagglutinin for 1–2 weeks but is usually self-limiting and (H antigen) and neuraminidase (N antigen). does not generally require treatment in otherwise Haemagglutinin facilitates the entry of the virus healthy adults. However, influenza can lead to into cells of the respiratory epithelium, while complications, including secondary bacterial neuraminidase facilitates the release of newly- infection. Complications are more common in produced viral particles (virions) from infected certain at-risk groups, including those aged over cells. An ion channel protein is also embedded in 1

the lipid membrane; in influenza A this is the M2 strains. Pandemics cause a very high morbidity protein and in influenza B it is the NB protein. and mortality burden;7 the 1918–19 pandemic is The influenza virus infects epithelial cells of the estimated to have caused up to 40 million deaths upper and lower respiratory tracts, attaching to worldwide. Pandemics usually originate in Asia the cell membranes, invading the host cell and where chickens, ducks, pigs and humans live in using the host cell machinery to reproduce. New very close proximity and where other social factors viral particles are released by lysis (breaking open) favour interspecies transmission of virus. However, of the host cells, which damages the epithelium as discussed above, pandemic influenza and avian and increases susceptibility to secondary bacterial influenza are not considered within this review. infections.6 Transmission Strains and subtypes Influenza virus is passed easily from person to The World Health Organization (WHO) person and is spread by virus-laden respiratory classification system for influenza is based on the secretions. Most infections appear to be antigenic type of the nucleoprotein core (A, B or transmitted by droplets that are expelled during C), the geographical location of first isolation, coughing and sneezing rather than by aerosols. the strain serial number, the year of isolation The incubation period is 1–3 days. People with and (for influenza A) the haemagglutinin (H) influenza may begin shedding virus 1–2 days before and neuraminidase (N) subtypes, with each item symptoms appear. Nasal shedding peaks about 48 separated by a slash, e.g. A/Wuhan/359/95 (H3N2). hours after onset of symptoms and adults usually remain infectious for up to 1 week (up to 2 weeks New strains and subtypes of influenza are produced in children; viral shedding may also be prolonged as a result of ‘antigenic drift’ and ‘antigenic in immunocompromised individuals).2 shift’. Antigenic drift arises from gene mutations causing changes in the amino acid sequence of Epidemiology haemagglutinin or neuraminidase, the main antigens associated with immunity, leading to Seasonal outbreaks of infection with influenza changes in the antigenic nature of the virus, occur most years during the winter months in the i.e. a new strain of influenza (within a subtype). northern hemisphere. The UK influenza season Antigenic drift is associated with annual outbreaks, may run from week 40 to week 25, but occurs as the virus is able to infect individuals who had typically between December and March.8 Illnesses developed immunity to previous strains. Many resembling influenza that occur in the summer individuals are likely to retain partial immunity, are usually caused by other viruses.8 Infections although infants have little or no immunity. with influenza A account for approximately 80% Influenza A undergoes antigenic drift to a greater of outbreaks, while influenza B accounts for extent than influenza B. approximately 20%.9 Comparative studies indicate that A/H3N2 infections produce more severe Antigenic shift is said to occur when an entirely illness than A/H1N1 infections and that influenza new subtype of influenza A is introduced into the B is intermediate in severity.2 Typically, there is an population, causing disease and onward human-to- annual outbreak which appears abruptly, peaks human transmission. Antigenic shift occurs when within 2–3 weeks and lasts for around 5–7 weeks. the H and/or N of the new subtype is introduced Successive or overlapping waves of infection by into humans from the avian reservoir of infection, different subtypes of influenza A or by influenza A primarily ducks that serve as a reservoir for 16 and B may result in a more prolonged period of different subtypes of H and nine subtypes of N for disease activity.10 the influenza A virus. Other animal reservoirs may also be implicated in antigenic shift. Antigenic shift Influenza is a common condition that may affect occurred in 1918, when an H1N1 influenza A virus all age groups. However, the risk of an individual adapted to man. It occurred also in 1957 and 1968, contracting the disease depends on a number of when the genomes of the circulating human viruses factors, including the virulence of the circulating were mixed with those of avian origin by genetic strain, the natural level of immunity (which reassortment; this process of ‘gene shuffling’ occurs depends on past exposure to influenza virus or during dual infections with influenza A viruses vaccination, and the degree of cross-immunity of differing subtypes. Antigenic shift results in to the circulating strain), health status, age (both ‘pandemic influenza’ because populations across those aged over 65 years and the very young are at 2 the world have little or no immunity to the new increased risk) and living arrangements. Influenza DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

outbreaks can occur within establishments where from work. In primary care, adults aged 15–64 several people live or work in close proximity, years account for most consultations for influenza- e.g. residential homes, hospitals, schools and related illness. In a large UK study of subjects who prisons. In addition, the virus is transmitted quite had one or more diagnoses of influenza or ILI frequently between individuals who live in the same recorded within the General Practitioner Research house. Many studies worldwide have shown that the Database (GPRD), 59.4% received prescription highest attack rates occur in young children and medications, the most frequently prescribed that school-aged children play a central role in the being antibiotics (45.2%) and antipyretics/ dissemination of influenza in households and the analgesics (22.5%).12 Patients with influenza community.10 were approximately six times more likely to use prescription medications than a matched control Incidence sample.12 The incidence of consultations due to influenza across the study period was reported as Influenza activity during recent years is illustrated being 14.5 per 1000 person-years.12 Complications in Figures 1 and 2. The rate of general practitioner arising from influenza may require hospitalisation, (GP) consultations for ILI is monitored in the UK, particularly in elderly people with underlying and thresholds for use in England are defined by cardiopulmonary disorders.13 the Health Protection Agency (HPA) as follows:8 The prevention of influenza also has resource • Baseline rate: fewer than 30 new GP implications for the NHS. In the UK, groups consultations per 100,000 population per recommended for influenza vaccination include week. people at risk of complications from influenza • Normal seasonal activity: 30–200 new GP [those aged over 65 years; individuals with chronic consultations per 100,000 population per respiratory disease, chronic cardiovascular disease, week. chronic renal disease, chronic liver disease, • Epidemic activity: more than 200 new GP chronic neurological disease or diabetes mellitus; consultations per 100,000 population per the immunosuppressed; individuals with human week. immunodeficiency virus (HIV) infection; and people in residential homes (elderly or other The thresholds for Wales are slightly different: the long-stay)], the carers of dependents whose baseline rate is fewer than 25 new GP consultations welfare would be put at risk should their carer fall per 100,000 population per week, normal seasonal ill and health-care workers involved directly in activity relates to 25–100 new consultations and patient care. Vaccination may also be considered epidemic activity is defined as more than 400 new for social care workers involved directly in care consultations per 100,000 population per week. and household contacts of immunosuppressed individuals.14 The requirement for influenza It should be noted that, since influenza activity vaccination has also been extended to poultry varies from season to season, attack rates, workers, in order to reduce the risk of the complications and mortality rates would also be development of a potentially serious new variant anticipated to vary. as a result of co-infection with avian and human influenza strains.15 Therefore, the guidelines Impact of influenza and for vaccination cover both healthy individuals significance for the National and people with underlying medical conditions. Health Service (NHS) Prophylaxis with the antiviral drug oseltamivir is currently recommended by the National Institute For most people, influenza causes illness lasting for Health and Clinical Excellence (NICE) for at- 1–2 weeks. A proportion of individuals may risk persons who are not adequately protected by experience asymptomatic infection or mild illness. vaccination and have been exposed to influenza However, the disease can lead to complications and (and for at-risk persons living in residential homes mortality, particularly in the elderly or those with who have been exposed to influenza, irrespective of certain co-morbidities. vaccination status), provided that the individual can start taking oseltamivir within 48 hours of exposure In terms of resource implications, influenza causes to influenza.16 These guidelines are described in an increase in GP consultations, medical treatment more detail in Current usage in the NHS (later in and hospitalisations, as well as increased absence this chapter).

500 450

400 2007–8 2006–7 350 X 1999–2000 300

250 X Epidemic activity 200 X Normal seasonal 150 X activity

X X Rate per 1000,000 population Rate 100 Baseline activity X X X 50 X X X X XXX X X X X X X XX XX X X X X 0 X X X X 40 41 42 43 44 45 46 47 48 49 50 5152 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Week

FIGURE 1 Royal College of General Practitioners (RCGP) weekly consultation rate for influenza-like illness, England: 2007–8, 2006–7 and 1999–2000.11

700

600

500 Epidemic activity (>400) 400

Higher than average seasonal activity 300 (>200–400) Epidemic activity (>200)

Rate per 100,000 population Rate 200 Normal seasonal activity Normal seasonal activity (50–200) (30–200) 100 Baseline activity (<30)

Baseline activity (<50) 0 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Year

FIGURE 2 Royal College of General Practitioners (RCGP) weekly consultation rate for influenza-like illness, England, 1988 to 2007–8.8

Measurement of influenza factors: (1) the number of cases of illness attributed activity in the community to ILI (based on e.g. the number of clinic visits or Influenza has no pathognomonic features and can absences from school/work) and (2) the laboratory- manifest itself, as can other respiratory viruses, in a based identification of influenza virus in samples range of ways, such as the common cold, bronchitis, from individuals with ILI. bronchiolitis, exacerbations of asthma or COPD, pneumonia, croup and febrile convulsions. In 1947, WHO established a global influenza Therefore, the level of influenza activity in a surveillance system (a network of laboratories) to 4 community is quantified by a combination of two monitor the emergence and spread of new strains DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

of influenza. The information generated by this requires treatment including antibiotics, and may system aids the development of vaccines against require hospitalisation. currently-circulating influenza strains. Vaccination is an important aspect of influenza prophylaxis NICE currently recommends zanamivir and and the degree of match between vaccine and oseltamivir for the treatment of at-risk adults circulating strains within a particular season who present with ILI and who can start therapy has considerable implications for the control of within 48 hours of the onset of their symptoms.17 influenza activity. In the UK, the HPA monitors Oseltamivir is recommended for the treatment of and records the incidence of seasonal influenza children who present with ILI and who can start and uptake of seasonal influenza vaccine. The therapy within 48 hours of the onset of symptoms.17 Centre for Infections conducts surveillance of At-risk individuals are defined within the NICE influenza activity in the UK, carries out laboratory guidance as those who: tests to identify which strains are in circulation and communicates this information to health • have chronic respiratory disease (including professionals and the public.8 asthma and COPD) • have significant cardiovascular disease Diagnosis (excluding people with hypertension only) • have chronic renal disease Influenza-like illness can be defined clinically • are immunocompromised according to symptoms; the exact definition • have diabetes mellitus varies, with different trials of influenza prevention • are aged 65 years or older.17 using a range of indicators, often including raised temperature (usually ≥ 37.8°C) and/or symptoms It should be noted that the current guidance for such as cough, headache, sore throat or myalgia. influenza vaccination differs to that outlined above in that, in addition to the at-risk groups defined To determine whether an individual case of ILI above, vaccination is recommended for patients is true influenza, presence of the influenza virus with chronic liver disease or chronic neurological must be determined in a laboratory test. This may disease and also for individuals who live within consist of isolation of influenza virus from a nose- long-stay residential care facilities, carers, health- and-throat swab or nasopharyngeal wash taken care workers and poultry workers.15,18,19 from the patient, by means of either viral culture or polymerase chain reaction (PCR). In addition, Current service cost serum samples from the patient may be tested for the presence of influenza-specific antibodies There is very limited evidence concerning the using a haemagglutination inhibition assay (HAI); total costs of treating influenza and ILI in the UK. influenza infection is usually defined as a fourfold The current value of the UK antiviral market for or higher increase in influenza-specific HAI titre the prophylaxis and treatment of influenza has between baseline and post-infection serum samples been estimated at approximately £800,000, of (known as seroconversion). Many influenza studies which around 89% is attributable to oseltamivir.20 use both viral culture and HAI serum testing, However, the true cost of managing influenza while some also use PCR, and generally a positive is likely to be considerably higher as a result result on one or more of the tests is taken to of the additional costs of vaccination and the indicate influenza infection. However, laboratory management of secondary complications arising confirmation of influenza would not routinely be from influenza infection. carried out on people presenting to their GP with ILI.1 Variation in services and/or uncertainty about best practice

Current service provision There is currently relatively little antiviral usage in Management of disease the UK, possibly as a result of lower levels of virus activity and/or consultation rates than in previous The symptoms of influenza and other ILI are often decades. In contrast, the use of oseltamivir in self-limiting and require no medical intervention. Japan has increased in recent years.21 Over-the-counter medications are available for symptomatic relief of influenza. The presence of It should be noted that the market authorisations secondary complications of influenza typically for the use of antiviral post-exposure prophylaxis 5

stipulate that prophylaxis should be initiated within replication.30 The antiviral activity of amantadine is a specified period of exposure to an index case. restricted to influenza A. In addition, amantadine This stipulation requires that patients present to has weak dopamine agonist activity. their GP promptly, the timescale being affected by an individual’s propensity to seek medical care and Licensed indications issues relating to access to GP services. Amantadine hydrochloride is indicated for:

There is variation in terms of the uptake of • the treatment of and prophylaxis against signs vaccination in indicated subgroups. Recent and symptoms caused by influenza A infection monitoring data from the HPA suggest that the (as Lysovir, Alliance Pharmaceuticals) uptake of influenza vaccination is around 79% in • the treatment of Parkinson’s disease (but not individuals aged over 65 years and around 42% in drug-induced extrapyramidal symptoms) (as at-risk individuals aged under 65 years. Symmetrel, Alliance Pharmaceuticals) • the treatment of herpes zoster (as Symmetrel). Relevant national guidelines Dosage and administration NICE has issued guidance relating to the use of Lysovir is available as reddish-brown, hard, amantadine and oseltamivir in prophylaxis16 and gelatine capsules containing 100 mg amantadine zanamivir, oseltamivir and amantadine in the hydrochloride, which are ingested orally. treatment of influenza.17 These recommendations Symmetrel is available as 50 mg/5 ml syrup. are outlined in detail in Current usage in the NHS (see below). Prophylaxis • Adults and children over 10 years: 100 mg/ In addition to national policy for influenza day for as long as protection from influenza vaccination in at-risk groups, vaccination for is required, usually for up to 6 weeks, or with people aged 65 years and above was promoted influenza vaccination for 2–3 weeks after within the National Service Framework for Older vaccination. People22 and for people with coronary heart disease in the National Service Framework for Coronary Treatment Heart Disease.23 Treatment should be initiated within 48 hours of the onset of symptoms.

Description of technology • Adults: 100 mg/day for 4–5 days under assessment • Children aged 10–15 years: 100 mg/day for 4–5 days Summary of interventions • Children under 10 years of age: dosage not The clinical effectiveness and cost-effectiveness established of amantadine, oseltamivir and zanamivir in the • Adults over 65 years of age: owing to the prophylaxis of influenza have been evaluated in longer elimination half-life and reduced this assessment. The following section summarises capacity for renal clearance of amantadine in the product characteristics of each of these elderly patients, a reduced dose of < 100 mg/ interventions using the Summary of Product day or 100 mg given at intervals of ≥ 1 day may Characteristics (SPC) for each drug24–29 (obtained be appropriate from the electronic Medicine Compendium at www. • Patients with renal impairment: dosage should medicines.org.uk) and information from the British be adjusted by reducing total daily dose or National Formulary (BNF).14 by increasing dosage interval in line with clearance of creatinine. Guidance is as follows: Amantadine (Lysovir, Alliance Pharmaceuticals) Creatinine clearance Description of intervention (ml/minute) Dose Amantadine is a symmetrical C-10 primary amine with a cage-like structure, which is water < 15 Lysovir contraindicated soluble in hydrochloride salt form.30 Amantadine 15–35 100 mg every 2–3 days hydrochloride exerts an antiviral effect on > 35 100 mg/day influenza type A by means of inhibition of the M2 ion channel, which results in the blocking of viral 6 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Contraindications drug inhibits viral release, preventing subsequent Amantadine hydrochloride is contraindicated in infection of adjacent cells. The SPC emphasises patients who: that oseltamivir is not a substitute for vaccination and that use should take into account official • have epilepsy recommendations and variability of epidemiology • have a history of gastric ulceration and impact across patient populations and • have severe renal impairment geographical locations. • are pregnant, wish to become pregnant or are breastfeeding Licensed indications • have known hypersensitivity to amantadine or Oseltamivir is indicated for: any excipients. • the post-exposure prophylaxis of influenza in Cautions patients aged 1 year and above who have had Amantadine hydrochloride should be administered contact with a clinically diagnosed influenza with caution to patients who: index case when influenza is circulating in the community. The SPC states that the • have hepatic impairment administration of oseltamivir should be • have renal impairment decided on a case-by-case basis and that • have congestive heart disease (as the drug may seasonal prophylaxis in subjects aged 1 year cause exacerbation of oedema) and above may be considered in exceptional • experience confusion or hallucinations circumstances (such as in the case of mismatch • have underlying psychiatric disorders between vaccine and circulating strains of • are elderly influenza or in the event of a pandemic). • are receiving concomitant medications with • the treatment of influenza in patients aged potential to affect the central nervous system 1 year and above who present with influenza (CNS). symptoms when influenza is circulating in the community. Treatment is effective when Abrupt withdrawal of amantadine therapy should initiated within 48 hours of onset of the first be avoided in patients with Parkinson’s disease. symptoms.

It should be noted that, while resistance to Dosage and administration amantadine is well documented,30 it has been Tamiflu is administered orally and is available as reported that levels of resistance among influenza grey-yellow capsules containing 75 mg oseltamivir isolates have risen dramatically on an international (as phosphate), 45 mg oseltamivir (as phosphate) or scale.31 Development of resistance can occur 30 mg oseltamivir (as phosphate), and as a powder relatively rapidly during treatment and can lead (as phosphate) for reconstitution with water (12 mg/ to the failure of prophylaxis, for example within ml) as an oral suspension. The administration of the management of outbreaks of influenza in long- 75 mg doses can be made up of one 75 mg capsule term care settings.32 or one 30 mg capsule plus one 45 mg capsule or one 30 mg capsule plus one 45 mg dose of suspension. Adverse events It should be noted that the BNF lists only the Adverse events associated with amantadine 75 mg dose of Tamiflu in capsule form. The hydrochloride include anorexia, nausea, administration of suspension is recommended in nervousness, insomnia, dizziness, inability to patients who are not able to swallow capsules. The concentrate, convulsions, hallucinations, blurred SPC recommends that powder for oral suspension vision, GI effects, livedo reticularis, peripheral should be reconstituted by a pharmacist before it is oedema and skin rashes. It has been documented dispensed to the patient. that adverse effects can occur frequently among recipients.33 Central nervous system adverse events Prophylaxis have been described as occurring most notably Prophylaxis should be initiated as soon as possible within the elderly population. within 48 hours of exposure to the index case.

Oseltamivir (Tamiflu®, Roche) Post-exposure prophylaxis Description of intervention Oseltamivir is a neuraminidase inhibitor that exerts • Adults and adolescents over 13 years: 75 mg for an antiviral effect on influenza A and B.34 The 10 days, for up to 6 weeks during an epidemic 7

• Children aged 1–13 years: body weight under recommend dosage adjustment in children with 15 kg, 30 mg once daily; body weight 15–23 kg, renal impairment. 45 mg once daily; body weight 23–40 kg, 60 mg once daily; body weight over 40 kg, adult dose. Contraindications Oseltamivir is contraindicated in patients who Seasonal prophylaxis During a community have hypersensitivity to oseltamivir or any of its outbreak of influenza, the recommended dose is excipients. 75 mg once daily for up to 6 weeks. Cautions Dose adjustment is recommended for patients with Oseltamivir should be administered with caution to severe renal impairment as follows: patients who:

Creatinine clearance • have renal impairment (ml/minute) Dose • are pregnant or breastfeeding • have conditions of such severity or instability > 30 75 mg once daily that imminent hospitalisation may be required > 10 to ≤ 30 75 mg every second day • are immunocompromised or 30 mg suspension once • have chronic cardiac and/or respiratory disease. daily The dose should be reduced if creatinine or 30 mg capsules once daily clearance in patients is < 10–30 ml/minute and ≤ 10 Not recommended administration should be avoided if creatinine Dialysis patients Not recommended clearance is < 10 ml/minute. Adverse events Treatment Adverse events associated with oseltamivir include Treatment should be initiated as soon as possible nausea, vomiting, abdominal pain, diarrhoea, within 48 hours of onset of symptoms. dyspepsia, headache, fatigue, insomnia, dizziness, conjunctivitis, epistaxis, skin rashes, and – in very • Adults and adolescents over 13 years: 75 mg rare cases – hepatitis, Stevens–Johnson syndrome every 12 hours for 5 days and toxic epidermal necrolysis. Neuropsychiatric • Children aged 1–13 years: body weight under disorders in children have also been reported. 15 kg, 30 mg every 12 hours; body weight 15–23 kg, 45 mg every 12 hours; body weight Zanamivir [Relenza®, 23–40 kg, 60 mg every 12 hours; body weight GlaxoSmithKline (GSK)] over 40 kg, adult dose. Description of intervention Zanamivir is a neuraminidase inhibitor that Dose adjustment is recommended for patients with inhibits the replication of influenza A and B.34 severe renal impairment as follows: The SPC states that zanamivir is not a substitute for vaccination, as protection only lasts for as long Creatinine clearance as the drug is administered, and that the use of (ml/minute) Dose zanamivir should be decided on a case-by-case basis according to circumstances and the population > 30 75 mg twice daily in need of protection. The SPC recommends > 10 to ≤ 30 75 mg once daily that the drug should be used only when reliable epidemiological data confirm the circulation of or 30 mg suspension twice influenza in the community. Use of zanamivir daily should take into account official recommendations, or 30 mg capsule twice daily epidemiological variation and varying impact of influenza across patient populations and ≤ 10 Not recommended geographical locations. Dialysis patients Not recommended Licensed indications Zanamivir is indicated for: No adjustment of dose is required in the elderly, with the exception of patients with severe renal 8 impairment. There is insufficient evidence to DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

• the post-exposure prophylaxis of influenza A Contraindications and B in adults and children aged 5 years and Zanamivir is contraindicated in patients who: above who have had contact with a clinically diagnosed case of influenza in a household. • are pregnant or breastfeeding Relenza may be considered for use in seasonal • are hypersensitive to any ingredient of the prophylaxis in exceptional circumstances, preparation. for example when there is mismatch between circulating or vaccine strains or in the event of Cautions a pandemic. Zanamivir should be administered with caution to • the treatment of influenza A and B in adults patients who: and children aged 5 years and above who present with ILI when influenza is active in the • have asthma and chronic pulmonary disease community. • have uncontrolled chronic illness • are immunocompromised Dosage and administration • are pregnant. Relenza is available in the form of predispensed dry powder for inhalation in blisters containing According to the BNF, zanamivir should be used 5 mg zanamivir per blister, delivered by means with caution in pregnancy and is contraindicated of oral inhalation using a Diskhaler device. in breastfeeding women. However, according to Each inhalation delivered (quantity released the FDA, pregnancy and breastfeeding are cautions via mouthpiece of the Diskhaler) contains 4 mg rather than contraindications. Other inhaled drugs, zanamivir (the remainder appears to be lost in such as asthma medication, should be administered the inhalation process and is presumably retained before zanamivir. within the Diskhaler apparatus). Adverse events Prophylaxis The following adverse events associated with zanamivir are described as occurring very Post-exposure prophylaxis Prophylaxis should be rarely: bronchospasm, respiratory impairment, initiated as soon as possible and within 36 hours of angioedema, urticaria and skin rashes. exposure to an infected index case. Identification of • Adults and children aged 5 years and above: important subgroups 10 mg once daily (i.e. two inhalations) for 10 days. A number of important subgroups should be considered in relation to the use of antivirals Seasonal prophylaxis During an epidemic, for influenza prophylaxis. Subgroups viewed prophylaxis may be administered. to be at risk of developing influenza-associated complications were described earlier in this chapter • Adults and children aged 12 years and above (see Description of health problem). Within the (as recommended in the BNF):18 10 mg once guidance issued by NICE for the prophylaxis16 and daily for up to 28 days. treatment17 of influenza, populations viewed to be at risk include individuals who: Treatment • are aged 65 years or above Treatment should be initiated as soon as possible • have chronic lung disease (including asthma and within 48 hours of onset of symptoms in and COPD) adults and within 36 hours of onset of symptoms in • have significant heart disease (excluding children. people with hypertension only) • have chronic renal disease • Adults and children aged 5 years and above: 10 • have diabetes mellitus mg twice daily for 5 days. • are immunocompromised.

No dose modification is required for individuals Current usage in the NHS with renal or hepatic impairment or for elderly patients. Guidance was issued by NICE relating to the use of oseltamivir and amantadine in the prophylaxis 9

of influenza16 and for the use of zanamivir, NICE did not recommend that oseltamivir should oseltamivir and amantadine for the treatment be used in post-exposure prophylaxis of influenza of influenza.17 These guidance documents were in healthy people aged under 65 years. The use issued in accordance with the expectation that of oseltamivir in seasonal prophylaxis was not vaccination would continue to be the mainstay recommended. The use of amantadine in post- of influenza prevention. Issued guidance relates exposure and seasonal influenza prophylaxis was solely to circumstances where it is known that not recommended. influenza A or B is circulating in the community. To this end, NICE recommended that community- Treatment based virological systems should be used to It was recommended that amantadine should not monitor the circulation of influenza virus in the be used in the treatment of influenza and that community. Guidance issued does not pertain to zanamivir or oseltamivir should not be used in the circumstances of a pandemic or impending the treatment of individuals who are healthy and pandemic, or to the emergence of a widespread are not at risk of developing complications from epidemic of a new influenza strain to which there is influenza. little or no community resistance. The use of zanamivir and oseltamivir in line with At-risk groups were defined according to NICE their licensed indications was recommended for the guidance as described above. treatment of:

Prophylaxis • adults (aged over 12 years) belonging to an at- NICE recommended that oseltamivir should be risk group used in the prevention of influenza as follows: –– who present with ILI –– and can begin treatment within 48 hours of • for individuals who are aged 13 years and the onset of symptoms. above –– and belong to an at-risk group The use of oseltamivir in line with licensed –– and are not effectively protected by indications was recommended for the treatment of: vaccination (e.g. individuals who have not received an influenza vaccination for • children (aged over 1 year) belonging to an at- that season, for whom vaccination may be risk group contraindicated or has yet to take effect, or –– who present with ILI for whom vaccination has been undertaken –– and can begin treatment within 48 hours of but there is a mismatch between vaccine and the onset of symptoms. circulating strains) –– and have been in close contact with an index It should be noted that, although the use of case with ILI amantadine in the prophylaxis and treatment –– and can start taking oseltamivir within 48 of influenza was not recommended by NICE, hours of contact with the index case this drug is also licensed for the treatment of • for individuals who are aged 13 years and Parkinson’s disease and herpes zoster. above –– and belong to an at-risk group (whether or Anticipated costs associated not they have been vaccinated) with intervention –– and live in a residential care establishment where another individual has ILI (resident The costs associated with amantadine, oseltamivir or staff member) and zanamivir are dependent on the setting for –– and can start taking oseltamivir within 48 the prophylaxis, the mode of administration hours of contact with the index case. and the age of the patient (oseltamivir only). Acquisition costs for post-exposure prophylaxis For the purposes of the guidance, a residential care and seasonal prophylaxis are presented in Tables establishment was classed as a location where an 1 and 2 respectively. The capsule/tablet forms at-risk person lived long term in order to receive of prophylaxis are likely to be most relevant to continuing care alongside other individuals with adult populations as these allow for more precise care needs. Exposure to ILI was defined as having measurements of dosage; for oseltamivir in close contact with an individual who resides in the children aged under 13 years, dosage is usually same home environment as a person who has been adjusted according to body weight. Prophylaxis 10 experiencing symptoms of ILI. is typically given to children under 13 years in DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 Cost/ course £5.55 £5.55 £4.80 £4.80 £2.40 £4.80 £24.55 £24.55 £16.36 £16.36 £16.36 £16.36 £16.36 £16.36 £16.36 £16.36 £16.36 £16.36 £16.36 £16.36 £16.88 £16.88 Packs Packs required Cost/pack 5 2 100 10 1 750 12 1 600 15 1 450 20 1 300 30 1 750 12 1 750 10 1 1000 15 1 1000 56 1 1000 14 1 1000 10 1 75 1 60 1 45 1 30 1 75 1 75 1 100 1 100 1 100 1 100 1 Prophylaxis Prophylaxis days/course mg/dose Doses/day mg/course Doses/pack 5 10 14 10 14 10 14 10 14 10 13 10 13 10 10 10 10 10 10 10 10 10 > > > > > Age (years) kg < kg < kg < kg < 40 15 ml syrup, Symmetrel) > Estimated post-exposure prophylaxis acquisition costs Zanamivir (powder) Oseltamivir (suspension) – children > Oseltamivir (suspension) – children 23–40 Oseltamivir (suspension) – children 15–23 Oseltamivir (suspension) – children < Oseltamivir (suspension) – adults Oseltamivir (cap) – adults Amantadine (150 Amantadine (56-cap pack, Symmetrel) > Amantadine (14-cap pack, Lysovir) Amantadine (five-cap pack, Lysovir) Amantadine (five-cap pack, Regimen

TABLE 1 TABLE 11

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Background £5.55 £11.10 £4.80 £9.60 £2.40 £12.00 £5.55 £16.65 £4.80 £14.40 £2.40 £21.60 £24.55 £73.65 £16.36 £65.44 £16.36 £49.08 £16.36 £49.08 £16.36 £32.72 £16.36 £65.44 £16.36 £81.80 £16.88 £16.88 £16.88 £16.88 Packs Packs required Cost/pack Cost/course 5 5 5 9 10 3 12 4 15 3 20 3 30 2 12 4 10 5 15 2 56 1 14 2 15 3 56 1 14 3 280 3150 2520 1890 1260 3150 3150 2100 2100 2100 2100 4200 4200 4200 4200 10 1 75 1 60 1 45 1 30 1 75 1 75 1 100 1 100 1 100 1 100 1 100 1 100 1 100 1 100 1 Prophylaxis Prophylaxis days/course mg/dose Doses/day mg/course Doses/pack 5 28 14 42 14 42 14 42 14 42 13 42 13 42 10 21 10 21 10 21 10 21 10 42 10 42 10 42 10 42 > < < < < > > > > > Age (years) ml syrup, Symmetrel) > Estimated seasonal prophylaxis acquisition costs kg kg kg kg ml syrup, Symmetrel) 40 15 Zanamivir (powder) Oseltamivir (suspension) – children > Oseltamivir (suspension) – children 23–40 Oseltamivir (suspension) – children 15–23 Oseltamivir (suspension) – children < Oseltamivir (suspension) – adults > Oseltamivir (cap) – adults Amantadine following vaccination (150 Amantadine following vaccination (56- cap pack, Symmetrel) Amantadine following vaccination (14- cap pack, Lysovir) Amantadine following vaccination (five- cap pack, Lysovir) Amantadine (150 Amantadine (56-cap pack, Symmetrel) > Amantadine (14-cap pack, Lysovir) > Amantadine (five-cap pack, Lysovir)Amantadine (five-cap pack, > Regimen

12 2 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

suspension form based on body mass. The reader reader should also note that in November 2007 should note that while the BNF lists only 75 mg the manufacturer of zanamivir (GSK) applied to capsules and suspension, the SPC accessed via the Department of Health for a price modulation the electronic Medicine Compendium26,27 (www. of two of their drugs, one of which was zanamivir. medicines.org.uk) cites the additional availability The current list price for zanamivir is £24.55 of 30 mg and 45 mg capsules of oseltamivir. (five disks, four blisters per disk); the proposed Amantadine, oseltamivir and zanamivir are self- price for zanamivir is £16.36 (Toni Maslen, administered and do not require administration Health Outcomes Programme Leader, GSK, 2007, by a health-care professional. It should be noted personal communication). This price reduction was that diagnostic testing for influenza is not standard approved by the Department of Health with effect practice in the UK and is unlikely to represent a from 1 February 2008 but was not listed in the relevant cost associated with these products. The BNF14 at the time of submission of this report.

DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Chapter 2 Definition of the decision problem

ICE has previously issued guidance on the would be in terms of exposure to an index case Nuse of amantadine and oseltamivir for the with ILI, which may or may not subsequently be prevention of influenza.16 When the original NICE confirmed as influenza. Post-exposure prophylaxis guidance was issued, the licensed indications for was considered in the prevention of transmission of zanamivir did not extend to its use as prophylaxis. influenza from index cases to household contacts Marketing authorisation has since been given and in outbreak control within establishments for the use of zanamivir for the prophylaxis where members of a community live or work of influenza. This review presents an updated in close proximity, for example within long- assessment of new and existing evidence for term care settings and boarding schools. In the amantadine and oseltamivir, and an assessment seasonal setting, the assessment evaluates the of the clinical effectiveness and cost-effectiveness clinical effectiveness and cost-effectiveness of the of zanamivir for the prophylaxis of influenza in interventions in adults and children for whom England and Wales. seasonal prophylaxis would be appropriate in exceptional circumstances. In this case, exceptional circumstances relate to a high degree of mismatch Decision problem between the circulating influenza virus and vaccine strains; as noted below, the effectiveness The decision problem has been defined as of influenza prophylaxis in pandemic situations is described below. beyond the remit of this assessment.

Interventions The clinical effectiveness and cost-effectiveness of influenza prophylaxis for people who are at a Three prophylactic interventions are included in higher risk of influenza infection or complications this assessment: were considered. Where evidence was available, vaccination status was also taken into consideration. 1. amantadine (Lysovir or Symmetrel, Alliance Pharmaceuticals) 2. oseltamivir (Tamiflu, Hoffman–La Roche Overall aims and Pharmaceuticals) objectives of assessment 3. zanamivir (Relenza, GlaxoSmithKline Pharmaceuticals). The objectives of the assessment are:

Relevant comparators • to evaluate the clinical effectiveness of amantadine, oseltamivir, and zanamivir in Amantadine, oseltamivir and zanamivir are the prophylaxis of influenza in terms of cases compared with each other and with no prophylaxis prevented, complications prevented, health- (in which subjects received one of the following: related quality of life (HRQoL), mortality, placebo, no treatment or expectant treatment hospitalisations prevented, length of influenza following onset of symptomatic influenza). illness and time to return to normal activities • to evaluate the incidence and impact of Populations and treatment-related adverse events relevant subgroups • to estimate the incremental cost-effectiveness of amantadine, oseltamivir and zanamivir The interventions are evaluated in the post- in comparison with each other and no exposure prophylaxis and seasonal prophylaxis prophylaxis settings. In the post-exposure setting, the • to identify gaps in the existing evidence base assessment evaluates the clinical effectiveness and and those areas requiring further primary cost-effectiveness of the interventions in adults and research children who have been exposed to a clinically- • to estimate the annual cost to the NHS. diagnosed case of influenza. In reality, effectiveness 15

As outlined in Chapter 1 and noted above, the considers a ‘typical’ influenza season as well as remit of this assessment does not include the the potential impact of higher attack rates and circumstances of a pandemic, an impending vaccine mismatch. The interventions are appraised pandemic or a widespread epidemic of a new according to their licensed indications, with strain of influenza to which there is little or no guidance to be issued in accordance with relevant community resistance. The economic analysis marketing authorisations.

16 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Chapter 3 Assessment of clinical effectiveness

Methods for reviewing data relating to the prevention of influenza A and B. The MEDLINE search strategy is presented in effectiveness Appendix 1.

A systematic review of the clinical effectiveness Search restrictions of amantadine, oseltamivir and zanamivir for Searches were restricted by publication type to influenza prophylaxis was undertaken according controlled clinical trials, systematic reviews and to the general principles recommended in the economics or quality of life studies. Searches were quality of reporting of meta-analyses (QUOROM) not restricted by the date of publication or by statement.35 Methods for the review are detailed language. below. Inclusion and exclusion criteria Identification of studies The following inclusion criteria were used to Systematic searches were undertaken to identify identify relevant studies for inclusion in the studies relating to the clinical effectiveness of assessment. amantadine, oseltamivir and zanamivir in the prevention of influenza A and B. The search Populations strategy comprised the following main elements: The included populations comprised:

• searching of electronic databases listed below • adults and children who have been exposed to • contact with experts in the field a clinically-diagnosed case of influenza (which • handsearching of bibliographies of retrieved may or may not be true influenza) papers • adults and children for whom seasonal • scanning of electronic archives of key journals prophylaxis would be appropriate in for relevant evidence published within the exceptional circumstances, such as in the event preceding 12 months (searched October 2007). of mismatch between the circulating influenza virus and vaccine strains; for the purposes of Sources searched this assessment, we have considered healthy The electronic databases searched included and at-risk children, adults and the elderly. MEDLINE; MEDLINE In-Process; EMBASE; Cochrane Database of Systematic Reviews, Interventions Cochrane Controlled Trials Register, Biosciences Interventions comprised the following medications Information Service (BIOSIS), Cumulative Index to used for influenza prophylaxis administered in line Nursing and Allied Health Literature (CINAHL), with current UK marketing authorisations: Database of Abstracts of Reviews of Effectiveness (DARE), NHS Economic Evaluation Database • amantadine (EED) and Health Technology Assessment (HTA) • oseltamivir databases; Office of Health Economics Health • zanamivir. Economic Evaluations Database (OHE HEED), National Research Register (NNR); Science Trials of these interventions in seasonal prophylaxis Citation Index (SCI); Current Controlled Trials and post-exposure prophylaxis (both in prevention (CCT); and ClinicalTrials.gov. Searches were of the transmission of influenza within households undertaken in July 2007. Sponsor submissions to and in outbreak control in settings where NICE were also handsearched. individuals live or work in close proximity) were included in the review. Trials in which interventions Keyword strategies were used in prophylaxis against experimentally- The search strategies included subject headings induced influenza in line with licensed indications and free text terms, combined using Boolean were also included. The results of these challenge logic, to identify all published and unpublished studies should be interpreted with caution owing 17

to their limited external validity. These studies are to uncertainty were reviewed independently by a presented to provide a comprehensive review of the second reviewer, and discrepancies, for example effectiveness of prophylaxis; they were not used to where studies were not clearly reported, were inform the health economic model. resolved by discussion. All data abstraction was checked and confirmed by a second reviewer. Comparators Interventions were compared with each other and Critical appraisal strategy no prophylaxis (in which subjects received one of the following: placebo, no treatment or expectant The quality of included RCTs was assessed using treatment following onset of symptomatic quality criteria based on those developed by the influenza). NHS Centre for Reviews and Dissemination;36 these are presented in Appendix 2. The purpose of Outcomes such quality assessment was to provide a narrative Outcomes considered included: account of trial quality for the reader. Quality assessment was confirmed by a second reviewer. • cases prevented (measured in terms of symptomatic, laboratory-confirmed influenza Methods of data synthesis or, in the absence of this outcome, clinical illness and/or infection) The outcomes defined above were presented within • complications prevented a narrative synthesis. Where quantitative synthesis • adverse events was considered to be appropriate, statistical • HRQoL meta-analysis was undertaken using a random- • mortality effects model using RevMan software (version • hospitalisations prevented 4.2.10) in order to calculate pooled estimates • length of influenza illness for RRs for outcomes of interest. The presence • time to return to normal activities of heterogeneity within the identified evidence • cost and cost-effectiveness (see Chapter 4). and the lack of any direct comparative RCTs of antiviral prophylaxis were considered to preclude Study type the use of sensitivity analyses and mixed-treatment The study employed randomised controlled comparisons. trials (RCTs). Had evidence not been available from RCTs, other study types would have been Efficacy data are presented as RRs and protective considered according to the hierarchy of evidence. efficacy (PE) (PE = 1 – RR, expressed as a Systematic reviews were not included in the percentage). Where the RR or PE values were not analysis, but were handsearched to identify RCTs described in the study publication, or where the meeting the inclusion criteria of this review and value differed (usually by only a small margin) from retained for discussion. that calculated from the formula below, the RR was calculated by the Assessment Group using the The following exclusion criteria were used: following formula (and marked with †):

• intervention medications not used in RR = (a/(a+c))/(b/(b+d)) accordance with their licensed indications • studies published only in languages other than where a = event present for treatment group, b = English. event present for control group, c = event absent for treatment group and d = event absent for Based on the above inclusion/exclusion criteria, control group. study selection was undertaken by one reviewer, with involvement of a second reviewer when Where publications have reported a 95% necessary to provide consensus on inclusion or confidence interval (CI) around the RR or PE, exclusion of studies. these have been presented. Where no CI was published, it was calculated using the following Data abstraction strategy formula (and marked with †):

Data were extracted with no blinding to authors SE [ln(RR)] = √[1/a – 1/(a + c) + 1/b – 1/(b + d)]. or journal, and were extracted by one reviewer using a standardised form. Any studies giving rise 18 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Lower 95% confidence limit for RR Papers that were excluded after close scrutiny = exp [ln(RR) – 1.96 × SE ln(RR)] are presented in Appendix 6, together with the justification for their exclusion. Twenty systematic Upper 95% confidence limit for RR reviews were identified; these were handsearched = exp [ln(RR) + 1.96 × SE ln(RR)]. and retained for discussion. Twenty-six citations relating to 22 RCTs were included in the review of clinical effectiveness. One additional unpublished Results report was provided as evidence as part of the 44 Quantity and quality of submissions by sponsors and is also presented. research available Quantity of research available As a result of the searches outlined above, a total of A total of 26 published references presenting 1010 citations were identified, following removal findings from 22 RCTs were considered relevant of duplicates, and were screened for inclusion in for inclusion in the review of clinical effectiveness the review of clinical effectiveness (Figure 3). Two of amantadine, oseltamivir and zanamivir for hundred and eighty citations were rejected at the the prophylaxis of influenza. An additional title stage, yielding 730 abstracts for screening, unpublished report was identified in the sponsor of which 551 were rejected on examination of submissions and included in the assessment, the abstract. Of 179 full papers retrieved, 153 resulting in a total of 23 RCTs.44 One included were excluded (of which 18 were not available for reference45 was a report of a pooled analysis of data retrieval by information specialists or could not relating to post-exposure prophylaxis of influenza be read as they were not available in English). using oseltamivir and zanamivir based on included Of these, seven citations were excluded, since trials.46–49 No ongoing trials or trials due to report the full text was not available in English.37–43 The that met the inclusion criteria were identified in articles that could not be obtained were unlikely searches. All included articles are described below to be relevant for inclusion, as they appeared to and grouped by intervention. be conference abstracts and discussion papers.

Potentially relevant citations identified and screened for retrieval (n = 1010)

Citations rejected at title stage (n = 280)

Total abstracts screened (n = 730)

Citations rejected at abstract stage (n = 551)

Total full papers screened (n = 179) Full papers excluded [n = 153 (including 18 that could not be obtained/read and 20 systematic review articles retained for discussion)] Total full papers accepted reporting RCTs [n = 26 (relating to 22 RCTs; an additional unpublished report was identified from sponsor submissions, resulting in a total of 23 RCTs)]

FIGURE 3 Quality of reporting of meta-analyses (QUOROM) diagram of study inclusion and exclusion in clinical effectiveness review. 19

Amantadine full text was not available in English, this citation A total of eight full papers reporting eight could not be included and is not presented in the RCTs that investigated the prophylactic use of review. amantadine against influenza were identified. Characteristics of these studies are presented in Oseltamivir Table 3. Nine studies (of which six were reported in full papers and a further three were abstracts) were The original HTA review reported by Turner et identified that investigated the use of oseltamivir in al.10 assessed the use of amantadine in influenza prophylaxis against influenza in six original RCTs. prophylaxis in children (aged under 18 years) Characteristics of these trials can be seen in Table 4. and the elderly (aged over 65 years) only, as a Cochrane review of the use of amantadine in Four oseltamivir prevention trials were covered adults had recently been reported.50 This Cochrane in the original HTA review;10 these were studies review has been subsequently updated33 and was WV15825,64,65 WV15673,66 WV1569766 and handsearched to identify any additional citations WV15799.49 Data for trials WV15673 and WV15697 for inclusion in the current review. Turner et al.10 were reported in the publication by Hayden et identified three trials of amantadine prophylaxis al.66 both individually and combined across the undertaken in children.51–53 However, these studies two studies. All of these trials are included in the and an additional trial54 are not included in this current assessment. An additional publication, technology assessment report, as the dosage of by Hayden et al.,47 examining the efficacy of amantadine is not established in children under 10 oseltamivir in post-exposure prophylaxis within years of age according to licensed indications. Two households present findings of an RCT published prevention trials in the elderly were also included subsequent to the HTA review.10 A further paper in the original assessment.55,56 Of these studies, describes a trial of experimentally-induced only the findings presented by Pettersson and influenza.67 An additional publication45 describes colleagues55 are included in this update, while the a pooled analysis of data from oseltamivir post- trial reported by Leeming56 was excluded, as twice exposure prophylaxis trials that are already the currently licensed dose was administered to included in the review.46–49 participants. An abstract in English was obtained for the trial An additional seven trials of amantadine by Kashiwagi et al.,41 in which oseltamivir was prophylaxis were identified by our searches. These administered to healthy adults at 75 mg once included two studies that evaluated seasonal daily versus placebo for 6 weeks. This trial was prophylaxis in healthy adults.57,58 Further trials previously reviewed by Jefferson et al.68 However, described amantadine prophylaxis in outbreak the report was not available in full in English and control in healthy adolescents in a boarding was therefore excluded from this review. school59 and in adults in semi-isolated engineering school populations.60,61 A further three reports Zanamivir of the prophylactic efficacy of amantadine A total of 10 published reports of eight original against experimentally-induced influenza were RCTs were included in the assessment, of which identified.57,62,63 One of these papers presented eight were full papers and two were abstracts results from two separate trials examining the providing further reports of included studies. A use of amantadine in seasonal prophylaxis and further trial was identified within the sponsor experimentally-induced influenza studies.57 submissions and is included, giving a total of nine RCTs.44 These are presented in Table 5. Four trials included in the Cochrane review of amantadine and rimantadine in influenza Turner and colleagues10 evaluated five A in adults33 have been included in our zanamivir prevention trials: studies NAIA2010,69 assessment.55,57,59,61 Justifications of study exclusions NAIA3005,70,71 NAIA30010,46 NAIA200972 and are reported in Appendix 6. NAIB2009.72 NAIA2009 and NAIB2009 were reported as a single trial in the published literature. An abstract was available in English for a double- All of these trials are included in the present blind, placebo-controlled trial by Plesnik et al.,38 assessment, with the exception of trial NAIA2010 which suggested that amantadine at 100 mg/day reported by Schilling et al.,69 in which the dose of reduced the incidence of serologically-confirmed zanamivir used was twice that of current licensed infection and was well tolerated. However, as the indications. 20 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued National Health Research National Health Research and Development of Canada and Program the Canadian Foundation for the Advancement of Clinical Pharmacology Study medication supplied by Ciba–Geigy Pharmaceuticals Medica Ltd and Orion Diagnostica Ltd Inc. and Company, days (1982–3) Seasonal 39 days (1980–1), 32 Preventative Preventative strategy duration Prophylaxis Source of funding Outbreak control 14 days Seasonal 9 weeks Seasonal 6 weeks Presumed de Nemours E.I. DuPont 94; 299; final 307; final = = 33 29; 1982–3, 74; 1981–2 = = = = 159 = 101; completing study, 101; completing study, = 18; 1982–3, n 48; 1981–2 under 28 years, = = 89 mg/day: 1980–1, n mg/day: randomised, n n mg/day, mg/day: randomised, n 21, over 29 years, n = = 159 = 269 267 = = 99 46 16, over 29 years, n = = = analysis, n n T1: amantadine 100 T2: placebo: randomised, n T2: placebo, n T2: no specific treatment: randomised, n T1: amantadine 100 under 28 years, n T2: placebo: 1980–1, n n completing study, T1: amantadine 100 T1: amantadine 100 analysis, n n n 79.0 = 77.4 years, T2 = Population characteristicsPopulation design arms (no. of patients in each arm) Trial years) living in a residential home, vaccination status but discussion states unclear, no adequate vaccine available Healthy adults in a military setting (age not defined) Six to eight individuals in each study year immunised against influenza in previous years Elderly subjects (mean ages T1 Healthy unvaccinated adults aged 18–55 years living in the community Adolescent males aged 13–19 years in boarding school setting, 87% vaccinated 55 Characteristics of included amantadine prophylaxis RCTs Characteristics of included amantadine prophylaxis RCTs 58 57 59 Pettersson et Pettersson al ., 1980 Study Aoki et al ., 1986 Reuman et al ., Reuman 1989 and Payler Purdham, 1984

TABLE 3 TABLE 21

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Assessment of clinical effectiveness Study medication supplied de by E.I. DuPont Nemours and Company, Inc. E.I. DuPont de Nemours E.I. DuPont Inc. and Company, de Nemours E.I. DuPont Inc. and Company, Study medication supplied de by E.I. DuPont Nemours and Company, Inc. populations dosed for 30 days, two populations dosed for 12 days 8 days (3 pre- challenge and 5 days post-challenge) 8 days 12 days (24 hours before challenge and daily for 11 days) Preventative Preventative strategy duration Prophylaxis Source of funding Outbreak control Five of seven Experimentally- induced influenza Experimentally- induced influenza Experimentally- induced influenza 307; = 2868, 2804 = 307 – 20 22 19 = = = 1011 775 2804 (3175 = = mg/day (50.7% of 10,053): assigned n mg/day, n mg/day, n mg/day, = 19 22 31 = = = 5092; onset of influenza prior to dosing, = 441; regularly or irregularly taking amantadine, 4559 3175; onset of influenza prior to dosing, n = = = included in analysis) T3: internal control: individuals at same engineering schools as amantadine and placebo groups, but living at home rather than school; received no prophylaxis (10.0% of 10,053), n T4: external control: individuals at an eighth engineering school; received no prophylaxis (7.7% of 10,053), assigned to group, n n T2: placebo (31.6% of 10,053): assigned to group, n receiving placebo, n n T2: placebo, n T2: placebo, n T2: placebo, n T1: amantadine 100 to group, n T1: amantadine 100 T1: amantadine 100 T1: amantadine 100 Population characteristicsPopulation design arms (no. of patients in each arm) Trial Male adults (recruitment pool aged 18–30 years), in semi- presumed healthy, isolated engineering school populations Healthy unvaccinated adults aged 18–40 years Healthy adults aged 18–40 years Healthy adults (age not defined) 60,61 62 Characteristics of included amantadine prophylaxis RCTs (continued) Characteristics of included amantadine prophylaxis RCTs 57 63 Study Smorodintsev et al ., 1970 Reuman et al ., Reuman 1989 Sears and Clements, 1987 Smorodintsev et al ., 1970

22 3 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 Hoffman–La Roche Hoffman–La Roche Hoffman–La Roche Hoffman–La Roche Hoffman – La Roche Hoffman–La Roche 6 weeks 6 weeks 7 days 6 weeks 7 days (1 day before challenge and 6 days after) 10 days Preventative strategyPreventative duration Prophylaxis Source of funding Seasonal Seasonal Post-exposure prophylaxis Seasonal Experimentally-induced Experimentally-induced influenza Post-exposure Post-exposure prophylaxis mg 392 = 400 = mg once daily, mg once daily, mg once daily, mg once daily, mg once daily, mg once daily, mg once daily, mg once daily, 268 251 462 272 19 = = = = = mg twice daily for 5 268 252 493 276 19 = = = = = Trial design arms (no. of patients Trial in each arm) T1: oseltamivir 75 n T2: placebo, n T1: oseltamivir 75 n T2: placebo, n T1: oseltamivir 75 n T2: placebo, n T1: oseltamivir 75 n T2: placebo, n n T2: placebo, n Oseltamivir: post-exposure prophylaxis vs treatment on influenza onset (expectant treatment); index cases in both groups received treatment T1: oseltamivir prophylaxis 75 daily for 10 days, n T2: oseltamivir treatment on influenza onset (expectant treatment) 75 days (less in children), n 81 = mg twice 82 years), 98% with = Healthy unvaccinated adults aged 18–65 years living in the community; conducted at study sites in Virginia, USA Healthy unvaccinated adults aged 18–65 years living in the community; and conducted at study sites in Texas USA City, Kansas Subjects of mixed age and health status living in households; adults and children aged 12 years and above (as contacts) Contacts of all index cases: T1: 11.4% vaccinated; T2: 13.9% vaccinated Index cases did not receive treatment At-risk elderly subjects living in a residential home (mean age T1 years, T2 concomitant disease in each group T1: 80.4% vaccinated; T2: 80.1% vaccinated Healthy adults aged 18–65 years T1: oseltamivir 75 daily for 5 days Subjects of mixed age and health status; adults and children aged 1 year above Contacts: T1: 8% vaccinated; T2: 7% vaccinated Index cases in both arms received treatment with oseltamivir 75 ) 65 ) ) ) ) 66 67 49 48,73,74 and De 64 Characteristics of included oseltamivir prophylaxis trials 67 WV15825 (Peters et WV15825 (Peters al ., 2001 WV15697 (Hayden et al ., 1999 WV15799 (Welliver et al ., 2001 WV16193 (Hayden et al ., 2004 WV15673 (Hayden et al ., 1999 Hayden et al ., 2000 Trial/data sourceTrial/data characteristics Population Bock et al ., 2000

TABLE 4 TABLE 23

47 44

2002 al., et 70,71 75 submission Data source and additional information 2007 1999a GlaxoSmithKline Sponsor GlaxoSmithKline Monto GlaxoSmithKline LaForce et al., Glaxo Wellcome Monto et al., 28 days 10 days 28 days 28 days Seasonal Post-exposure Post-exposure prophylaxis Preventative strategyPreventative duration Prophylaxis Source of funding Seasonal Seasonal mg mg mg mg 158 630 554 1685; 161 661 553 ======1595 = 1678; completed 1594 = = T2: placebo, n T1: zanamivir 10 n once daily, T2: placebo, n Trial design arms (no. Trial of patients in each arm) T1: zanamivir 10 once daily: randomised, n n study, T2: placebo: randomised, n completed study, n T1: zanamivir 10 n once daily, T2: placebo, n T1: zanamivir 10 n once daily, Health-care workers aged 18 years and above Population Population characteristics At-risk adolescents and adults aged 12 years and above; high-risk defined as aged 65 years and above or chronic disorders of pulmonary or cardiovascular system or diabetes mellitus T1: 67% vaccinated; T2: 68% vaccinated Subjects of mixed age and health status; adults and children aged 5 years and above (as contacts) Index cases: T1: 8% vaccinated; T2: 5% vaccinated Contacts: T1: 11% vaccinated; T2: 10% vaccinated Index cases did not receive treatment Healthy adults aged 18 to 64 years from University communities T1: 14% vaccinated; T2: 14% vaccinated Characteristics of included zanamivir prophylaxis trials GlaxoSmithKline study 167/101 Trial NAI30034 NAI30031 NAIA3005

24 5 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

46 76,77 78 Kaiser et al., 2000 Kaiser 2005 2005 Data source and additional information 2000 Presumed Glaxo Presumed Wellcome Glaxo Wellcome Ambrozaitis et al., Glaxo Wellcome Gravenstein et al., Glaxo Wellcome Hayden et al., 5 days 10 days Post-exposure Post-exposure prophylaxis Outbreak control 14 days Outbreak control 14 days Preventative strategyPreventative duration Prophylaxis Source of funding Post-exposure Post-exposure prophylaxis 144 mg mg 144 252 423 13, for 414 12 for ======242 = mg daily, n mg daily, T2: placebo, n T1: zanamivir 10 n inhaled daily, T1: zanamivir 10 n once daily, influenza B outbreak T2: placebo n influenza B outbreak Trial design arms (no. Trial of patients in each arm) T1: zanamivir once n daily, T2: placebo, n T1: zanamivir inhaled 10 T2: placebo, n 74.8 67.2 = = 76.3 years, T2 66.8 years, T2 = = health status; unvaccinated adults and children aged 13–65 years (as contacts) Index cases did not receive treatment years); 96% of subjects at randomisation at risk of complications or death due to influenza T1: 99% vaccinated; T2: 92% vaccinated At-risk elderly subjects in long-term care (mean age T1 Population Population characteristics years); 85% of subjects at randomisation at risk of complications or death due to influenza T1: 9.6% vaccinated; T2: 8.8% vaccinated At-risk elderly subjects in long-term care (mean age T1 Subjects of mixed age and health status; adults and children aged 5 years and above Contacts: T1: 14% vaccinated; T2: 18% vaccinated Index cases were randomised to zanamivir twice daily or placebo NAIA2009/NAIB2009 Subjects of mixed age and NAIA3003 Trial NAIA3004 NAI30010 25

An additional six citations relating to zanamivir interventions were identified with the potential to were identified by the systematic searches for affect outcomes, including vaccination,57–61 intake inclusion in the clinical effectiveness review. of medications that may affect study outcomes,64 Findings from a trial of zanamivir seasonal and previous exposure to the experimental prophylaxis in at-risk adolescents and adults have challenge strain.62 The blinding of participants, been presented.75 A report on the use of zanamivir those administering the intervention and outcome in post-exposure prophylaxis within households assessors was similarly difficult to judge and while has also been published,47 while two additional many publications reported that a double-blind papers and one abstract provide reports of the use design was used, no further details were presented. of zanamivir in outbreak control in at-risk elderly Although all studies included at least 80% of subjects within long-term care settings.76–78 An randomised participants in the final analysis additional paper describes a pooled analysis of data and only one study failed to report reasons for from zanamivir post-exposure prophylaxis trials participants’ withdrawal,60,61 adherence to the that are already included in the review.45 intention-to-treat analysis was variable between studies. Quality of included research The quality of the evidence included within the Oseltamivir assessment was variable in terms of study design The quality of the oseltamivir prophylaxis characteristics and clarity of reporting. Key evidence presented was considerably more robust study quality characteristics are summarised and in terms of study design and reporting than that presented in Appendices 3, 4 and 5. for amantadine. However, the randomisation methods used and concealment of allocation were Amantadine unclear in the reporting of some studies.48,49,73–74 The quality of the included eight RCTs relating to All studies stated the number of participants the prophylactic use of amantadine was relatively randomised, and only one report failed to describe poor. No new amantadine prevention trials clearly the baseline characteristics and eligibility published since the original HTA assessment10 were criteria,74 with all others judged to have achieved identified. A considerable number of the older baseline comparability among subjects. A number amantadine trials utilised a dose of 200 mg/day of authors identified vaccination status,48,49,64,66 as opposed to the currently licensed adult dose of and recent use of antivirals48,64 or antibiotics48 as 100 mg/day18 and were therefore not considered potentially confounding co-interventions. Clarity of to be suitable for inclusion in this review (see reporting of blinding was variable among studies, Inclusion and exclusion criteria, p. 17). Other and one study was described as being open-label amantadine prevention trials incorporated the use in design.48,73–78 All studies retained at least 80% of doses in line with the current licence alongside of randomised subjects for use in the analysis and inappropriate doses, but did not present data all, with the exception of two reports,64,67 presented appropriate for inclusion separately and were reasons for withdrawal, but the analysis of only therefore also excluded. Details of these studies can two studies could be considered to adhere to the be found in Appendix 6. intention-to-treat principle.47,67,73-74

Much of the amantadine prophylaxis evidence Zanamivir was not reported clearly, with a lack of detail The evidence base for the use of zanamivir in on, for example, methods of randomisation of prophylaxis against influenza could also be study subjects.57,59–63 It was unclear in a number considered to have a greater degree of internal of trials whether allocation of treatment group validity than the trials of amantadine prophylaxis. was concealed.55,57–59,62,63 One study publication However, there was a lack of detail on methods failed to state clearly the number of participants of randomisation46,47,72 and concealment of randomised.62 As only one report presented allocation.46,72,76,77 All studies outlined the number details of baseline characteristics of participants,55 of subjects who were randomised to each group and it was generally not possible to assess whether described baseline characteristics, with baseline baseline comparability between treatment groups comparability considered to have been reached to had been achieved. It is therefore possible that varying degrees in all trials. Baseline comparability potentially confounding variables may not have was considered to be relatively weaker in one trial.78 been adequately balanced among participants Vaccination status46,47,70,75,76,78 and recent use of randomised to each trial arm. An additional four antivirals46,76,78 were identified as co-interventions. publications failed to state the eligibility criteria for More information was available on blinding 26 participation in the trials.55,60–62 A number of co- procedures used in the zanamivir research (with DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

additional information obtained from sponsor Amantadine submissions) than for oseltamivir and amantadine The included evidence focusing on amantadine prophylaxis trials, although there were some gaps prophylaxis against influenza was taken from in reporting in a number of studies.46,47,70–72,75 relatively old trials of lower quality that were However, all studies included more than 80% of conducted across a broad range of population randomised subjects in analyses, described reasons subgroups. There was considerable variability for withdrawal and utilised intention-to-treat between trials in terms of vaccination levels, setting analysis. and duration of prophylaxis. Eight references reporting eight RCTs were identified. The Assessment of effectiveness Cochrane review investigating amantadine and Critical review and synthesis rimantadine in influenza A incorporated the use of of information meta-analysis in their study.33 However, the large degree of heterogeneity and variation in primary The outcomes considered in the clinical outcomes used in terms of cases prevented between effectiveness review of the interventions used in the studies included in our review would suggest influenza prophylaxis included cases prevented, that the use of statistical meta-analysis would be complications prevented, adverse effects of inappropriate; as such, the results of these trials are treatment, HRQoL, mortality, hospitalisations presented in the form of a narrative synthesis. prevented, length of influenza illness, time to return to normal activities, cost and cost- Evidence for amantadine prophylaxis in children effectiveness. Not all of these outcomes were under 10 years is not presented in this systematic represented in the identified clinical effectiveness review; such data were excluded as amantadine trials included in the review; none of the included dosage is not established in this age group studies reported outcomes relating to HRQoL according to licensed indications. The limited or mortality. The primary outcome reported in evidence that exists relating specifically to this the majority of included trials related to cases younger age group was reported within the original of influenza prevented as measured in terms HTA review.10 No clinical trial evidence relating to of the incidence of symptomatic, laboratory- the use of amantadine in the paediatric population confirmed influenza (SLCI). Where SLCI data has been published subsequently. were not presented – typically in older trials of relatively lower quality – cases prevented by Seasonal prophylaxis with amantadine prophylaxis within trials were described in terms In healthy adults Two trials by Reuman et al.57 and of clinical influenza, acute respiratory disease and/ Aoki et al.58 examining the use of amantadine or infection.58,60–63 The efficacy of prophylaxis in seasonal prophylaxis in healthy adults were in preventing cases of SLCI was most frequently identified and included in the systematic review of reported as a protective efficacy statistic (1 – RR, clinical effectiveness. expressed as a percentage). While a minority of papers presented some SLCI data by influenza The RCT conducted by Reuman et al.57 was type, the numbers of observed cases were too undertaken in a healthy, unvaccinated adult small to allow meaningful estimates of efficacy to population aged 18–55 years. Although this study be made by influenza type and therefore the total also investigated the effects of amantadine at daily numbers of cases of SLCI are presented. These doses of 50 mg and 200 mg, only data relating to values are tabulated where appropriate within the the use of the drug at the licensed dose of 100 mg data synthesis. In a small number of trials, this per day are presented here. The reporting of the evidence was categorised by subgroup, in terms of duration of the intervention is unclear within age, risk (according to age and health status) and the reporting of this trial; it is assumed from vaccination status, and is presented where available. the description of the trial methods to be over The majority of trials also presented information a period of 6 weeks. Subjects were excluded if on the occurrence of adverse events among chronic disease and abnormal clinical history and participants, which is presented in text format, physical examination were evident prior to study due to the large degree of variability in adverse entry. Clinical symptoms with influenza A infection events reported. A limited amount of information were observed in 5 of 159 subjects in the placebo was reported relating to complications prevented, group (3.1%) and 2 of 159 subjects (1.3%) in the hospitalisations prevented, length of influenza amantadine at 100 mg/day dosage group (RR illness and time to return to normal activities. 0.40,† 95% CI 0.08†–2.03†). The authors described

a higher rate of adverse events in the treatment No amantadine-related differences in adverse group receiving the higher dose of 200 mg/day effects were observed between the placebo and but no differences between the arms receiving the amantadine 100 mg/day groups (no further data licensed dose of 100 mg/day and placebo. Total were presented). adverse events were reported at a rate of 49/159 (31%) versus 47/159 (30%) in the placebo and In the elderly A single trial by Pettersson et al.55 amantadine arms respectively. Gastrointestinal in which amantadine was used for seasonal adverse events occurred in 8% of subjects in each prophylaxis in elderly subjects was included arm (12/159 for each arm). CNS-related adverse in the systematic review. While the trial also events were observed in 14% of amantadine- investigated amantadine prophylaxis in different treated subjects (23/159) and 16% (25/159) of population groups and settings, the only data for subjects in the placebo arm. One subject of the amantadine administered in line with licensed 159 in the placebo arm (0.6%) withdrew as a result indications and therefore suitable for inclusion of adverse events; no withdrawals were described related to residents of a home for the elderly in the amantadine 100 mg/day group. However, who received amantadine at a dose of 100 mg/ adherence to amantadine was relatively poor, with day versus placebo over a period of 9 weeks. 49% of the amantadine-dosed participants and The vaccination status of subjects was not clearly 58% of the placebo arm taking fewer than the total described in the trial publication, although it allotted tablets. This study suggests that the use was stated in the discussion of the report that of amantadine at the lower dose results in fewer no adequate vaccine was available at the time of adverse effects but that the low influenza attack study; this suggests that the population could rate does not allow meaningful conclusions to be be considered to be unprotected by vaccination. drawn in relation to the efficacy of amantadine in Primary outcomes were reported in terms of the preventing influenza illness and infection. incidence of serologically-confirmed influenza infection, incidence of respiratory infections and A study in which amantadine was administered adverse events. No data were reported for the to healthy military personnel for seasonal incidence of serologically-confirmed influenza prophylaxis over two seasons for 32 days and 39 infection or incidence of respiratory infections days respectively was reported by Aoki et al.58 As in the elderly study population, as there was no discussed in Inclusion and exclusion criteria (p. evidence of an influenza epidemic in this group. 17), only data comparing effects in treatment arms Amantadine prophylaxis was described as being receiving amantadine at a dose of 100 mg per day terminated in 5 of 94 (5.3%) and 2 of 101 (2.0%) or placebo are presented in this review. Reasons subjects in the amantadine and placebo arms for the unequal numbers in each treatment arm respectively. Although this evidence would suggest are unclear. Six to eight individuals per study a potentially higher incidence of adverse events in season were described as being vaccinated in the amantadine arm, a range of apparently non- previous years (proportions not estimable). drug-related reasons were cited for termination, Primary outcomes that were reported related to the including one fracture of caput femoris, two proportion of participants who developed acute deaths attributable to carcinoma and myocardial respiratory tract infection, classification of disease infarction, no reason given (in one case) and and adverse effects. No differences in the incidence compliance and practical issues (in a further two or classification of acute respiratory illness (ARI) cases). One case of GI symptoms and one of chest were observed between the treatment arms. The pains were cited in the placebo arm. trial findings were not reported clearly, in that one subject in the 1980–1 season and two subjects in Post-exposure prophylaxis with amantadine the 1982–3 season are stated as developing acute In households No studies investigating the use influenza A, but no further detail was presented of amantadine in the prevention of influenza in concerning the treatment arm in which these household contacts of influenza-infected index cases developed. However, the observed attack cases were identified for inclusion in the systematic rates were so low that meaningful comparison of review. efficacy between arms is limited. In the 1980–1 season, withdrawals due to adverse effects were Outbreak control in healthy adults and adolescents Two reported at a frequency of 1/49 (2.0%) in the trials were identified in which amantadine was placebo group and 1/75 (1.3%) in the amantadine used for the control of influenza outbreaks. 100 mg/day group. In 1982–3, these rates were The trial reported by Payler and Purdham59 was described as 1/34 (2.9%) in the placebo group and undertaken in adolescent males in a boarding 28 1/47 (2.1%) in the amantadine 100 mg/day group. school, of whom 87% (525/606) were vaccinated for DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

that season. Subjects were randomised to receive as mild or severe. Mean duration of overall illness either amantadine 100 mg/day for 14 days or no was shorter in the amantadine group than in treatment. In this study, the control arm was not the placebo group (p < 0.05). A subset of non-ill placebo controlled. However, it is unlikely that subjects (n = 1825) were questioned about adverse a lack of blinding would have an impact on the effects, which occurred in 7.2% (94/1313) and 5.1% reported incidence of SLCI, due to the nature of (26/512) of those questioned from the amantadine the manifested infectious illness and requirement and placebo groups respectively, showing a non- of infection confirmed by laboratory tests. The significant 2.1% excess in the amantadine group. incidence of clinical influenza was reported as Statistically-significant (at 5%) excesses in dyspepsia being 7/267 (2.6%) in the amantadine arm versus (1.72%) and sleep disturbances (1.14%) were noted 42/269 (15.6%) in the control group (p < 0.001, in the amantadine-dosed subjects. The applicability RR 0.17,† 95% CI 0.08†–0.37†). The incidence of of this evidence is considerably hindered by poor clinical influenza that was laboratory confirmed was reporting and lack of detail on population baseline 3/267 (1.1%) in the subjects receiving amantadine characteristics. However, some limited evidence compared with 29/269 (10.8%) in the control group of the efficacy of amantadine in preventing and (p < 0.001), resulting in a protective efficacy of shortening the duration and severity of clinical 90% (95% CI 0.66†–0.97†). Of the three subjects influenza disease, and of a higher rate of adverse developing symptomatic, laboratory-confirmed effects resulting from amantadine prophylaxis, influenza in the amantadine arm, two were were presented. described as being vaccinated, while one subject was reported as unvaccinated. No information was Outbreak control in the elderly No studies given for the control arm. Urticaria was reported investigating the use of amantadine in outbreak in 1 of 267 participants receiving amantadine control in elderly populations were identified. (0.4%), while no adverse events were observed in the control group. The authors observed that eight Prophylaxis with amantadine against of the nine subjects who developed laboratory- experimentally-induced influenza confirmed influenza A 3 days after the 14-day Three further trials of amantadine prophylaxis, in prophylactic period had ceased had received which subjects were challenged experimentally with amantadine, highlighting that protection against influenza virus, were included in the systematic influenza is not extended beyond the prophylactic review.57,62,63 period. Reuman et al.57 undertook an RCT to determine The second included RCT of amantadine in the efficacy of amantadine in preventing outbreak control was presented by Smorodintsev experimentally-induced influenza A. Although et al.60,61 The composition of the study population the use of doses of amantadine at 50 mg/day and was not clearly reported but appears to have 200 mg/day were also investigated, only data consisted of healthy, unvaccinated adults based relating to the use of amantadine at 100 mg/day in semi-isolated engineering schools. Subjects in and placebo are presented within this systematic five of seven schools were dosed for 30 days, while review. Subjects were healthy, unvaccinated subjects in two schools were dosed for 12 days. adults aged 18–40 years. Individuals who The reporting of the study was very unclear, with had a pre-study abnormal clinical history and conflicting descriptions of the vaccination status physical examination or chronic disease were of populations, varying from unvaccinated to excluded from participation. Infection was noted partially vaccinated. Regardless of whether subjects in 18/19 (95%) placebo subjects and in 12/20 received drug medication regularly or irregularly, (60%) of amantadine-dosed subjects (p = 0.012). clinical influenza occurred at rates of 214/4559 Symptomatic, laboratory-confirmed influenza was (4.7%) and 224/2804 (8.0%) in the amantadine observed in a smaller proportion of subjects, i.e. and placebo groups respectively (RR 0.59,† 95% 11/19 (58%) in the placebo arm and 3/20 (15%) CI 0.49†–0.70†). Of 400 influenza cases that were in the amantadine arm (p = 0.0055), resulting selected at random, severity of symptoms in the in an RR of 0.26 (95% CI 0.09†–0.79†) and a amantadine group was reported as 56.0% mild and protective efficacy of 74%. Amantadine at all 9.0% severe; while symptoms were described as doses was described as suppressing respiratory 38.0% mild and 19.0% severe in the placebo group symptoms on days 2–6 following viral challenge (p < 0.01 for severe symptoms, p < 0.001 for mild and systematic symptoms on days 2 and 3 post symptoms), demonstrating milder disease in the challenge. Total length of illness was not reported. amantadine-treated group. No further information Total adverse events judged to be potentially drug was provided on the criteria for classing symptoms related occurred in 50% of placebo subjects and 29

80% of subjects receiving amantadine at 100 mg/ the study period, suggesting a relatively high level day (p = 0.27). These were stated as being mostly of adherence.60 However, Reuman et al.57 reported mild and transient and related to the GI and CNS that approximately half of their study participants systems. Three adverse events were rated as severe, did not take all of the allotted study treatment comprising two cases of severe headache, of which (49% and 58% of amantadine and placebo groups one occurred in each treatment arm, and one respectively). The study by Aoki et al.58 utilised case of dream abnormality in a subject receiving laboratory testing of samples taken from tested amantadine. No withdrawals were made in the study participants and demonstrated that 10% placebo or amantadine at 100 mg/day arms. and 22% of subjects who had been randomised to receipt of amantadine and were tested in different Further evidence of the use of amantadine study seasons showed no drug in samples. No prophylaxis against experimentally-induced amantadine was present in samples from placebo influenza A was published by Sears and Clements.63 subjects. Healthy, unvaccinated adult subjects aged 18–40 years were randomised to receive either Viral resistance to amantadine amantadine at 100 mg/day or placebo over a period No trials presented data on analysis of sensitivity of of 8 days. Infection was serologically confirmed in viral isolates to amantadine (see below). 17/22 (77%) amantadine subjects and 20/22 (91%) subjects in the placebo group. Influenza illness Discussion was observed in 2/22 (9.1%) subjects receiving As noted in the review by Jefferson et al.,79 amantadine and 9/22 (40.9%) subjects receiving the evidence base relating to amantadine in placebo, yielding a protective efficacy of 78% prophylaxis against influenza was comparatively (p < 0.04) and an RR of 0.22† (95% CI 0.05†–0.91†). old and relatively poor in terms of study quality Severity of illness was also lower in the amantadine- and reporting. The resulting data should therefore dosed group. The authors stated that no adverse be interpreted with caution. events were reported in the group who received amantadine. Owing to low attack rates, evidence of efficacy against SLCI in seasonal prophylaxis was limited. Smorodintsev et al.62 demonstrated the efficacy One study of amantadine used in outbreak control59 of amantadine at the lower dose of 100 mg/day suggested high efficacy against SLCI in a boarding- versus the previously-used dose of 200 mg/day school setting and demonstrated that protection and placebo in the prevention of experimentally- against influenza is not conferred beyond the induced influenza A in healthy medical student prophylactic period. Limited evidence for a lower volunteers. Only data in which the licensed incidence of clinical influenza and milder disease dose of 100 mg/day and placebo are compared of shorter duration was presented.60,61 Some are presented here. A protective efficacy of evidence relating to the efficacy of amantadine in 42% against clinical influenza was reported for preventing experimentally-induced infection and amantadine at 100 mg/day versus placebo (10/19 SLCI was also identified. As such challenge studies in the amantadine arm, 28/31 in the placebo arm; are undertaken under experimental rather than RR 0.58, 95% CI 0.37†–0.91†). This increased to clinical conditions, data drawn from these studies a protective efficacy of 86% against serologically- should be interpreted with caution with respect confirmed influenza (1/19 in the amantadine to external validity and applicability to clinical arm, 12/31 in the placebo arm; RR 0.14,† 95% CI effectiveness, particularly with respect to the nature 0.02†–0.96†). No data were reported on adverse of challenge and the comparability of subjects in effects relating to a comparison of amantadine at terms of pre-challenge antibody titres. However, as the licensed dose with placebo; however, no drug- the evidence concerning amantadine prophylaxis related side effects were reported overall. against naturally-acquired influenza is sparse, it was considered useful to present the findings of the use Adherence to amantadine prophylaxis of the drug in accordance with licensed indications Four trials presented evidence of varying levels against the development of experimentally-induced of adherence to the study protocols. Payler and influenza in healthy adults, in order to supplement Purdham59 stated that only 2% of their subjects the evidence base presented here. Very limited did not take amantadine, while 85% (number interpretation can be made concerning the impact of subjects not reported) of participants in an of vaccination status on the efficacy of amantadine additional trial of outbreak control were reported prophylaxis, although the study reported by Payler as taking amantadine without interruption over and Purdham59 demonstrated that a small number 30 of cases of SLCI developed in both vaccinated and DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

unvaccinated subjects in the amantadine-treated effects or intercurrent illness occurred in 8/520 arm. (1.5%) of the oseltamivir 75 mg/day group and in 10/519 (1.9%) of the placebo group. Upper GI Withdrawals due to adverse events and illness were adverse effects were greater in subjects receiving similar in the amantadine and placebo groups, and oseltamivir 75 mg/day (12.1%) than in those adverse effects were similar in both groups, with receiving placebo (7.1%) (difference 5.0%, 95% CI the exception of the trial reported by Smorodintsev 1.4–8.6). Vomiting occurred in a higher proportion et al.60,61 and the experimental challenge study of subjects receiving the oseltamivir dose (2.5%) by Reuman et al.,57 both of which demonstrated than in those receiving placebo (0.8%) (difference a higher incidence of adverse effects in the 1.7%, 95% CI 0.2–3.3). amantadine-treated subjects. Severe adverse effects also appeared to be higher in the amantadine- In the elderly Peters et al.64 and De Bock et al.65 treated group.57 presented the results from study WV15825, an RCT of oseltamivir in seasonal prophylaxis None of the amantadine prophylaxis trials in a frail, elderly population residing within a included in this review reported the assessment residential care setting (Table 7). Prophylaxis with of sensitivity of influenza isolates to amantadine. oseltamivir at 75 mg once daily for 6 weeks resulted However, as noted in Chapter 1, reports of the in a 92% protective efficacy for SLCI (p = 0.002). increasing emergence of amantadine-resistant When incidence in the vaccinated population influenza A strains31 present a significant challenge only was analysed, a protective efficacy of 91% to the clinical effectiveness of amantadine in against SLCI (p = 0.003) was observed. For all prophylaxis against influenza, and must be taken individuals, receipt of oseltamivir resulted in an into account during the interpretation of the 86% relative reduction in secondary influenza evidence presented in the clinical effectiveness complications [where complications included review. bronchitis (4/272), pneumonia (3/272) and sinusitis (1/272) in the placebo arm and bronchitis (1/276) Oseltamivir in the oseltamivir group] (p = 0.037). In subjects Nine references reporting six original RCTs of with laboratory-confirmed influenza, the relative oseltamivir for the prophylaxis of influenza were reduction in secondary complications was 78% identified. (p = 1.14). Withdrawals due to adverse events or illness occurred at rates of 6.5% (18/276) and Seasonal prophylaxis with oseltamivir 4.0% (11/272) in the oseltamivir and placebo arms In children No evidence that specifically relates to respectively. A similar proportion of subjects in seasonal prophylaxis in children was identified. each group experienced mild to moderate adverse events (around 60%); however, most of these were In healthy adults Two RCTs investigating oseltamivir not considered by the study investigators to be for seasonal prophylaxis were reported by Hayden drug related. Headaches occurred at a higher et al.66 (Table 6). The two trials were identically- frequency in the oseltamivir group than in the designed multicentre studies undertaken in placebo group (8.3% versus 5.5%) and GI adverse healthy, unvaccinated adults aged 18–65 years; the events were also more common among individuals first trial was undertaken in Virginia (WV15673) receiving oseltamivir (14.9% versus 12.9%). and the second at sites in Texas and Kansas City (WV15697). Prophylaxis was administered for 6 Post-exposure prophylaxis with oseltamivir weeks. Oseltamivir administered to subjects at a In mixed households Two RCTs, WV15799 reported dose of 75 mg once daily conferred a protective by Welliver et al.49 and WV16193 reported by efficacy against SLCI of 84% (95% CI 53–96) in Hayden et al.,48,73 and Belshe et al.,74 investigating trial WV15673 and a non-significant protective oseltamivir in the prevention of influenza in efficacy of 50% (95% CI –55 to 94) in trial household contacts of index cases were identified WV15697. The authors reported a pooled estimate (Table 8). for protective efficacy against SLCI of 76% (95% CI 46–91; RR 0.24). When a meta-analysis of the data Welliver et al.49 randomised household contacts reported separately for each trial was undertaken of index cases to receive either 75 mg oseltamivir by the Assessment Group, the RR of developing once daily or placebo for 7 days. Index cases did influenza for oseltamivir versus placebo was 0.27 not receive antiviral treatment in either trial arm. (95% CI 0.09–0.83). Total withdrawals occurred in Children under 12 years of age were excluded as 21/519 (4%) of the placebo and 17/520 (3%) of the contacts, but were eligible as index cases. A minor oseltamivir subjects. Withdrawals due to adverse point is that subjects aged 12 years and above 31

TABLE 6 Oseltamivir for seasonal prophylaxis in healthy, unvaccinated adults: WV15673 and WV15697 (Hayden et al., 199966)

No. in No. in placebo Total no. in oseltamivir Total no. in group with an oseltamivir group with an Outcome Trial placebo group event group event RR (95% CI) SLCI WV15673 268 19 268 3 0.16 (0.04–0.47) SLCI WV15697 251 6 252 3 0.50 (0.06–1.55) Pooled 0.27 (0.09– 0.83) (random effects) (p = 0.21, I2 = 35.4%)

TABLE 7 Oseltamivir for seasonal prophylaxis in at-risk elderly subjects in residential care (80% vaccinated): WV15825 (Peters et al., 200164)

No. in No. in placebo Total no. in oseltamivir Total no. in group with an oseltamivir group with an Outcome Trial placebo group event group event RR (95% CI) SLCI WV15825 272 12 276 1 0.08 (0.01†–0.63†) SLCI WV15825 218 11 222 1 0.09 (0.01†–0.69†) (vaccinated subjects only)

TABLE 8 Oseltamivir for post-exposure prophylaxis in mixed households: WV15799 (Welliver et al., 200149) and WV16193 (Hayden et al., 200448)

No. in oseltamivir Total no. No. in control Total no. in prophylaxis in placebo group with an oseltamivir group with an Outcome Trial group event group event RR (95% CI) SLCI in WV15799 462 34 493 4 0.11 (0.04–0.29) contacts of all WV16193 392 40 400 11 0.27 (0.14–0.53) index cases Pooled 0.19 (0.08–0.45) (random effects) (p = 0.15, I2 = 52.9%) SLCI in WV15799 206 26 209 3 0.11 (0.03, 0.33) contacts of WV16193 258 33 244 10 0.32 (0.16 to 0.65) influenza- positive index Pooled 0.21 (0.08–0.58) cases (random effects) (p = 0.13, I2 = 56.3%) 32 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

received the adult dose of 75 mg once daily, while form of disease. Withdrawals due to adverse events dosing according to body weight is recommended occurred at a rate of 1/410 (0.2%) in the post- in subjects aged less than 13 years. Although exposure prophylaxis arm and 4/402 (1.0%) in individuals with well-controlled co-morbidities the expectant treatment arm. Nausea was more were eligible for participation in the study, common in subjects receiving oseltamivir for post- potential subjects with cancer, immunosuppression exposure once daily than treatment twice daily (8% or chronic renal or liver disease were excluded. versus 7%). However, vomiting was more frequent Prophylaxis resulted in a protective efficacy among in the expectant treatment arm (10% versus 4.5%). individual contacts of all index cases of 89% (95% CI 71–96, p < 0.001). For individual contacts of When the data for SLCI in the mixed adults and influenza-positive index cases only, the protective children populations from the Welliver et al.49 and efficacy was also 89% (95% CI 67–97, p < 0.001). Hayden et al.48 trials were pooled by meta-analysis Withdrawals due to adverse effects or illness using random effects, the resulting RR among occurred in 2/461 (0.4%) in the placebo arm and household contacts of all index cases was 0.19 (95% 5/494 (1.0%) oseltamivir subjects. Gastrointestinal CI 0.08–0.45), equating to a protective efficacy of adverse effects were reported in 7.2% of the 81%. For contacts of influenza-infected index cases placebo and 9.3% of the oseltamivir subjects, only, the corresponding pooled RR was 0.21 (95% while nausea was evident in 2.6% and 5.5% of the CI 0.08–0.58) and the resulting protective efficacy placebo and oseltamivir subjects respectively. No was 79%. A pooled RR for withdrawals generated abnormal results for safety or vital signs and no by the Assessment Group yielded an RR of 0.85 serious adverse events were observed. (95% CI 0.09–7.72), favouring treatment.

A randomised, open-label trial (WV16193) in adults An additional pooled analysis of data from the and children aged 1 year and above undertaken trials by Welliver et al.49 and Hayden et al.48 was by Hayden et al.48,73 and Belshe et al.74 investigated reported by Halloran et al.,45 who presented the use of oseltamivir (75 mg once daily) in post- a pooled estimate of protective efficacy of exposure prophylaxis in household contacts of oseltamivir post-exposure prophylaxis against index cases for 10 days versus expectant treatment, illness of 81% (95% CI 35–94) and an 80% in which oseltamivir (75 mg twice daily) was reduction in infectiousness (95% CI 48–72). The administered for 5 days at the onset of influenza secondary analysis by Halloran et al. also assessed illness in contacts. In both trial arms, index cases pathogenicity of influenza in the treatment and received treatment. Post-exposure prophylaxis with control arms of the household post-exposure oseltamivir for 10 days in individual household prophylaxis trials. Pathogenicity was defined as the contacts resulted in a protective efficacy against ability of the virus to cause disease in an infected SLCI of 73% (95% CI 47–86), including all person. It was calculated as the number of contacts households irrespective of whether the index case with SLCI divided by the number of contacts developed influenza. For individual contacts of with laboratory-confirmed influenza infections influenza-positive index cases, the corresponding (symptomatic or asymptomatic). Pathogenicity was protective efficacy was lower, at 68% (95% CI lower among subjects treated with oseltamivir than 35–84). The proportion of contacts with laboratory- among control subjects. In the study by Welliver et confirmed influenza with at least one secondary al.,49 reported pathogenicity in the control group complication was broadly comparable between was 34/60 (57%) and in the oseltamivir group it was the post-exposure prophylaxis group and subjects 4/33 (12%); these data included contacts, regardless receiving expectant treatment [7% (3/46) versus of whether the index case was influenza positive. 5% (4/75)]; however, the more severe respiratory In the study by Hayden et al.,48 pathogenicity in complications occurred in the expectant treatment the control group was 33/75 (44%) and in the arm only. The median time from start of treatment oseltamivir group it was 10/46 (22%); note that to alleviation of symptoms in contacts was also for this study, data for contacts with an influenza- shorter in the post-exposure prophylaxis arm positive index case only were available for this (n = 10) than in the expectant treatment arm analysis. (n = 33) [5.5 hours (0–87) versus 39.8 hours (0– 627) (p = 0.103)]. Fewer contacts with laboratory- In the trials reported by Hayden et al.48 and confirmed influenza in the post-exposure Welliver et al.49 it was noted that, in some instances, prophylaxis arm were bed bound compared with the strain of influenza with which the contact cases subjects in the expectant treatment group [7% were infected did not match that of the index case, (3/46) versus 28% (21/75)], demonstrating a milder thus indicating that illness was transmitted not 33

TABLE 9 Oseltamivir for post-exposure prophylaxis in paediatric household contacts (1–12 years): WV16193 (Hayden et al., 2004)48

No. in oseltamivir No. in control Total no. in prophylaxis Total no. in group with an oseltamivir group with an Outcome Trial placebo group event group event RR (95% CI) SLCI in WV16193 111 21 104 7 0.36 (0.15– contacts of all 0.84) index cases SLCI in WV16193 74 18 55 6 0.45 (0.18– contacts of 1.13) influenza- positive index cases

from the index case but from a source external to 0.53,† 95% CI 0.05†–5.34†). No serious adverse the household setting. effects were reported. Adverse effects related to study treatment occurred in 1/19 (5.3%) subjects in each group. No treatment-related adverse effects In paediatric household contacts Clinical outcomes were observed during the off-treatment follow-up from the trial by Hayden et al.48 were also reported period. separately for paediatric household contacts aged 1–12 years (Table 9). It should be noted Adherence to oseltamivir prophylaxis that this study allocated doses according to the Adherence to the study regimens was reasonably child’s age banding, rather than body weight, as high. In one study, 7% percent of placebo recommended by the BNF.18 However, subsequent subjects and 11% of those in the oseltamivir arm analysis has shown that the dosages used were were reported as taking less than 80% of study broadly equivalent to those approved.80 For medication.64 In another study, 53% of subjects individual contacts of all index cases, the protective in both oseltamivir and placebo arms took 100% efficacy against SLCI was 64% (RR 0.36, 95% of the prescribed doses, according to returned CI 16–85). When contacts of influenza-infected capsules.66 In the study by Welliver et al.,49 fewer index cases only were included in the analysis, the than 1% of contacts in both placebo and oseltamivir protective efficacy dropped to 55% (RR 0.45, 95% arms did not take the allocated treatment. CI –13 to 82). Vomiting was more common in the expectant treatment group (20% versus 10%). No Viral resistance to oseltamivir children withdrew as a result of adverse events. A number of trials tested viral isolates for resistance to oseltamivir in vitro and found no evidence of Outbreak control No studies describing the use of reduced sensitivity (see below). 48,49,66,67 oseltamivir for control of influenza outbreaks were identified. Discussion The trials included in this systematic review Prophylaxis with oseltamivir against suggest that oseltamivir has a relatively high experimentally-induced influenza protective efficacy against SLCI in healthy A single trial by Hayden et al.67 of oseltamivir adults. The protective efficacy against SLCI was used in accordance with licensed indications notably high among the frail elderly living in in prophylaxis against experimentally-induced residential care, among whom a clear reduction influenza B in healthy adults was identified. in influenza-associated complications was also Influenza B infection was observed at rates of observed. The efficacy against SLCI was broadly 17/19 (89%) in the oseltamivir group and 16/19 equivalent in vaccinated and unvaccinated (84%) in the placebo group (RR 1.06,† 95% CI individuals. The evidence for oseltamivir in post- 0.83†–1.36†). Symptoms of upper respiratory tract exposure prophylaxis in the household setting illness were present in 2/19 (11%) oseltamivir has been reinforced by the publication of an subjects compared with 4/19 (21%) in the placebo additional trial48 since the original assessment.10 arm (RR 0.50,† 95% CI 0.10†–2.41†), while fever Oseltamivir conveys a high protective efficacy was observed in 1/19 (5%) and 2/20 (10%) in the against SLCI in household contacts and any 34 oseltamivir and placebo groups respectively (RR resulting disease appears to be milder and of DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

shorter duration.48 As in the Cochrane review by protective efficacy against SLCI (95% CI 37†–83†). Matheson et al.81 of neuraminidase inhibitors in When the unvaccinated subjects were analysed the prevention of influenza in children, only one as a subgroup, the protective efficacy was 60% RCT trial, WV16193,48 in which data relating (95% CI 24–80). Potential symptoms relating to specifically to children were presented, was drug use were reported by 75% of subjects in both identified. Prophylaxis in paediatric contacts arms. Adverse effects considered by the authors was demonstrated to be reasonably effective. An to be potentially drug related were observed in experimental challenge study also demonstrated 5% (27/554) of the placebo and 5% (30/553) of a lower incidence of illness in subjects receiving the zanamivir group, of which less than 1% in prophylaxis.67 each arm was classed as severe. Total withdrawals occurred in 3% (17/554) and 2% (10/553) of Withdrawals due to adverse events and illness were the placebo and zanamivir arms respectively. similar in both groups in all trials, bar one,64 which Potentially drug-related withdrawals were made demonstrated a slightly higher incidence in frail, in 1.3% of the placebo and 0.7% of the zanamivir elderly subjects receiving oseltamivir. Two studies groups. A conference abstract71 presenting further suggested that GI adverse effects were marginally information on the trial stated that significantly higher among the oseltamivir-treated subjects.49,66 less time was lost from work in the zanamivir group (mean hours lost 1.4 hours versus 0.6 No evidence of reduced sensitivity of viral hours, p = 0.001). Total productive time lost was isolates to oseltamivir was obtained. A number also less in the zanamivir group (1.8 hours versus of publications have postulated that levels of 3.0 hours, p = 0.001). The authors stated that the resistance to neuraminidase inhibitors have trial was undertaken during a season in which the been low.82–84 However, additional reports from predominant circulating influenza A strain did not Japan85 and Europe86 (including the UK) have match the administered vaccine, demonstrating demonstrated the emergence of oseltamivir- efficacy of prophylaxis during a circumstance of resistant strains of influenza A. Recent surveillance strain mismatch. data87 from within the UK have indicated that approximately 5% of influenza A (H1N1) isolates An unpublished report of a randomised, double- were oseltamivir resistant, but the HPA drew no blind, placebo-controlled trial, presented as part conclusions with regard to the clinical significance of the sponsor submissions, described the use of of this finding, stating a requirement for the zanamivir in seasonal prophylaxis in adult health- completion of further research before a judgement care workers (who were presumed to be healthy in could be made. The clinical effectiveness evidence the current assessment).44 No statistical significance for the use of oseltamivir in prophylaxis against between treatment groups in the development influenza should therefore be interpreted in light of SLCI was observed (3/160 versus 6/156 in the of the above reports of emerging resistance. zanamivir and placebo arms respectively in the non-vaccinated set, p = 0.3314). Adverse events Zanamivir occurred at similar rates in the zanamivir (67.7%) Ten published articles presenting the results and placebo (62.2%) arms, of which 1.2% in the from eight RCTs were identified for inclusion zanamivir subjects and 1.3% in the placebo subjects in the systematic review of clinical effectiveness. were considered to be drug related. One serious An additional unpublished report was identified adverse event, which was not judged to be drug in the sponsor submissions and included in the related, occurred in a zanamivir-treated subject. assessment, resulting in a total of nine RCTs. The use of inhaled zanamivir only is considered within In at-risk adolescents and adults Since the original this assessment, hence trial arms in which doses HTA assessment was undertaken,10 a large- of intranasal zanamivir were administered were scale study of zanamivir seasonal prophylaxis in excluded. community-dwelling adolescents and adults aged 12 years and above at risk of complications of Seasonal prophylaxis with zanamivir influenza has been published75 (Table 11). High risk In children No data relating specifically to seasonal was defined as being aged 65 years and above or prophylaxis in children were identified. having chronic pulmonary or cardiovascular disease or diabetes mellitus. For the intention-to-treat In healthy adults Study NAIA3005 reported by (ITT) population assessed for the development Monto et al.70,71 evaluated the use of zanamivir of SLCI during days 1–28 of prophylaxis, a in seasonal prophylaxis in healthy adults (Table protective efficacy of 83% was observed (RR 0.17, 10) aged 18–64 years and demonstrated a 68%† 95% CI 0.07–0.44, p < 0.001). For the per-protocol 35

TABLE 10 Zanamivir for seasonal prophylaxis in healthy adults: NAIA3005 (Monto et al., 199970) and GSK study 167/10144

No. in No. in Total no. placebo Total no. in zanamivir RR (95% CI, in placebo group with an zanamivir group with an p-value if Outcome Trial group event group event available) SLCI NAIA3005 554 34 553 11 0.32 (0.17†– 0.63†) SLCI in NAIA3005 No data No data No data No data 0.40 unvaccinated (0.20–0.76, subjects only p = 0.004) SLCI in GSK study 156 6 160 3 0.49 unvaccinated 167/101 (0.12†–1.92,† subjects only p = 0.3314)

TABLE 11 Zanamivir for seasonal prophylaxis in at-risk adults and adolescents (67–68% vaccinated): NAI30034 (LaForce et al., 200775)

No. in No. in Total no. placebo Total no. in zanamivir RR (95% CI, in placebo group with an zanamivir group with an p-value if Outcome Trial group event group event available) SLCI in all cases NAI30034 1685 23 1678 4 0.17 (0.07– 0.44) SLCI in NAI30034 1141 6 1116 1 0.17 (0.02†– vaccinated 1.41†) subjects SLCI in NAI30034 544 17 562 3 0.17 (0.05†– unvaccinated 0.58†) subjects SLCI in NAI30034 695 17 684 3 0.18 (0.05†– subjects with 0.61†) respiratory disease SLCI in NAI30034 307 1 331 0 Not estimable subjects with cardiovascular disease SLCI in subjects NAI30034 370 3 359 0 Not estimable with diabetes

population, this value dropped to 75% (RR 0.25, (0.71%); below 50 years: zanamivir: 3/402 (0.75%), 95% CI 0.09–0.70, p = 0.014). Protective efficacies placebo: 14/415 (3%).44 Relative risks were also against the development of SLCI during days 2–28 calculable by vaccination status, with RRs of 0.17 and 3–28 of the prophylactic period were 81% (95% CI 0.02†–1.41†) and 0.17 (95% CI 0.05†–0.58†) and 80% respectively. Data were also presented by of developing SLCI in vaccinated and unvaccinated high-risk condition, with RR values calculable for subjects respectively. Confirmed influenza with a number of subgroups: subjects with respiratory complications was observed in 0.06% of zanamivir disease (RR 0.18, 95% CI 0.05†–0.61†), subjects with subjects and in 0.48% of those in the placebo cardiovascular disease (no events in the zanamivir arm, giving an RR of 0.12 (95% CI 0.02–0.73). group) and subjects with diabetes (no events in Zanamivir was well tolerated, with no significant the zanamivir group). When presented according differences in total adverse effects between the to age, the incidence of SLCI was lower in the two groups, with 51% in each group experiencing zanamivir group than the placebo group in subjects adverse effects (placebo: 851/1685, zanamivir: aged both below and above 50 years (50 years and 850/1678). Potentially drug-related adverse events 36 above: zanamivir: 1/1276 (0.08%), placebo: 9/1270 were observed in 9% and 10% of the placebo and DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

zanamivir arms respectively. Drug-related serious al.72 and a report by Monto and colleagues47 that adverse events occurred in 2/1685 of placebo was published subsequent to the cut-off date for subjects (0.12%, cardiac arrhythmia and dyspnoea/ inclusion of evidence in the original HTA review10 cough) and 1/1678 of zanamivir subjects(0.06%, (Table 13). acute resistant asthmatic bronchitis/acute rhinositis). In subjects with respiratory disease any Hayden et al.46 presented evidence from trial adverse event was observed in 59% of each group NAI30010 that zanamivir, when administered (405/684 and 412/695 in the zanamivir and placebo to household contacts (aged 5 years and above) arms respectively).44 Subjects with cardiovascular of index cases with ILI for 10 days, conveyed an disease for whom any adverse event was reported RR of SLCI of 0.18 (95% CI 0.08†–0.39†). For comprised 48% (159/331) and 49% (149/307) of individual contacts of influenza-positive index the zanamivir and placebo arms respectively.44 In cases, the RR was 0.20 (95% CI 0.09†–0.47†). Total diabetic subjects any adverse event was observed adverse events occurred in 50% of the placebo in 62% of the zanamivir group (223/359) and arm and 44% of subjects receiving zanamivir, of 52% of the placebo group (191/370).44 There which 5% and 6% respectively were possibly drug were 39 hospitalisations in the ITT population related. Withdrawals for any reason were made in after the study commenced: 19 in the placebo 5/423 (1.2%) and 3/414 (0.7%) of subjects in the group and 20 in the zanamivir group.44 The mean placebo and zanamivir groups. One withdrawal length of stay across those subjects hospitalised due to adverse effects was made in the zanamivir was 3.8 days in placebo-treated subjects and group while none was made in the placebo group. 3.3 days in zanamivir-treated subjects,44 mean Study medication was discontinued due to adverse values 0.4 days and 0.3 days in the placebo and events in 0.2% of the placebo group and 0.5% of zanamivir groups respectively demonstrating no the zanamivir arm. In contacts with laboratory- significant differences between arms.44 Median confirmed influenza, the median time to alleviation time to alleviation of symptoms was shorter in the of symptoms without use of medication was 8.0 zanamivir group than in the placebo group (2.5 days in the placebo group and 5.5 days in the days versus 4.0 days). zanamivir group. The percentage of cases with complications requiring antibiotics was 8% in In the elderly Trial NAI3003475 also evaluated the placebo arm and 5% in the zanamivir arm. the efficacy of zanamivir in seasonal prophylaxis Index cases in households randomised to receive in subjects aged 65 years and above (Table 12). zanamivir also received zanamivir as treatment, Of these, 13% had respiratory disease, 15% had while index cases in the placebo arm received cardiovascular disease, 9% had diabetes and 10% placebo treatment. had two or three of the above risk factors.44 SLCI was observed in 1/946 and 5/950 of the zanamivir Trials NAIA2009 and NAIB2009, performed by and placebo group subjects respectively, resulting Kaiser et al.72 and reported as a single trial in the in an RR of 0.20 (0.02†–1.72†). The proportion literature, investigated the use of zanamivir for 5 experiencing any adverse events was 53% in each days in household contacts of index cases with ILI. group (498/946 and 501/950 in the zanamivir and Index cases received no treatment. During the 5 placebo arms respectively).44 days of prophylaxis, the RR for developing SLCI was 0.33 (95% CI 0.09†–1.21†) and during the 10 Post-exposure prophylaxis with zanamivir days after initiation of medication, the RR for SLCI In mixed households A total of four trials of the was 0.36 (95% CI 0.12†–1.12†). Length of illness was use of zanamivir in post-exposure prophylaxis in shorter in the zanamivir group than in the placebo households were included in the review. These were group (mean duration of significant influenza-like studies published by Hayden et al.46 and Kaiser et symptoms 0.2 days versus 0.6 days, p = 0.016).

TABLE 12 Zanamivir for seasonal prophylaxis in the elderly: NAI30034 (LaForce et al., 200775)

TABLE 13 Zanamivir for post-exposure prophylaxis in mixed households: NAI30010 (Hayden et al., 200045), NAIA/B2009 (Kaiser et al., 200072) and NAI30031 (Monto et al., 200247)

No. in No. in Total no. placebo Total no. in zanamivir RR (95% CI, in placebo group with an zanamivir group with an p-values if Outcome Trial group event group event available) SLCI in NAI30010 423 40 414 7 0.18 (0.08†– contacts of all 0.39†) index cases NAI30031 630 55 661 12 0.21 (0.11†– 0.38†) NAIA/B2009 144 9 144 3 0.33 (0.09†– 1.21†) Pooled 0.21 (0.13– (random 0.33) effects) (p = 0.72, I2 = 0%) SLCI in NAI30010 215 33 195 6 0.20 (0.09†– contacts of 0.47†) influenza- positive index cases SLCI in NAI30031 398 51 368 9 0.19 (0.10†– contacts of 0.38†) influenza- positive index cases Pooled 0.19 (0.11– (random 0.33) effects) (p = 0.93, I2 = 0%)

Potentially drug-related adverse effects occurred the contact cases and index cases were infected, in 17% (25/144) of the placebo group and 19% demonstrating infection from an additional (27/144) of the zanamivir group, and comprised source of exposure. Significantly fewer households primarily headaches, fatigue, nasal symptoms and randomised to zanamivir prophylaxis reported a throat discomfort. contact developing a complication of laboratory- confirmed influenza (2% versus 6%, p = 0.01). In trial NAI30031, reported by Monto et al., which Adverse events (all of which were consistent with investigated the efficacy of zanamivir administered ILI) occurred in 52% of the placebo group and for 10 days as post-exposure prophylaxis in 42% of the zanamivir group. Adverse events household contacts of index cases with ILI,46 considered by the investigators to be drug related protective efficacy for individual contacts was were observed in 7% of placebo subjects and 6% of 79%† (95% CI 62†–89†; RR 0.21) in the ITT zanamivir subjects. Total withdrawals were made population (when calculated by the Assessment in 1.7% (11/630) of the placebo subjects and 0.9% Group) and 81%† among individual contacts of (6/661) of the zanamivir subjects. No withdrawals influenza-positive index cases (95% CI 62†–90†; were due to adverse events. RR 0.19). Index cases did not receive treatment. For influenza A, the protective efficacy was 79% In contacts with SLCI from the zanamivir-treated (95% CI 55–90; RR 0.21), and for influenza B, group, the median time to alleviation of symptoms the reported protective efficacy was 87% (95% CI (5 days) was reduced by 1.5 days, from 6.5 days 64–95; RR 0.13). However, when calculated by the in the placebo group, demonstrating milder Assessment Group, the protective efficacy against disease.47 This is supported by evidence that influenza B was 79%† (95% CI 46†–92†; RR 0.21). households randomised to zanamivir and with at The authors observed that, in some cases, there least one symptomatic ILI contact case spent less 38 was a mismatch between the strains with which time confined to bed/incapacitated, with nearly a DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

1-day difference in the mean time confined to bed/ pathogenicity of influenza in the treatment and incapacitated per household between treatment control arms of the household post-exposure arms (1.8 days versus 2.6 days, p = 0.053). prophylaxis trials. Pathogenicity was defined as the ability of the virus to cause disease in an Additional data relating to trial NAI30031 were infected person and was calculated as the number identified from the sponsor submissions.43 One of contacts with SLCI divided by the number contact case in the placebo group was hospitalised of contacts with laboratory-confirmed influenza for more than 5 days. Two zanamivir-treated infections (symptomatic or asymptomatic). contact cases were also hospitalised. One contact Pathogenicity was lower among subjects treated case was hospitalised for less than 1 day and with zanamivir than among those in the placebo another for more than 5 days. The numbers were group. In the study reported by Hayden et al.,46 too low to make a meaningful comparison. pathogenicity in the control group was reported as 40/66 (61%) while in the zanamivir group it was The need for non-prescription medications in 7/26 (27%). In the study presented by Monto et households randomised to zanamivir was lower al.47 pathogenicity in the control group was 55/105 in subjects receiving zanamivir versus placebo (52%) and in the zanamivir group this value was (13% zanamivir versus 19% placebo, p = 0.076). 12/48 (25%). Data from both of these studies The number of households requiring prescription included all contacts, whether or not the index case medications was also lower (11% of zanamivir was influenza positive. subjects versus 17% of placebo subjects, p = 0.100). Significantly fewer households receiving zanamivir Outbreak control in the elderly in long-term care Two required additional health-care contacts (20% of trials investigating zanamivir in preventing zanamivir subjects versus 32% of placebo subjects, outbreaks of influenza in the elderly in long-term p = 0.004). Among those households reporting at care settings were included.76–78 least one contact case with symptomatic ILI, the zanamivir group required a mean time off work/ Limited data relating to the prophylactic efficacy school of 10.9 hours per household compared of zanamivir could be drawn from the trial by with 15.1 hours for those in the placebo group Gravenstein et al.78 The study compared zanamivir (p = 0.693). with standard of care (rimantadine for influenza A and placebo for influenza B). As only 25 subjects When data relating to SLCI were pooled by were randomised during two outbreaks of influenza meta-analysis using a random-effects model, B and no subjects developed influenza, the data the combined protective efficacy was 79% [RR relating to influenza B were excluded from further 0.21, 95% CI 0.13–0.33 (test of heterogeneity: analysis in the published report. Potentially drug- p = 0.72, I2 = 0)]. The trial reported by Kaiser et related adverse effects were reported in 38% of al.72 differed from the trials by Hayden et al.46 and placebo subjects and 34% of zanamivir subjects. Monto et al.47 in that all subjects were unvaccinated Withdrawals from the study due to adverse events and prophylaxis was administered for 5 rather occurred at rates of 0/13 in the placebo arm than 10 days. When data abstracted from the and 2/238 (0.8%) in the zanamivir arm. Early study reported by Kaiser et al.72 were removed, medication discontinuation due to adverse events the RR decreased to 0.20 (95% CI 0.12–0.32), was necessary in 0/13 of the placebo subjects and corresponding to a slightly higher protective 11/238 (4.6%) of the zanamivir group. efficacy of 80% (test of heterogeneity: p = 0.77, I2 = 0). The study by Ambrozaitis et al.76,77 differed from that described above in that the elderly, at-risk When data for the incidence of SLCI in contacts subjects living in long-term care had a much of influenza-positive index cases from trials lower proportion of vaccination (Table 14). During NAI3001046 and NAI3003147 were pooled, an RR influenza A outbreaks, prophylaxis conferred a of 0.19 (95% CI 0.11–0.33) was obtained (p = 0.93, 32%† protective efficacy against SLCI as calculated I2 = 0%). by the Assessment Group (95% CI –27† to 67†). The authors noted that all cases of SLCI occurred Halloran et al.45 presented a pooled analysis of in Lithuania (where none of subjects had been data from the trials by Hayden et al.46 and Monto vaccinated). A higher protective efficacy of 70% et al.,47 proposing a prophylactic efficacy against (95% CI 13–89) was observed for laboratory- illness of 75% (95% CI 54–86) and a reduction in confirmed febrile illness. When subjects who infectiousness of 19% (95% CI –160 to 75). The became ill on days 1 or 2 were excluded, the secondary analysis by Halloran et al. also assessed protective efficacy against SLCI as calculated by 39

TABLE 14 Zanamivir in outbreak control in elderly subjects in long-term care: NAIA3004 (Ambrozaitis et al., 2005)76,77 (9–10% vaccinated)

No. in No. in placebo Total no. in zanamivir Total no. in group with an zanamivir group with an Outcome Trial placebo group event group event RR (95% CI) SLCI NAIA3004 249 23 240 15 0.68† (0.36†–1.27†)

the Assessment Group was 35%† (95% CI –40† to study doses over a 23–28 day period.70 In another 70†).44 No differences in SLCI were observed by age study, 90% of zanamivir subjects and 89% of group.44 Complications of SLCI during the first 28 placebo subjects took at least 24 doses for at least days following prophylaxis initiation were observed 24 days, with fewer than 1% requiring assistance in at a lower rate in the zanamivir-treated subjects administering the drug.75 In a further study, 97% than in the placebo group, although this difference of placebo group contacts and 99% of zanamivir was not statistically significant (5% versus 6%, group contacts took 8–10 doses (80–100%) of p = 0.653). Respiratory tract infections occurred study medication.47 Compliance in an additional in fewer subjects in the zanamivir arm (3% versus study was high, with 98% of all participants taking 6%), as did complications requiring antibiotics 8–10 doses of the study drug.46 In the studies (2% versus 3%, p = 0.445). Withdrawals from the by Ambrozaitis et al.76,77 and Gravenstein et al.,78 study due to adverse events were reported as 1/249 undertaken in the elderly, subjects who missed (0.4%)in the placebo arm and 2/240 (0.8%) in the two or more consecutive days of medication were zanamivir arm. Early discontinuation of medication considered non-compliant. These proportions were due to adverse events occurred in 2/249 (0.8%) very low, at 1% of total participants76 and 2% or less and 6/240 (2.5%) of the placebo and zanamivir of total participants.77 subjects respectively. The following additional data were identified in the sponsor submissions.44 Drug- Viral resistance to zanamivir related adverse effects were slightly higher in the Several trials tested viral isolates for their zanamivir-treated arm [16/242 (7%)] than in the susceptibility to zanamivir.46,75,76,77 No evidence of placebo arm [14/252 (6%)]. Serious adverse events resistance to zanamivir was observed, although occurred in 6/252 (2.4%) of placebo subjects and rimantadine-resistant variants were reported by 6/242 (2.5%) of zanamivir subjects. There were no Gravenstein et al.78 serious adverse events that were considered to be related to the study drug. Adverse events during Discussion prophylaxis in high-risk subjects were lower in the Convincing data were obtained for a relatively zanamivir group than in the placebo arm [64/202 high protective efficacy of seasonal prophylaxis (32%) versus 80/215 (37%)]. Subjects with high- in healthy adults. The evidence base has been risk respiratory conditions also experienced fewer strengthened considerably by the publication of adverse events when receiving zanamivir than did a large-scale trial specifically investigating the their placebo counterparts [(30/83 (36%) versus efficacy of zanamivir in seasonal prophylaxis 32/80 (40%)]. in at-risk adolescents and adults, including the elderly. A very high protective efficacy was Prophylaxis with zanamivir against obtained; protective efficacy was also high when experimentally-induced influenza data were presented by age and risk subgroups. No trials in which zanamivir was used in Post-exposure prophylaxis was also shown to be accordance with licensed indications in prophylaxis efficacious in preventing transmission of SLCI against experimentally-induced influenza were in households, with shorter and milder disease, identified. fewer complications and a more rapid return to normal activities among subjects receiving the Adherence to zanamivir prophylaxis intervention. The evidence for outbreak control Adherence in the zanamivir trials appeared to in the elderly in long-term care was more limited, be high, suggesting the use of the Diskhaler for but a relatively low protective efficacy against SLCI topical oral inhalation of drug to be acceptable to was demonstrated, with all cases occurring in study participants. In one study, 95% and 97% of unvaccinated subjects. Adverse events were similar placebo and zanamivir-allocated participants took in both treatment arms and across all studies. 40 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

TABLE 15 Summary of efficacy of interventions in prophylaxis against symptomatic, laboratory-confirmed influenza (SCLI)

Relative risk of developing SCLI (95% CI)

Prophylactic strategy Amantadine Oseltamivir Zanamivir

Seasonal prophylaxis In healthy children Dosage not established in NDA NDA children In at-risk children Dosage not established in NDA NDA children In healthy adults 0.40 (0.08–2.03)56 (from 0.27 (0.09–0.83)66 (pooled 0.32 (0.17–0.63)70 (from one trial) estimate from two trials as one trial) reported by Assessment Group) In at-risk adults and NDA NDA 0.17 (0.07–0.44)75 (from adolescents one trial) In healthy elderly subjects No data reported55 NDA 0.20 (0.02–1.72)75 (from one trial) In at-risk elderly subjects No data reported55 0.08 (0.01–0.63)63 (98% 0.20 (0.02–1.72)75 (from subjects with concomitant one trial) disease; from one trial)

Post-exposure prophylaxis In mixed households NDA 0.19 (0.08–0.45)48,49 (from two 0.21 (0.13–0.33)46,47,72 (from trials) three trials) In healthy children Dosage not established in 0.36 (0.15–0.84)48 (from one NDA children trial) In at-risk children Dosage not established in NDA (subjects with a number of NDA children chronic conditions excluded)47 In healthy adults and 0.10 (0.03–0.34)59 (from NDA NDA adolescents one trial) In at-risk adults and NDA NDA NDA adolescents In healthy elderly subjects NDA NDA NDA In at-risk elderly subjects NDA NDA 0.68 (0.36–1.27)76 (subjects 85% at risk of complications)

NDA, subgroup categories for which no data were available.

Assessment of effectiveness post-exposure prophylaxis in mixed households. Discussion Variation in the measurement and reporting of The relative efficacies of amantadine, oseltamivir adverse events was observed among trials. However, and zanamivir in preventing SLCI are summarised no clear trends for the higher incidence of adverse in Table 15. As in the previous HTA review,10,88 events in treatment groups than in control groups evidence for effectiveness of amantadine in (and vice versa) were observed for amantadine, prophylaxis was limited. However, amantadine oseltamivir or zanamivir or across interventions. was reported to be effective in preventing Interventions appeared to be well tolerated, SLCI in healthy adolescents. The effectiveness with few serious drug-related adverse events of oseltamivir in prophylaxis against SLCI or drug-related withdrawals. Less evidence was was demonstrated in a number of subgroups, available to demonstrate the effectiveness of the particularly in seasonal prophylaxis in at-risk interventions in reducing the impact of influenza elderly subjects and in post-exposure prophylaxis in terms of complications, hospitalisations, length in mixed households. Zanamivir was also shown of illness and time to return to normal activities. to prevent influenza, most notably in seasonal The identified studies suggested that oseltamivir prophylaxis among at-risk adults and adolescents, and zanamivir may be effective in preventing healthy and at-risk elderly individuals and in influenza-associated complications. While there 41

was no significant difference in numbers of subjects shorter time to return to normal activities. No hospitalised between zanamivir and placebo evidence relating to HRQoL or mortality could be groups, limited evidence was presented suggesting identified for inclusion in the clinical effectiveness that individuals receiving zanamivir experienced a review. As stated previously, the findings from the hospital stay of shorter duration. Limited evidence included trials in the clinical effectiveness review suggested that amantadine, oseltamivir and should be considered in conjunction with evidence zanamivir were effective in shortening the length for the development of antiviral resistance by of influenza illness. The severity of symptoms influenza strains, particularly against amantadine, was also reduced in amantadine-treated subjects. and of adverse events associated with amantadine, Additional evidence also suggested that fewer issues which may not be presented within the trials, subjects receiving oseltamivir or zanamivir were but have the potential to have considerable impact incapacitated due to influenza illness, with a on the use of the interventions in clinical practice.

42 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Chapter 4 Assessment of cost-effectiveness

his chapter reports the methods and met the inclusion criteria for the review described Tresults of a systematic review of existing in Chapter 3 (see Inclusion and exclusion criteria, economic evaluations of influenza prophylaxis p. 17). In addition, one sponsor submission was and the development of an independent health received from Roche; this report included the economic model to evaluate the cost-effectiveness details of a mathematical model to assess the cost- of amantadine, oseltamivir and zanamivir for effectiveness of oseltamivir for the prophylaxis of the seasonal prophylaxis and post-exposure influenza. Evidence concerning cost-effectiveness prophylaxis of influenza. The systematic review of was not submitted by the manufacturers of existing economic evaluations is presented below. zanamivir or amantadine. In total, seven economic The methods and results of the Assessment Group evaluations were included in the systematic review. model are presented in Independent economic A summary of studies included or excluded from assessment (p. 61) and Cost-effectiveness results (p. the review of cost-effectiveness is presented in 84) respectively. Figure 4.

Table 16 details the characteristics of the seven Systematic review of existing studies included in the review of cost-effectiveness. cost-effectiveness evidence Review of existing economic Methods evaluation studies The methods used to systematically search Roche submission to NICE electronic databases to identify studies relating to The Roche submission to NICE20 reports the the cost-effectiveness of amantadine, oseltamivir use of a mathematical model to estimate the and zanamivir for the post-exposure prophylaxis cost-effectiveness of oseltamivir for the seasonal and seasonal prophylaxis of influenza are prophylaxis and post-exposure prophylaxis of described in Chapter 3 (see Methods for reviewing influenza. The cost-effectiveness model was effectiveness, p. 17, and Appendix 1). Economic submitted to NICE for scrutiny by the Assessment evaluations identified for inclusion in the review Group. The model presented within Roche’s were also handsearched to identify other relevant submission is based on the simulating anti- cost-effectiveness studies of influenza prophylaxis influenza value and effectiveness (SAVE) model, that were not identified by the electronic searches. and as such the structure and parameter set is Alongside published economic evaluations, similar to the model reported by Sander et al.91 manufacturers’ submissions to NICE, where Twenty variations of the SAVE model were made available, were also included in the review of available to the Assessment Group. The model economic evaluations. Appraisal of study quality compares oseltamivir prophylaxis with amantadine was undertaken based on checklists for assessing prophylaxis, zanamivir prophylaxis and no quality in economic evaluations89 and mathematical prophylaxis in the seasonal and post-exposure models.90 settings for four populations: otherwise healthy adults (including children > 12 years), at-risk Results adults (including children > 12 years), children Studies included in the review aged 1–12 years and children aged 1–5 years. of cost-effectiveness The analysis for children aged 1–5 years includes only usual care as a comparator for oseltamivir The systematic searches identified 580 citations due to restrictions in the licensed indications of of studies relating to the cost-effectiveness of amantadine and zanamivir prophylaxis. It should amantadine, oseltamivir and zanamivir in the also be noted that amantadine is licensed only in prevention of influenza. Titles and abstracts of each children aged 10 years or over; this prophylactic citation were screened for possible inclusion in the option is, however, included in the analysis for review. Of the initial 580 citations identified by the children aged 1–12 years. The base-case analysis searches, full papers of 65 studies were retrieved was undertaken from the perspective of the NHS; for further detailed evaluation. Six of these studies secondary analysis was also reported from the 43

Sponsor submissions Potentially relevant to NICE containing citations identified by economic analysis the systematic searches (n = 1) (n = 580) Non-economic studies excluded at abstract stage (n = 515) Full economic studies retrieved for detailed evaluation (n = 65) Studies excluded from review following full evaluation (n = 59) Published economic evaluation of influenza prophylaxis included (n = 6)

Number of studies included in review of cost-effectiveness (n = 7)

FIGURE 4 Details of study inclusions and exclusions.

societal perspective. The model is reported to use to be unjustified; even if equivalence trials were a lifetime horizon, whereby all important events available, the comparative prophylactic effects occur within a 1-year time horizon with longer- would remain subject to uncertainty and should term adjustments for quality-adjusted life-years therefore be considered within the health economic (QALYs) lost as a result of premature death due to analysis. Importantly, the Roche submission states ILI. Cost-effectiveness is expressed in terms of the that the preventative efficacy estimates have a incremental cost per QALY gained, although this considerable impact on the cost-effectiveness of is based on pairwise comparisons of oseltamivir oseltamivir prophylaxis.20 versus an alternative prophylactic option. In line with current recommendations from NICE,96 health Vaccination is not explicitly considered within the outcomes were discounted at a rate of 3.5%; owing model, either as an option for influenza prevention to the time frame used within the model, costs were or as a characteristic of the patient cohort. The not subjected to discounting. studies used to estimate the preventative efficacy of zanamivir and oseltamivir included some patients The submission states that for oseltamivir versus who had been vaccinated and some patients who amantadine and usual care, a cost-effectiveness had not been vaccinated. analysis was undertaken.20 The model assumes that oseltamivir and zanamivir are equivalent in terms The model uses a deterministic decision tree of preventative efficacy and the submission reports approach which is reported to be appropriate as it a cost minimisation exercise for this comparison. captures a simple ILI pathway and events do not However, the submission does not report the occur more than once.20 The Roche submission results of any head-to-head trials of zanamivir argues that the results are conservative as the and oseltamivir prophylaxis (i.e. superiority, non- benefits of a contact case receiving prophylaxis and inferiority or equivalence trials) which provide subsequently not infecting other individuals are not any evidence to support the assumption of captured (herd immunity effects). The structural equivalence. Furthermore, the systematic review assumptions employed in the model are identical of clinical effectiveness presented in Chapter for seasonal and post-exposure prophylaxis 3 did not identify any clinical evidence which settings. The model is reported to be based on ILI could be considered to validate this assumption. rather than true influenza alone, as it is intended to Consequently, the use of a cost minimisation capture the impact of both true influenza and other analysis for oseltamivir and zanamivir appears ILI on costs and health outcomes. 44 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 91 days)

≈ continued 95 Patriarca et al. , Patriarca 1987 Cost-effectiveness analysis Not reported (direct costs only included in evaluation) (1) No control; (2) vaccination, no chemoprophylaxis; (3) vaccination plus chemoprophylaxis; (4) outbreak control prophylaxis, no vaccination; (5) continuous chemoprophylaxis, no vaccination Post-exposure (outbreak) prophylaxis for 30 days; continuous seasonal prophylaxis for 3 months ( 94 Demicheli et al. , 2000 Cost-effectiveness analysis Ministry of Defence (1) Vaccination; (2) amantadine prophylaxis; (3) NI Seasonal prophylaxis for 62 days 93 Scuffham and 2002 West, Cost-effectiveness analysis Health-care financier (1) No intervention; (2) opportunistic vaccination; (3) comprehensive vaccination; (4) oseltamivir chemoprophylaxis; (5) rimantadine chemoprophylaxis; (6) oseltamivir treatment; (7) rimantadine treatment Seasonal prophylaxis for 4 weeks (28 days) 10 Turner et al. , Turner 2003 Cost-effectiveness analysis and cost– utility analysis NHS (1) No intervention; (2) vaccination, no prophylaxis; (3) no vaccination, amantadine prophylaxis; (4) no vaccination, oseltamivir prophylaxis; (5) no vaccination, zanamivir prophylaxis; (6) vaccination plus amantadine prophylaxis; (7) vaccination plus oseltamivir prophylaxis; (8) vaccination plus zanamivir prophylaxis Seasonal prophylaxis for 6 weeks (42 days) 92 Risebrough et al. , 2005 Cost-effectiveness analysis payer (1) Oseltamivir prophylaxis; (2) amantadine prophylaxis; (3) no prophylaxis Post-exposure prophylaxis; median duration of prophylaxis without ILI reported to be 12 days 91 Sander et al. , 2006 analysis and cost– utility analysis Health-care payer Single government (1) Oseltamivir prophylaxis, no treatment; (2) no prophylaxis, no treatment; (3) no prophylaxis, oseltamivir treatment Post-exposure prophylaxis; duration appears to be 7–10 days 20 Roche submission, Roche 2007 Cost–utility analysis Cost-effectiveness NHS (1) Oseltamivir; (2) Zanamivir; (3) Amantadine; (4) usual care (28–42 days depending on drug) and post-exposure prophylaxis (10 days) Characteristics of studies included in the cost-effectiveness review Type of economic Type analysis Health economic perspective Health economic comparisons of prophylaxisType Seasonal prophylaxis

TABLE 16 TABLE 45

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Assessment of cost-effectiveness 95 Patriarca et al. , Patriarca 1987 Elderly nursing home residents (average) Typical influenza season (including years of potential life lost due to premature death) Incremental cost per illness averted; incremental cost per hospitalisation averted; incremental cost per death averted US dollars ($) Decision tree model Not reported ad 94 consultant for Hoffman–La Roche Demicheli et al. , 2000 One author is an hoc British army effectives Single influenza season per cost Incremental avoided case Pounds sterling (£) Pounds 93 65 years in UK Scuffham and 2002 West, Study funded by grants from Solvay, Chiron, Aventis, Berna and Medeva Elderly patients (age > analysis) (average) Typical influenza season (including years of potential life lost due to premature death) Cost per life-year gained; cost per hospitalisation averted; cost per death averted; cost per morbidity day averted Euro ( € ) consultant 10 for Hoffman–La and has Roche received fees by other influenza prophylaxis sponsor companies Turner et al. , Turner 2003 One author is an ad hoc Healthy adults, children, residential high- care elderly, risk adults Single influenza season; adjustments for loss in lifetime due to QALYs premature death Incremental cost gained; per QALY incremental cost per illness day avoided 92 Risebrough et al. , 2005 Elderly vaccinated patients in long- term care facility 30 days (intended to reflect a single institutional outbreak) Incremental costs (or savings) per ILI case avoided Decision tree model Decision tree model Decision tree model Decision tree model Study funded by Hoffman–La Roche 13 years 91 Sander et al. , 2006 Families with members ≥ Single influenza season; adjustments for loss in lifetime due to QALYs premature death Incremental cost per ILI case avoided; incremental cost per gained QALY model evaluated using Monte Carlo sampling Study funded by Hoffman–La Roche 15 15 years); 20 Roche submission, Roche 2007 Healthy children (1–5 years); at-risk children (1–5 years); healthy children (1–15 years); at- risk children (1–15 years); healthy adults (> at-risk adults (> Single influenza season; adjustments for loss in lifetime due to QALYs premature death Incremental cost gained per QALY (pairwise, i.e. oseltamivir versus comparator) sterling (£)Pounds sterling (£) Pounds Canadian dollars ($) sterling (£) Pounds Manufacturer of oseltamivir (Roche) years) Characteristics of studies included in the cost-effectiveness review (continued) Population Population characteristics Time horizon used in the analysis Health economic outcomes Currency Modelling approach Decision tree model Decision tree conflicts of Potential interest life-year. quality-adjusted ILI, influenza-like illness; NI, neuraminidase inhibitor; QALY,

46 16 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

The structures of the seasonal prophylaxis and across the whole influenza season; this is likely to post-exposure prophylaxis models are simple. be optimistic as patients may become susceptible For the post-exposure model, an individual who to infection after they stop taking prophylaxis (see has been in contact with an ILI index case in Chapter 3). Seasonal prophylaxis using zanamivir a household may visit his or her GP to receive and oseltamivir are assumed to be equivalent prophylaxis or may do nothing. For the seasonal to post-exposure prophylaxis using zanamivir prophylaxis model, the individual may or may and oseltamivir. The relative difference between not have been in contact with an index case when amantadine as post-exposure prophylaxis and as prophylaxis is initiated. The model assumes that seasonal prophylaxis was assumed to be the same one household member can obtain prescriptions as the relative difference for oseltamivir in each for three contacts in the household. Contact cases setting due to a lack of clinical trial evidence. The may or may not go on to develop ILI. Individuals model does not include the possibility of resistance who develop ILI may be treated using oseltamivir to amantadine, oseltamivir or zanamivir. (at-risk populations only) or usual care. Individuals who develop ILI may or may not develop The probability of experiencing specific complications. ILI complications are treated in an complications of ILI were sourced from a study inpatient or outpatient setting depending on the reported by Meier et al.12 It should be noted that severity of the complication. The model includes these complication rates relate to ILI rather than three complications: bronchitis, pneumonia and true influenza alone (despite the claim that the otitis media in children. Patients who develop ILI model operates in terms of ILI, the Roche model complications may survive or may die. actually appears to be based on true influenza attack rates). Complication rates due to influenza The model includes different attack rates for the in children are assumed to be the same for both seasonal prophylaxis models and for the post- the 1–5 years age group and the 1–12 years exposure prophylaxis models; post-exposure age group.20 The incidence of pneumonia and attack rates are assumed to be higher than those bronchitis was sourced from Meier et al.12 However, for the seasonal prophylaxis models as contacts the submission states that the incidence of otitis have by definition had previous exposure to an media is likely to be under-reported by Meier et al. index case who may have influenza (Gavin Lewis, Instead, the Roche model uses estimates sourced Head of Health Economics, Roche, personal from oseltamivir clinical trial data;20 however, this communication). The submission states that the estimate is only slightly higher than the estimate attack rates used in the post-exposure prophylaxis reported by Meier et al. (28% in Meier et al. versus model are intended to represent the proportion 32.4% in the oseltamivir trials). of patients who, after being exposed to ILI, go on to develop ILI.20 However, these are sourced The probability of hospitalisation was taken from from the oseltamivir post-exposure prophylaxis two US studies;98,99 these may not reflect UK trial reported by Hayden et al.48 and represent practice. The model assumes that the probability of only laboratory-confirmed influenza, rather than hospitalisation due to bronchitis is the same as that all ILI. The attack rate for adults in the seasonal for other ILI. The probability of hospitalisation due prophylaxis models was taken from Hayden et al. to specific complications of ILI is assumed to be (assumed to be 4.8%).66 The attack rate for children the same across the model populations. The model in the seasonal prophylaxis models was reported assumes the length of hospital stay to be 4 days for to be in the region of 10%,20 although the basis of influenza and 7 days for pneumonia irrespective this assumption is not reported in the submission. of patient population. The risk of death due to The methods used to derive upper and lower CIs ILI is assumed to be the same as the risk of death around these attack rates are unclear from the due to ILI complications; this assumption is submission. unlikely to be reasonable as ILI complications are known to increase the risk of death. It is likely that The preventative efficacies of oseltamivir and this assumption would overstate the benefits of zanamivir prophylaxis were sourced from a avoiding a case of influenza. meta-analysis reported by Halloran et al.45 The effectiveness of amantadine prophylaxis was The model includes HRQoL adjustments derived from Monto et al., although it should for individuals who develop influenza and be noted that within this study patients received complications of ILI. Utility estimates for amantadine at a dose of 200 mg, which does not patients experiencing an episode of influenza reflect its current licensed indications.97 The model were derived from Likert valuations of patients assumes that seasonal prophylaxis is effective with laboratory-confirmed influenza within the 47

oseltamivir treatment trials. These rating scale by zanamivir in this indication even when wastage data were converted to visual analogue scale is excluded. (VAS) valuations and subsequently converted to time trade-off (TTO) utilities using a similar The model assumes a single cost associated with methodology to Turner et al.10 Utility scores for hospitalisation due to ILI or ILI complications; patients with ILI, bronchitis and pneumonia were this is quoted as £286 per day. This estimate is based on a Dutch person trade-off study reported based on the cost of an inpatient day for mental by Stouthard et al.100 Utility scores are applied for health services; the justification for using this the duration of illness, based on clinical trial data hospitalisation cost is unclear.102 The model does (Gavin Lewis, Head of Health Economics, Roche, not explicitly include the possibility of patients personal communication). In addition, the model requiring intensive therapy unit (ITU) care or includes the number of potential QALYs lost due to mechanical ventilation. A further potential problem premature death resulting from ILI complications. with the SAVE model is that it assumes that all Importantly, the model assumes that each potential patients with ILI will incur GP consultation costs; year of life lost is valued at a state of perfect health; this is not necessarily true as not all patients with this assumption biases in favour of more effective ILI (whether influenza or not) will consult their prophylaxis options. The submission itself notes GP.104 Further, the model does not consider any this assumption as a weakness of the model.20 costs associated with adverse events of prophylaxis or treatment using amantadine, oseltamivir or The model includes costs associated with zanamivir. drug acquisition, GP consultations, diagnostic tests, antibiotics and associated treatments, The submission includes the details of one-way and hospitalisation for the treatment of ILI and probabilistic sensitivity analysis to explore complications. Resource use estimates used uncertainty surrounding model parameters. The in the model were derived from a variety of probabilistic sensitivity analysis was undertaken sources. Estimates of drug prescriptions, tests and using @r i s k software alongside Microsoft e x c e l . investigations performed, primary and secondary care resource use for patients with influenza Cost-effectiveness results presented by Roche and certain complications were derived from It should be noted from the outset that the cost- the National Ambulatory Medical Care Survey effectiveness analysis presented within the Roche (NAMCS);101 this is a US database, and may not submission to NICE was not fully incremental; reflect UK treatment patterns. Assumptions taken instead, 20 incremental cost-effectiveness ratios from this database were validated by Roche through were presented for pairwise comparisons of a structured interview with one clinical expert. oseltamivir versus amantadine, oseltamivir versus Sources for estimates of unit costs included the zanamivir and oseltamivir versus usual care for Personal Social Services Research Unit (PSSRU),102 each population group across seasonal and post- the Monthly Index of Medical Specialties (MIMS) exposure prophylaxis settings. The Assessment database,103 the MEDTAP database and the BNF.14 Group reanalysed the results presented within the Rates of antibiotic use were based on expert Roche submission to generate fully incremental opinion. estimates of the cost-effectiveness of each prophylactic option compared with each other and Importantly, the model does not include the cost usual care. The results of the reanalyses of the post- of drug wastage, and the cost of each prophylaxis exposure models are presented in Tables 17–20. course is calculated on the basis of the mean cost per tablet. The difference between the The results suggest that the incremental cost- cost of oseltamivir with and without wastage is effectiveness of oseltamivir for post-exposure most pronounced in the seasonal prophylaxis prophylaxis is consistently expected to be below indication for adults, these costs being £68.88 £27,000 across all paediatric and adult populations. without wastage and £81.80 when wastage is The finding that zanamivir is consistently included (see Modelling resource use and costs dominated by oseltamivir is unsurprising, as the associated with influenza and other ILI, p. 76). model assumes that oseltamivir and zanamivir have Consequently, the acquisition cost of oseltamivir equivalent preventative efficacy and no differential as seasonal prophylaxis is underestimated in the impact on HRQoL due to adverse events, yet Roche submission. However, given the assumption zanamivir is assumed to be more expensive than of equivalence between oseltamivir and zanamivir, oseltamivir over the course of prophylaxis (the and the lower cost of a seasonal prophylaxis course submission does not include the proposed price 48 using zanamivir, oseltamivir is actually dominated reduction for zanamivir). Uncertainty surrounding DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

TABLE 17 Incremental cost-effectiveness results: post-exposure prophylaxis for children aged 1–5 years

Incremental Option Costs QALYs Incremental cost QALYs ICER Usual care £44.54 109.619 – – – Oseltamivir £73.54 109.624 £29.00 0.005 £5800

ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

TABLE 18 Incremental cost-effectiveness results: post-exposure prophylaxis for children aged 1–12 years

Incremental Option Costs QALYs Incremental cost QALYs ICER Usual care £44.84 108.678 – – – Amantadine £122.75 108.68 Dominated by oseltamivir Oseltamivir £84.74 108.683 £39.90 0.005 £7980 Zanamivir £139.34 108.683 _ _ Dominated by oseltamivir

ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

TABLE 19 Incremental cost-effectiveness results: post-exposure prophylaxis for otherwise healthy individuals over 12 years of age

Incremental Option Costs QALYs Incremental cost QALYs ICER Usual care £12.61 91.336 – – – Amantadine £89.65 91.337 £77.04 0.001 Extendedly dominated Oseltamivir £92.84 91.339 £3.19 0.002 £26,743 Zanamivir £126.35 91.339 – – Dominated by oseltamivir

ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

TABLE 20 Incremental cost-effectiveness results: post-exposure prophylaxis for at-risk individuals over 12 years of age

Incremental Option Costs QALYs Incremental cost QALYs ICER Usual care £13.30 85.119 – – – Amantadine £89.54 85.138 £76.24 0.019 Extendedly dominated Oseltamivir £91.50 85.159 £78.20 0.04 £1955 Zanamivir £123.60 85.159 – – Dominated by oseltamivir

ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year. 49

the relative efficacies of oseltamivir and zanamivir equivalence between these products; this is are not included in the model. The model suggests inappropriate as there is clearly uncertainty that amantadine is dominated or extendedly surrounding the relative efficacies of these drugs. dominated by oseltamivir within each indication. Consequently, the correct interpretation of the probabilistic sensitivity analysis is problematic. The results of the reanalyses of the seasonal prophylaxis models are presented in Tables 21–24. Tables 25 and 26 show the probabilities that oseltamivir has a cost-effectiveness ratio that The reanalysis of the seasonal prophylaxis is better than £20,000 and £30,000 per QALY models presented in Tables 21–24 suggests that gained compared with the next best comparator the incremental cost-effectiveness of oseltamivir identified in the incremental reanalysis of the is expected to be around £46,000 per QALY deterministic cost-effectiveness analysis submitted gained for children aged 1–5 compared with by Roche. These tables have been constructed by best supportive care, and around £116,000 per the Assessment Group from the simulation outputs QALY gained for children aged 1–12 compared used to generate the CEACs within the Roche with amantadine. As noted above, amantadine submission. is licensed only in children aged over 10 years, hence this comparison can be considered valid Tables 25 and 26 suggest that the probability that only for children aged 11 or 12 years. Oseltamivir post-exposure prophylaxis using oseltamivir is is expected to be dominated by zanamivir for optimal at thresholds of £20,000 is in excess of otherwise healthy and at-risk individuals aged 0.90 in the paediatric and at-risk populations (i.e. over 12 years. The Roche models suggest that there is a high probability that oseltamivir produces prophylaxis using amantadine or zanamivir is likely more net benefit than its relevant comparators at a to have a cost-effectiveness ratio below £20,000 per threshold of £20,000 per QALY). The probability QALY gained in the at-risk population aged 12 that oseltamivir post-exposure prophylaxis has a years or older. cost per QALY ratio below £20,000 is around 0.18 for healthy adults; the probability that oseltamivir The Roche submission reported the results of post-exposure prophylaxis has a cost per QALY several one-way sensitivity analyses as well as ratio below £30,000 is around 0.65 in the healthy probabilistic sensitivity analysis for each of the adult group. In the seasonal prophylaxis setting, pairwise cost-effectiveness comparisons. The one- oseltamivir is unlikely to be cost-effective at way sensitivity analysis was undertaken to explore £30,000 per QALY gained in children aged 1–5 the impact of changing assumptions regarding and 1–12 years. Within its adult indications, attack rates, GP visits to receive prophylaxis, oseltamivir was dominated by zanamivir within health utilities for ILI, bronchitis and pneumonia, the deterministic analysis; given the assumption preventative efficacy rates and the number of years of equivalent efficacy between oseltamivir and of life lost. Both the seasonal prophylaxis and zanamivir, one would expect zanamivir to be post-exposure prophylaxis models were reported optimal irrespective of the assumed willingness-to- to be highly sensitive to changes in assumptions pay threshold. regarding attack rates and the number of GP visits required per household. Sander et al. – Post-exposure influenza prophylaxis with In a similar manner to the deterministic health oseltamivir: cost-effectiveness and economic analysis, the results of the probabilistic cost–utility in families in the UK sensitivity analysis were reported using cost- Sander et al.91 present the methods and results effectiveness planes and cost-effectiveness of a cost-effectiveness and cost–utility analysis of acceptability curves (CEACs) only for pairwise oseltamivir as post-exposure prophylaxis from comparisons of oseltamivir versus amantadine and the perspective of the NHS (health-care payer oseltamivir versus usual care. This is inappropriate perspective). The model simulates the experience as all options should be compared incrementally. of 100,000 hypothetical family members aged A fully incremental reanalysis of uncertainty was ≥ 13 who receive oseltamivir prophylaxis or not possible due to the structural limitations of no prophylaxis (with or without treatment for the model (the model was capable of comparing symptomatic ILI). The cost-effectiveness and only two prophylaxis options simultaneously). cost–utility of oseltamivir prophylaxis is estimated In addition, the submission states that pairwise by means of comparison with two alternatives: comparisons were not undertaken for oseltamivir (1) no prophylaxis and no treatment and (2) no 50 versus zanamivir due to the assumption of prophylaxis followed by treatment of ILI using DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

TABLE 21 Incremental cost-effectiveness results: seasonal prophylaxis for children aged 1–5 years

Incremental Option Costs QALYs Incremental cost QALYs ICER Usual care £28.58 109.623 – – – Oseltamivir £168.25 109.626 £139.67 0.003 £46,556.67

ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

TABLE 22 Incremental cost-effectiveness results: seasonal prophylaxis for children aged 1–12 years

Incremental Option Costs QALYs Incremental cost QALYs ICER Usual care £20.72 108.681 – – – Amantadine £95.48 108.683 £74.76 0.002 £37,380 Oseltamivir £214.04 108.684 £118.56 0.001 £118,560 Zanamivir £306.32 108.684 – – Dominated by oseltamivir

ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

TABLE 23 Incremental cost-effectiveness results: seasonal prophylaxis for otherwise healthy individuals over 12 years of age

Incremental Incremental cost QALYs ICER Option Costs QALYs Usual care £8.18 91.337 _ – – Amantadine £87.22 91.338 £79.04 0.001 £79,040 Zanamivir £302.07 91.339 £214.85 0.001 £214,850 Oseltamivir £302.48 91.339 _ – Dominated by zanamivir

ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

TABLE 24 Incremental cost-effectiveness results: seasonal prophylaxis for at-risk individuals over 12 years of age

Incremental QALYs Incremental cost QALYs ICER Option Costs Usual care £8.63 85.134 – _ – Amantadine £86.93 85.146 £78.30 0.012 £6525.00 Zanamivir £300.78 85.16 £213.85 0.014 £15,275.00 Oseltamivir £301.21 85.16 – – Dominated by zanamivir

ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year. 51

TABLE 25 Probability that oseltamivir has a cost-effectiveness ratio better than £20,000 per QALY gained and £30,000 per QALY gained: post-exposure prophylaxis

Probability cost-effective Probability cost-effective at £20,000 per QALY at £30,000 per QALY Population Comparison (non- gained gained dominated) Children aged 1–5 years Usual care 0.91 0.97 Children aged 1–12 years Usual care 0.94 0.99 Otherwise healthy individuals Usual care 0.18 0.65 aged > 12 years At-risk individuals aged > 12 Usual care 1.00 1.00 years

NA, not applicable; QALY, quality-adjusted life-year.

TABLE 26 Probability that oseltamivir has a cost-effectiveness ratio better than £20,000 per QALY gained and £30,000 per QALY gained: seasonal prophylaxis

Probability cost-effective Probability cost-effective at £20,000 per QALY at £30,000 per QALY Comparison (non- gained gained Population dominated) Children aged 1–5 years Usual care 0.07 0.2 Children aged 1–12 years Amantadine 0.01 0.04 Otherwise healthy individuals Dominated by zanamivir in NA NA aged > 12 years the deterministic analysis At-risk individuals aged > 12 Dominated by zanamivir in NA NA years the deterministic analysis

NA, not applicable; QALY, quality-adjusted life-year.

oseltamivir. The model does not include options treatment and eventual death. The model does for sequential prophylaxis and treatment using not include the impact of herd immunity upon antivirals, nor does it include other licensed clinical effectiveness or cost-effectiveness outcomes. prophylactic options such as amantadine or The model includes two types of influenza-related zanamivir. The health economic outcomes used complications: pneumonia and bronchitis. These within the analysis were the incremental cost per are reported to have been included in the model ILI case avoided and the incremental cost per because of their high incidence within the model QALY gained. The analysis uses a time horizon of a population and their definite association with single influenza season; the cost–utility analysis also influenza, and because oseltamivir reduces the risk includes adjustments for QALYs lost as a result of of these complications and other hospitalisation.91 premature death due to secondary complications of The model assumes that patients cannot develop influenza. more than one complication attributable to ILI.

The model uses a decision tree modelling The base-case ILI attack rate in contact cases approach, evaluated using Monte Carlo simulation was assumed to be 8%, based on clinical trials of methods to evaluate first-order uncertainty oseltamivir prophylaxis within households.48,49 surrounding costs and health outcomes for each The GP diagnostic certainty rate (i.e. sensitivity) option. The decision tree model includes chance was assumed to be 70%; however, a reference is nodes describing the uncertainty surrounding not provided for the source of this assumption. the probability of ILI infection, the treatment of The rate of true influenza infection in index ILI (oseltamivir or no antiviral treatment), the cases was taken from clinical trials of oseltamivir onset of complications due to ILI or influenza as prophylaxis.48,49 The model assumes that 52 and subsequent outpatient treatment, inpatient oseltamivir reduces the number of cases when DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

used prophylactically and the duration of disease state that the adverse events observed in clinical when used as treatment. The model also assumes trials of oseltamivir were ‘generally mild, self- that while prophylaxis may reduce the probability limiting and did not result in health-care service of experiencing ILI, and hence the probability utilisation’.91 The impact of adverse events of of secondary complications, it does not affect treatment using oseltamivir, however, is included the clinical course of complications once they in the QALY estimate, which serves to reduce manifest. The probability of avoiding clinically- the number of QALYs gained for the oseltamivir proven influenza using post-exposure prophylaxis treatment group. Resource use data relating to the with oseltamivir was assumed to be 89%, based prevention and treatment of influenza was derived on a clinical trial reported by Welliver et al.49 This from the NAMCS.101 This resource use relates estimate of efficacy is noticeably higher than the to estimates for drug prescriptions, diagnostic efficacy rates demonstrated in the trial reported tests and investigations for ILI, bronchitis and by Hayden et al.48 (62%), which are not used in the pneumonia, and primary and secondary care base-case health economic analysis. admissions for patients with influenza and selected complications. Other resource use items included The model includes HRQoL impacts associated the cost of oseltamivir, GP visits, specialist visits, with the incidence of ILI, bronchitis, pneumonia antibacterials for the treatment of ILI-related and QALY losses due to premature death. The complications, bronchitis, pneumonia, over-the- approach to valuing the number of QALYs lost counter medications and hospitalisation. The use because of premature death from secondary of these resource use data may be problematic, influenza complications is similar to that as US treatment patterns for ILI and secondary reported by Turner et al.,10 but certain underlying complications may not reflect those in the UK. assumptions differ between the models. Patient HRQoL was measured within the clinical trials used A number of sensitivity analyses were undertaken to inform the health economic model using Likert alongside the underlying probabilistic analysis. visual analogue scales for health, sleep and usual These included varying the ILI attack rate for activities (based on studies WV15670, WV15671, contact cases, varying assumptions regarding WV 15730 and M76001). Visual analogue scale health-care resource utilisation and assumptions scores were transformed into TTO index utilities regarding the diagnostic accuracy of GPs in using an algorithm based on econometric work identifying influenza, as well as undertaking undertaken by researchers at the University of the analysis from the societal perspective. The York.104 Time with complications was multiplied sensitivity analysis also considers the impact of by their respective utility scores to estimate QALY a lower efficacy rate of 60%, which reflects the losses. Life-years lost due to premature death results of the oseltamivir post-exposure prophylaxis were calculated using UK life tables, based on clinical trial reported by Hayden et al.48 The an assumed age at death. The analysis assumes simulation model uses Monte Carlo sampling to that premature death due to complications was handle both first- and second-order uncertainty associated with a loss of 34.24 life-years, each of surrounding costs and health outcomes. which is valued at a state equivalent to perfect health (one life-year lost is assumed to equal one Under the base-case assumptions, the model QALY lost). As noted above, this assumption is estimates the incremental cost-effectiveness of also applied in the Roche submission to NICE.20 oseltamivir post-exposure prophylaxis versus This assumption is highly optimistic, and favours no prophylaxis to be £467 per ILI case avoided, the oseltamivir prophylaxis option as this has the while the incremental cost–utility is estimated to greatest efficacy in terms of avoiding influenza be £29,938 per QALY gained. The incremental and related complications. The impact of this cost-effectiveness and cost–utility of oseltamivir assumption on the cost-effectiveness of oseltamivir prophylaxis versus no prophylaxis followed by prophylaxis is not addressed within the sensitivity oseltamivir treatment were estimated to be £451 analysis. The majority of events occurred within per ILI case avoided and £52,202 per QALY 1 year and were not subjected to discounting, gained. The results of the uncertainty analysis which is appropriate. The loss of QALYs due to suggested that reduced prophylactic effectiveness premature death was discounted at a rate of 1.5% for oseltamivir results in considerably less per year. favourable estimates of cost-effectiveness and cost–utility. Assumptions concerning higher attack The cost impact of oseltamivir-related adverse rates and reduced GP utilisation resulted in marked events is not included in the model; the authors 53

improvements in the cost-effectiveness and cost– expected effects of herd immunity. The model does utility of oseltamivir. When the economic analysis not differentiate between specific complications was undertaken from the societal perspective, experienced by individuals developing ILI. The oseltamivir was reported to dominate the no incidence of ILI complications has an impact only prophylaxis options. The probabilistic sensitivity on the cost side of the model; the impact of ILI analysis suggests that the probability that post- and prophylaxis on HRQoL is not included in the exposure prophylaxis using oseltamivir has a economic analysis. cost-effectiveness of better than £30,000 is 50% compared with no prophylaxis and 10% compared The authors assume an ILI attack rate in with oseltamivir treatment. vaccinated residents of 17%. This estimate was reported to have been derived from a number Risebrough et al. – Economic of case–control studies and RCTs. The precise evaluation of oseltamivir phosphate statistical methods used to derive this baseline for post-exposure prophylaxis of attack rate (e.g. statistical meta-analysis) is unclear. influenza in long-term care facilities The model does not include the possibility of Risebrough et al.92 report the methods and results patients receiving antiviral treatment following of a decision-analytic model to evaluate the cost- the onset of ILI. At the time of the analysis, effectiveness of post-exposure prophylaxis versus the authors reported that there were no RCTs no prophylaxis in long-term care facilities. The evaluating oseltamivir or amantadine as post- model includes three treatment options: post- exposure prophylaxis in the nursing home exposure prophylaxis using oseltamivir, post- setting.91 Therefore, the authors assumed that exposure prophylaxis using amantadine and post-exposure prophylaxis using oseltamivir would no prophylaxis. The analysis was undertaken be at least as effective as seasonal prophylaxis from the perspective of the single government using oseltamivir, and that amantadine would payer in Canada. Zanamivir was excluded be at least as effective as rimantadine. Relative from the analysis because of difficulties in drug risk reductions in ILI incidence of 60% and 63% administration experienced by elderly patients. were assumed for amantadine and oseltamivir The primary health economic outcome for the respectively. The authors assumed that prophylaxis analysis was reported to be the incremental cost using either amantadine or oseltamivir would per ILI case avoided compared with usual care result in a 50% relative reduction in antibiotic use, (no prophylaxis); however, the model results are serious complications and death; no evidence is presented only in terms of costs and consequences provided to support the validity of this assumption. which are not synthesised to produce incremental The model includes the possibility of patients cost-effectiveness ratios. All patients are assumed withdrawing from therapy as a result of the to have received prior vaccination for influenza. incidence of adverse events. The model uses a time horizon of 30 days, which is intended to represent the approximate duration of The model includes acquisition costs for one institutional outbreak. amantadine and oseltamivir, serum creatinine tests and oral antibiotics, as well as the cost of The model uses a decision tree structure to evaluate hospitalisation for the management of influenza the costs and health outcomes associated with or other respiratory infections and the cost of each of the three options. The first chance node hospitalisation due to adverse events. A cost relates to whether an outbreak occurs within the is included for death resulting from ILI in an given care facility. Following an outbreak, patients acute hospital. Dose adjustments are included in the prophylaxis arms begin post-exposure in the cost of amantadine. Acquisition costs for prophylaxis for 12 days using either amantadine amantadine were taken from the Ontario Drug or oseltamivir. For patients receiving amantadine, Benefit Formulary, while the cost of oseltamivir the model includes the possibility of developing was based on the manufacturer’s wholesale price. amantadine resistance, while adverse events may Serum creatinine test costs were taken from the be experienced by individuals receiving either Ministry of Health Schedule of Benefits.106 The prophylactic option. The model then includes costs of hospitalisation due to adverse events were the possibility that the individual develops ILI based on authors assumptions. The cost of transfer from which they may experience a complication, to an acute care facility for treatment of influenza recover without complication, or die. If the ILI case complications was based on the average of all is complicated, the patient may be treated in the hospitalisations for influenza or other respiratory care facility or, alternatively, may be transferred procedures per case mix group, derived from the 54 to hospital. The model does not include the Ontario Case Costing Initiative.106 Higher costs DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

were assigned to those complications that have of influenza A and B. This study formed the potentially life-threatening complexity; the same assessment report used to inform the 2003 NICE cost was assumed irrespective of the patient’s appraisal of oseltamivir and amantadine for outcome. Neither costs nor health outcomes were the prevention of influenza.16 The analysis was adjusted for time preferences. undertaken from the perspective of the NHS, although reduced time from work is considered The authors undertook one-way sensitivity analysis within the sensitivity analysis. The model includes and best/worst-case scenario analysis, varying cost eight preventative options: (1) no prophylaxis, and event probability parameter values to identify (2) vaccination, (3) amantadine prophylaxis, (4) the key determinants of cost-effectiveness. The zanamivir prophylaxis, (5) oseltamivir prophylaxis, sensitivity analysis explored the impact of changing (6) vaccination plus amantadine prophylaxis, assumptions concerning the relative efficacy of (7) vaccination plus zanamivir prophylaxis and amantadine and oseltamivir versus placebo, the (8) vaccination plus oseltamivir prophylaxis. All cost of serum creatinine testing, the incidence of antiviral strategies relate to seasonal prophylaxis adverse events, the attack rate for ILI, the outbreak over a period of 6 weeks (42 days). Post-exposure rate and the rate of amantadine resistance. The prophylaxis using amantadine, oseltamivir and sensitivity analysis also explored the impact of zanamivir are not included in the economic model; including the cost of nurse or pharmacist time the model has since been adapted to examine the to review the patient chart and to calculate the cost-effectiveness of post-exposure prophylaxis; creatinine clearance. Finally, the cost-effectiveness however, the results of this work have not been of rimantadine was also explored in the sensitivity released into the public domain.107 The assessment analysis. Probabilistic sensitivity analysis was not report also evaluated the cost-effectiveness of undertaken within this study. treatment options for influenza A and B; however, these options are considered separately from the In the base-case analysis, the study suggests that antiviral prophylaxis options. Cost-effectiveness post-exposure prophylaxis using oseltamivir or is expressed in terms of the incremental cost amantadine is expected to reduce the incidence of per QALY gained and the incremental cost per ILI cases, hospitalisation and death compared with influenza illness day avoided. The model uses a no prophylaxis. Both options are also expected time horizon of a single influenza season, and to produce cost-savings as compared against no includes QALY losses resulting from premature prophylaxis. When compared in terms of the death due to influenza. The model estimates the incremental cost per ILI case avoided, oseltamivir cost-effectiveness of prophylaxis in four discrete is expected to dominate both amantadine and no subgroups: healthy adults, high-risk adults, prophylaxis. The sensitivity analysis suggests that children and residential care elderly. the analysis is sensitive to the amantadine dose calculation. The use of alternative assumptions The model uses a decision tree approach to concerning the attack rate for ILI, the outbreak evaluate the costs and health outcomes for each rate and the rate of amantadine resistance did not prophylactic option. Chance nodes are used to affect the base-case conclusions. The sensitivity describe the probability of a patient developing analysis also suggested that if rimantadine influenza (dependent on the prophylaxis option), were available in Canada, at 32% of the cost of and QALY losses and costs are assigned to each oseltamivir, it would be the least expensive option; branch. Costs and benefits for patients with however, the authors suggest that oseltamivir would influenza are modified for strategies including remain the most effective option. The worst-case vaccination, on the basis that vaccination may scenario for amantadine resulted in improvements reduce the severity of secondary complications. in ILI cases avoided, albeit at a greater cost than no The model includes two complications: pneumonia prophylaxis. In the worst-case scenario, oseltamivir and otitis media (the latter is included only in the remained more effective and less costly compared paediatric model). with the amantadine and no prophylaxis options. The model operates on the basis of true influenza Turner et al. – Systematic review and rather than ILI. As treatments for influenza economic decision modelling for the are evaluated separately from prophylaxis and prevention of influenza A and B vaccination options, the exclusion of ILI may be Turner et al.10 report the methods and results reasonable because costs and benefits in patients of a mathematical decision model to evaluate with ILI which is not true influenza are not the cost-effectiveness of amantadine, zanamivir expected to differ between prophylaxis options and oseltamivir in the prevention and treatment (and would therefore cancel each other out in the 55

cost-effectiveness calculations). Baseline attack profile. Adverse events resulting from the use of rates for true influenza were estimated using oseltamivir and zanamivir were assumed to have random-effects meta-analyses of placebo arm no impact on HRQoL. The valuation of secondary outcomes from relevant trials included in the complications of influenza (pneumonia and otitis systematic review. The preventative efficacy of each media) was based on WHO disability weights for prophylaxis option was estimated by calculating lower respiratory conditions.109 the odds ratio of developing influenza, adjusted for the probability of compliance. The protective The model includes the costs associated with GP benefit of the prophylaxis options was assumed to visits, prophylaxis and vaccination acquisition apply only to the period over which patients are and inpatient hospital stays. The cost of a GP taking prophylaxis. The benefit of prophylaxis in consultation in the surgery or at home was derived vaccinated patients was assumed to be cumulative, from the PSSRU; this cost was weighted by the such that the relative benefit of prophylaxis was frequency of home and surgery visits to generate a applied to the baseline influenza attack rate mean cost per visit for the elderly population and excluding the expected number of cases protected for the healthy adult population. The mean cost by prior vaccination. The probability that an of a GP visit for the paediatric model was assumed individual presents to the GP with influenza was to be the same as for the healthy adult model. based on a UK study of excess ILI consultations The cost of antiviral prophylaxis was based on a over a 10-year period reported by the Royal 6-week course, assuming 50% of the recommended College of General Practitioners (RCGP)5 and the dose. Each drug cost was inflated to account for baseline influenza attack rate derived from the container fees and pharmacy prescribing fees, meta-analysis.10 The probability of presentation although these cost adjustments do not form was estimated by dividing the number of excess part of NICE’s methods guidance.96 The cost of ARI consultations by the expected number of vaccination was taken from payments to GPs for individuals who are expected to develop influenza vaccination and included an administration cost. in each population group. As the number of Hospitalisation costs were based on Health-care patients who present with true influenza is Resource Groups (HRGs); the HRGs assumed for unknown, the numerator for this calculation was hospitalisation differed according to the population based on excess ARI consultations, assuming under consideration. Owing to the short time that all excess consultations are due to influenza. horizon for the analysis, costs were not subjected to This approach, therefore, implies that the rate of discounting. non-influenza ILI consultations is constant over the year, and is likely to represent the maximum Simple uncertainty analysis was undertaken theoretical impact of influenza over a season.5 using one-way and two-way sensitivity analyses surrounding the base-case model specification. The model includes HRQoL impacts associated This included varying assumptions in relation to with the incidence of influenza, adverse events influenza attack rates, the probability of death resulting from the use of amantadine, the and the value of QALY losses due to premature incidence of pneumonia and otitis media, and a death resulting from influenza complications. Joint QALY loss resulting from premature death due uncertainty in model parameters was evaluated to complications. QALY losses due to influenza using probabilistic sensitivity analysis; parameter were derived from VAS scores collected in trials of uncertainty was propagated through the model oseltamivir for the treatment of influenza (studies using Monte Carlo sampling techniques. However, WV15670, WV15671, WV15730, WV15819, results are presented as CIs surrounding the cost- WV15876, WV15978, WV15812 and WV15872). effectiveness ratio; CEACs for prophylaxis are not QALYs were derived by recalibrating Likert score presented in the report. data to VAS scores which were then converted into TTO scores.104 QALY losses due to premature In the base-case analysis, amantadine, oseltamivir death were estimated on the basis of mean age of and zanamivir were dominated by vaccination. The death due to influenza within the model subgroup, combined option of amantadine plus vaccination remaining life expectancy, age-specific utility scores yielded an incremental cost per QALY gained and the discount rate. QALYs lost due to premature of £28,920 compared with vaccination alone in death were discounted at a rate of 1.5% in the base- the residential care population. The incremental case analysis in line with recommendations from cost-effectiveness ratio (ICER) of amantadine for NICE at the time of the assessment. The valuation all other populations was considerably higher, of serious adverse events due to amantadine ranging from £124,854 to £909,210. When adverse 56 was based on an assumed EuroQol-5D (EQ-5D) events were excluded from the model, the results DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

of the probabilistic sensitivity analysis suggested ILI, a percentage of whom will visit their GP for that the probability that amantadine resulted treatment and may receive symptomatic treatment in an incremental cost per QALY gained below or antibiotics for complications of ILI. The model £30,000 was around 45% for the elderly residential includes the possibility that patients who develop care population. However, this is a conservative complications may require hospitalisation and assumption which favours amantadine. For the the possibility that complications may lead to other populations, the probability that amantadine premature death. The model does not include any has an incremental cost per QALY gained below herd immunity effects associated with vaccination £30,000 was less than 1%. For the combined option or prophylaxis. of oseltamivir plus vaccination, the incremental cost per QALY gained for the residential The model includes the cost of hospitalisation population was £64,841 compared with vaccination due to complications including influenza and alone. For all of the remaining populations, the pneumonia, other ARI and congestive heart failure. ICERs were markedly less favourable, ranging The model does not include any valuation of the from £251,004 to £1,693,168. The probabilistic impact of influenza complications upon HRQoL, sensitivity analysis suggested that the probability hence complications appear to be included in the that oseltamivir has an incremental cost per QALY model only in terms of costs avoided. The number gained that is below £30,000 was 3% or less for of premature deaths due to influenza by age group all populations. Zanamivir was also dominated by was taken from a study by Fleming et al.5 Based on vaccination. For the combined option of zanamivir UK hospitalisation data, the authors estimated the plus vaccination, the incremental cost per QALY years of potential life lost for the healthy 80-year- gained for the residential population was £84,682 old population to be 7 years; owing to the likely compared with vaccination alone. The incremental presence of co-morbidities, the authors assumed cost per QALY gained ranged from £324,414 to that premature death due to influenza would result £2,188,039 for the remaining populations. The in a mean loss of 3.5 potential years of life. The uncertainty analysis suggested that the probability authors did not discount costs as almost all relevant that zanamivir has an ICER that is below £30,000 events occur within a single influenza season. The per QALY gained was less than 1%. potential life-years lost due to premature death resulting from secondary influenza complications Scuffham and West – Economic was discounted at a rate of 1.5%. evaluation of strategies for the control and management of influenza in Europe The authors assumed an attack rate for ILI of Scuffham and West93 report the use of a decision 10%. This estimate was sourced from excess GP model to estimate the ICER of six influenza consultation rates, current rates of vaccination and control strategies compared with no intervention expert opinion. Excess GP consultation rates were in elderly populations in England, France and taken from a study based on national data collected Germany. The options included in the model by the Weekly Returns Service (WRS) of the RCGP are opportunistic vaccination, comprehensive and from national data for hospital admissions vaccination, chemoprophylaxis using oseltamivir, and deaths.110 These are modelled independently chemoprophylaxis using rimantadine, treatment of ILI attack rates. The probability of after-hours using oseltamivir and treatment using rimantadine. GP consultations was derived from expert opinion, The costs and health effects of zanamivir and while the percentage of GP home visits was taken amantadine were not included in the model. The from the UK population-based study of incidence, analysis was undertaken from the perspective of the risk factors, complications and drug treatment of health-care financier for each country. The analysis influenza reported by Meier et al.12 The efficacy reports marginal health economic outcomes in of chemoprophylaxis was taken from a review terms of the cost per hospitalisation averted, cost reported by Demicheli et al.94 Based on this review, per death averted, cost per life-year gained and the authors assumed that neuraminidase inhibitors cost per morbidity day averted. The time horizon (NIs), specifically oseltamivir, reduce the incidence used within the model was a typical (average) of influenza by 55%, while ion-channel inhibitors, influenza season. specifically rimantadine, reduce the incidence of influenza by 35%. The authors assumed that when The modelling approach adopted by the authors taken as prophylaxis, these therapies result in was not explicitly stated; however, the text indicates the same proportional reductions as vaccination that a decision tree modelling methodology was in terms of GP consultation, hospitalisation and employed. The model estimates the proportion death. The model does not appear to include of patients who develop clinical symptoms of parameters describing the probability that a patient 57

with ILI has true influenza. However, the estimates the sensitivity analysis based on the latter outcome of the clinical efficacy of prophylaxis relate measure are particularly difficult to interpret in specifically to laboratory-confirmed influenza, not a policy context. The analysis is reported to be ILI. This appears to represent an inconsistency in most sensitive to changes in the timing of the the parameterisation of the model. programme, the price and dose of the prophylactic, and the assumed loss in potential life-years due to The model includes a number of different resource premature death. use items including GP consultations, after-hours visits and home visits, antibiotics, hospitalisations Demicheli et al. – Prevention and early due to influenza and pneumonia, other respiratory treatment of influenza in healthy adults illness and congestive heart failure, vaccination Demicheli and colleagues93 report the use of acquisition and administration costs, and antiviral a model to estimate the cost-effectiveness and prophylaxis and treatment. Unit costs were cost–utility of influenza prevention in healthy derived from the PSSRU,111 national sources of adults from the perspective of the Ministry of hospitalisation data,112 Department of Health Defence (MOD). The health economic analysis was publications on prescription costs113 and national undertaken alongside three ongoing Cochrane tariff estimates.114 The authors assumed that reviews; the results of these reviews led to marked prophylaxis and treatment did not result in any changes in the scope of the proposed economic adverse events. Non-compliance with prophylaxis analysis and the final economic models presented was included in the model at a weekly rate of 5%. in the paper.94 The authors state that potential preventative options to be evaluated within the The authors report the results of a large number of final model were vaccination, oral amantadine, simple sensitivity analyses relevant to each option oral rimantadine and oral oseltamivir. However, for the prevention and/or treatment of influenza. costs and health outcomes are presented for three This included varying assumptions concerning preventative options: vaccination, amantadine the years of potential life lost resulting from prophylaxis and a third option denoted ‘NI premature death due to influenza complications, prophylaxis’. Although the authors justify the the discount rate for health outcomes, ILI attack exclusion of zanamivir from the analysis because rates, excess GP consultations, the number of trials apparently including only laboratory- of excess hospital admissions for influenza confirmed outcomes, the exclusion of rimantadine complications and the number of premature is not justified within the paper, and the NI option deaths due to ILI complications. Specifically with is not directly specified as representing oseltamivir. regard to the prophylaxis options, the sensitivity The primary health economic outcome for the analysis included varying assumptions regarding analysis was the incremental cost per avoided case. GP consultations to receive chemoprophylaxis, The time horizon used within the analysis was not compliance rates, the dosage of oseltamivir, explicitly reported; however, the analysis appears to the percentage of prophylaxis used during relate to a single influenza season (i.e. a 1-year time the 4-week peak of the influenza season and horizon). drug price. Despite the extensive use of simple sensitivity analysis, the authors did not undertake The authors adopted a decision tree approach to probabilistic sensitivity analysis, and the impact evaluate the differences in benefits and costs of the of joint uncertainty in model parameters is not alternative options for the prevention of influenza. captured within the analysis. The authors report that they simplified an initially complicated decision tree model structure to Under the base-case assumptions, the authors include only the possibility of developing influenza report the marginal cost per life-year gained for and the possibility of experiencing adverse events oseltamivir to be €197,919 compared with no due to prophylaxis. The model does not include intervention. The cost per hospitalisation averted the costs and health impacts of complications due for oseltamivir is reported to be €114,774, while to influenza or ILI and, as a consequence, the the cost per death averted is reported to be model does not include the possibility of death. It €657,544. The cost per morbidity day averted, is reasonable to argue that the specification of this excluding and including deaths, is reported to be model is poor, as the results of the analysis ignore €1198 and €373 respectively. The results of the key costs and benefits associated with influenza sensitivity analysis are reported only in terms of prevention. the benefit : cost ratio (ratio of the strategy costs minus the costs of hospitalisation averted) and the The model appears to operate in terms of true 58 cost per morbidity day averted. The findings of influenza cases rather than ILI cases, although this DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

is not entirely clear. Influenza attack rates were model and the limited reporting of the economic derived from influenza sickness rates for 1997 evaluation. obtained from the Defence Analytical Services Agency (DASA). The model assumes an incidence Patriarca et al. – Prevention rate for influenza of 5.7 per 1000; while this value and control of type A influenza appears very low, incidence rates of up to 400 per infections in nursing homes 1000 were explored within the sensitivity analysis. This study95 reports the methods and results of a The model does not include the possibility of a model of the cost-effectiveness of options for the patient with symptomatic influenza presenting prevention of influenza A in the elderly nursing to a health-care professional for treatment. home population. The model includes four options The effectiveness of the amantadine, NIs and for the prevention of influenza A: vaccination vaccination were obtained from three Cochrane without chemoprophylaxis, vaccination with reviews of the clinical effectiveness of vaccination amantadine post-exposure prophylaxis following and prevention of influenza. an outbreak of influenza (30 days’ duration), amantadine post-exposure prophylaxis following The model includes acquisition costs associated an outbreak of influenza (30 days’ duration) with influenza prevention, which were derived from with no prior vaccination, and amantadine as the Defence Medical Supply Agency and authors’ seasonal prophylaxis (3 months’ duration) with assumptions.94 No other cost components appear to no prior vaccination. All options are compared be included in the results of the model. The impact with a strategy of no control. Cost-effectiveness of administration costs on overall cost-effectiveness is expressed in terms of the incremental cost is explored within the sensitivity analysis. A formal per illness averted, the incremental cost per price year is not reported. The authors do not hospitalisation averted and the incremental cost mention the use of discounting, which appears to per death averted. The perspective of the analysis be appropriate given the restrictive scope of the is not explicitly reported; however, the authors state model (i.e. the exclusion of complications and that only direct costs were included in the analysis. death). The time horizon for the analysis is unclear; however, the authors state that they did not include The authors undertook simple sensitivity future medical costs associated with deaths averted. analysis exploring the impact of improved/ worsened preventative efficacy of vaccination and The authors used a decision tree model to evaluate prophylaxis, improved adverse event profiles for the incremental costs and health outcomes for vaccination and antiviral prophylactics, duration each preventative option. Chance nodes are used of prophylaxis and the inclusion of administration to describe the probability that an individual costs for prevention. Probabilistic sensitivity is immune or susceptible to influenza A, the analysis was not undertaken in this study. probability of community exposure, the efficacy of vaccination, the possibility of a nursing home Costs and health outcomes are not reported outbreak and the possibility that an individual in a disaggregated form, and it is difficult to will or will not become ill. Patients who become ill establish whether the results are true incremental experience one of four possible outcomes: infection comparisons between the options, or whether they and survive, infection and die, hospitalisation and are compared marginally against a policy of no survive or hospitalisation and die. The model is prevention. The text appears to indicate the latter reported to include the impact of herd immunity to be the case. Under the base-case assumptions, although the precise methods for including this the marginal cost per case avoided for vaccination, factor are unclear. Respiratory complications only amantadine and NI (presumably oseltamivir) are included in the model. are reported to be £2807, £9458, and £88,193 respectively. The uncertainty analysis suggests that The incidence of disease during the course of under most conditions vaccination is likely to be an outbreak was based on the experience of 41 the most cost-effective option. The key determinant separate vaccine efficacy studies conducted in of cost-effectiveness appears to be the influenza nursing homes during the period 1972–85. The incidence rate, for which higher rates are expected probability of an outbreak was estimated according to result in more favourable cost-effectiveness ratios to the results of a case–control study;115 this for vaccination and prophylaxis. The robustness probability was adjusted for the vaccination and and reliability of the results of this analysis are chemoprophylaxis options to account for herd severely restricted by the limited scope of the immunity effects. The model assumes an overall attack rate of 43% during influenza outbreaks 59

and 16% at other times. The model does not continuous chemoprophylaxis versus vaccination include the possibility of antiviral treatment for alone, and continuous chemoprophylaxis patients who develop ILI. The authors assumed versus vaccination plus chemoprophylaxis. The that 80% of residents who completed the course combination of vaccination and chemoprophylaxis of chemoprophylaxis would be fully protected. during an outbreak was reported to result in The probability of recovery/death with or without demonstrable improvements in outcome at hospitalisation following influenza infection for a modest increase in cost. However, the cost- patients receiving amantadine prophylaxis was effectiveness calculations include only the assumed to be the same as for vaccination. More program costs, and do not account for expected favourable outcomes were assumed for patients cost savings in medical care costs. This omission who received both vaccination and prophylaxis, biases against more effective prevention options. although this was reported to be based on only The authors report that changing assumptions limited clinical evidence. The impact of adverse regarding efficacy and the risk of hospitalisation events is not included in the effectiveness aspect of and death exerted only minor or negligible effects the model. on the clinical and economic outputs of the model. The authors report that varying exposure The model includes costs associated with to influenza led to a proportionate reduction in vaccination, acquisition costs for amantadine the number of cases and a subsequent reduction prophylaxis and costs of diagnostic tests, in the cost-effectiveness of each programme. treatments, ambulance and hospitalisation for Increasing the level of coverage of vaccination and influenza infections and associated complications. chemoprophylaxis led to a progressive decline in Administrative costs were excluded from the morbidity and increases in cost-effectiveness. analysis for the chemoprophylaxis options, but were included for vaccination. The authors state Summary of existing economic evaluations that adverse events associated with amantadine of amantadine, oseltamivir and zanamivir are not associated with excess medical care costs; for the prophylaxis of influenza however, the authors did include the costs of The economic models included in this systematic treating fractures and soft-tissue injuries resulting review cover a broad range of prophylaxis from dizziness or postural hypotension for patients options and settings including seasonal, post- receiving amantadine. Costs of influenza infections exposure and outbreak control prophylaxis and associated complications were sourced using amantadine, oseltamivir and zanamivir. from 1986 prospective payment schedules for The relevant populations examined within the appropriate diagnosis-related groups and other economic analyses include children, elderly, at- sources. Physician charges were based on Medicare risk adults and healthy adults with or without Part B payments. The authors do not make any prior vaccination. However, the majority of studies reference to the use of discounting within the included in the review do not include all relevant analysis. prophylaxis options for the prevention of influenza (i.e. amantadine, oseltamivir and zanamivir). One-way and multiway sensitivity analyses were The Roche submission20 and the study reported undertaken surrounding the efficacy of influenza by Turner et al.10 adopted the broadest scope in vaccination, the efficacy of chemoprophylaxis, terms of prophylaxis options and populations. and assumptions concerning risk reductions in Included studies consistently adopted a short time hospitalisation and death for patients receiving horizon (a typical influenza season); however, most prophylaxis. The authors also undertook a also accounted for long-term survival or quality- threshold analysis to determine how much adjusted survival losses resulting from death due to amantadine and vaccination would have to cost secondary complications of influenza. Only three before these options would no longer result in studies10,20,91 presented health economic results in savings in direct medical costs. Finally, the authors terms of the incremental cost per QALY gained. explored the impact on cost-effectiveness of changing the exposure rate to influenza viruses. The majority of the models included in the review Probabilistic sensitivity analysis was not undertaken. appear to operate on the basis of ILI rather than true influenza alone. However, one study93 appears The option of outbreak prophylaxis was excluded inappropriately to apply relative reductions from the analysis as it was the least effective and of true laboratory-confirmed influenza to the most expensive programme.95 Marginal cost- baseline ILI attack rate. The models include a effectiveness ratios are presented for vaccination range of secondary complications affecting costs 60 plus chemoprophylaxis versus vaccination alone, and consequences; these include pneumonia, DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

BOX 1 Key limitations of previous economic models of influenza bronchitis, other ARI and congestive heart failure prophylaxis in adult populations and otitis media in children. One study did not specify which complications were 92 1. Failure to include all relevant prophylaxis options in the included in the economic model, yet costs and evaluation consequences of managing these complications were included in the economic analysis. One study 2. Failure to model secondary complications and death did not include the costs and health consequences 3. Failure to account for the impact of disease and resulting from secondary complications, nor did it prevention on health-related quality of life include the possibility of premature death due to 4. Use of unrealistically favourable assumptions regarding influenza.94 the value of avoiding death due to secondary complications (i.e. one life-year lost is equal to one The review highlights a paucity of good quality QALY lost) evidence relating to many aspects of the decision 5. Application of laboratory-confirmed influenza problem. In particular, many of the models preventative efficacy estimates to reduction in ILI are underpinned by assumptions concerning baseline attack rate fundamental parameters such as the underlying 6. Failure to incorporate all relevant cost components into ILI or influenza attack rate, the probability that cost-effectiveness estimates an individual with influenza presents to his or her 7. Use of US resource use data which may not reflect UK GP and assumptions regarding the treatment of treatment patterns for the management of secondary secondary influenza-related complications, each of complications of influenza which has the propensity to considerably influence 8. Failure to undertake incremental cost-effectiveness the resulting cost-effectiveness estimates. A key analysis (including uncertainty analysis) problem concerns the absence of robust estimates 9. Failure to account for joint uncertainty in model of the effectiveness of prophylaxis in the specific parameters using probabilistic sensitivity analysis. population under consideration, and the need to make assumptions of equivalence for prophylaxis across different population subgroups. In instances prophylaxis (see Chapter 3) and updated estimates where the impact of influenza on HRQoL has been of cost and health outcomes associated with incorporated into the analysis, this has been drawn influenza and other ILI-related complications. consistently from Likert scale data, from clinical trials of oseltamivir which are then mapped onto Model scope health utilities or from indirect utility estimates. Interventions and comparators None of these data are ideal. The limitations of the The model evaluates the incremental costs and existing economic models included in the review health outcomes of seasonal prophylaxis and studies are summarised in Box 1. post-exposure prophylaxis of influenza using amantadine, oseltamivir and zanamivir in comparison with each other and no prophylaxis. Independent economic assessment Model population Cost-effectiveness estimates for influenza Cost-effectiveness prophylaxis using oseltamivir, amantadine and modelling methods zanamivir are presented for six discrete subgroups: This section details the methods employed in children aged 1–14 years (with at-risk medical the development of the independent Assessment condition or otherwise healthy), adults aged 15–64 Group model to assess the cost-effectiveness years (with at-risk medical condition or otherwise and cost–utility of influenza prophylaxis using healthy) and elderly adults aged over 65 years (with amantadine, oseltamivir and zanamivir. The model at-risk medical condition or otherwise healthy). structure and many of the parameter values draw In addition, the analysis considers the impact upon the modelling work undertaken by Turner of prophylaxis for individuals who have been et al.10 in the previous assessment of oseltamivir, vaccinated against influenza and for individuals amantadine and zanamivir for the seasonal who have not been previously vaccinated. Although prophylaxis of influenza. Key differences between the model structure is identical for all subgroups, these models include the incorporation of NICE the analyses differ in terms of influenza attack guidance on the use of NIs for the treatment of rates, prophylaxis dose, prophylactic efficacy and symptomatic influenza-like illness,116 the inclusion prognosis following influenza onset. of post-exposure prophylaxis options, an updated systematic review of the effectiveness of influenza 61

Health economic outcomes group of ILI including influenza.12 Costs and The primary health economic outcome used in the health outcomes are estimated for three groups economic model is the incremental cost per QALY of patients: (1) individuals who develop true gained. This is calculated for all non-dominated influenza; (2) individuals who develop other ILI prophylactic options compared with the next which is not influenza; and (3) individuals who do most effective option. Options that are dominated not develop influenza or ILI. The prophylactic (simple or extended) are ruled out of the analysis. options evaluated within the model are effective only against the influenza virus, thus effective Time horizon and time preferences protection against influenza is assumed to reduce The model assumes that all events of interest the probability of developing true influenza but will occur within a single influenza season; hence, the have no impact on other ILI. time horizon is effectively 1 year in duration. As such, costs and health outcomes arising within this A simplified description of the model structure is period are not subjected to discounting. However, presented in Figure 5. Patients may receive seasonal as secondary complications of influenza and other or post-exposure prophylaxis using amantadine, ILI may result in premature death, the model also oseltamivir or zanamivir, or no prophylaxis. accounts for potential years of life lost beyond The probability that a contact case will develop this time horizon; these are adjusted to account influenza is dependent on the influenza attack for the expected level of quality of life. Quality rate, the prophylactic efficacy of the strategy adjusted life-years lost because of premature death under consideration over the period in which the resulting from the incidence of influenza-related patient is taking prophylaxis, the probability that complications are discounted at a rate of 3.5%, in the influenza is influenza A (amantadine only), line with current recommendations from NICE.96 A the degree of resistance to the prophylactic drug summary of the scope of the economic comparisons (amantadine only), and whether the patient has is presented in Table 27 (note that the duration of been previously vaccinated. In terms of post- prophylaxis is assumed to be in line with licensed exposure prophylaxis, the model assumes that indications). the patients are prescribed prophylaxis within 48 hours of exposure to an infected index case, in Model structure line with licensed indications. Patients receiving The model uses a decision-analytic (decision tree) vaccination and/or prophylaxis (amantadine only) approach to estimate the incremental costs and may experience adverse events which may detract health outcomes associated with each influenza from the their HRQoL and may incur additional prophylaxis strategy compared with each other medical treatment costs. If patients do not and no prophylaxis. The model operates on develop ILI, no further costs or health outcomes the basis of ILI which includes true influenza as are considered for these patients in the model. well as other illnesses that are clinically similar If a patient does develop influenza or other ILI, to influenza, e.g. respiratory syncytial virus he or she may seek medical treatment in either (RSV). The costs and health outcomes of other primary care (i.e. GP consultation) or secondary ILI are included in the model as these are often care [i.e. presenting at an accident and emergency indistinguishable from true influenza and may (A&E) department]. If the patient presents with result in additional health-care management symptomatic ILI, he or she may be considered costs as well as QALY losses. Furthermore, much appropriate for treatment using oseltamivir or of the literature relating to the consequences of zanamivir (if the patient presents within 48 hours influenza infection is actually based on the broader of developing ILI symptoms and is considered to

TABLE 27 Description of prophylaxis options included in the health economic model of post-exposure prophylaxis

Duration of prophylaxis Duration of prophylaxis Prevention strategy (seasonal) (post-exposure) Dosage per day Amantadine 42 days (21 days for patients 10 days 100 mg who have previously been vaccinated) Oseltamivira 42 days 10 days 75 mg Zanamivir 28 days 10 days 10mg

a Oseltamivir dosage for children: < 15 kg: 30 mg, 15–23 kg: 45 mg, 23–40 kg: 60 mg, > 40 kg: 75 mg14 62 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Survive Complication NI treatment Die No complication Patient presentation Survive Complication No NI treatment Die Develop ILI No complication Survive Complication Prophylaxis No presentation Die No complication No ILI Survive Complication NI treatment Die No complication Patient presentation Survive Complication No NI treatment Die Develop ILI No complication Survive Complication No prophylaxis No presentation Die No complication No ILI

FIGURE 5 Simplified decision-analytic model structure. be at risk of developing secondary complications of for individuals with severe complications of ILI. influenza).116 Quality-adjusted life-year losses are included for individuals who develop uncomplicated ILI, A proportion of patients who develop ILI are adverse events of prophylaxis (amantadine only), expected to develop secondary complications, complications of ILI and premature death due to including respiratory complications such as ILI complications. bronchitis, pneumonia or otitis media, or an exacerbation of an existing underlying condition Key model assumptions (including cardiac, renal and CNS complications).12 • Other ILI which is not influenza may also If a patient develops an ILI complication, he result in complications (including RSV and or she is assumed to seek medical attention for Mycoplasma pneumoniae). It should be noted treatment. The model assumes that antibiotics may that the complications arising from influenza be prescribed for the treatment of uncomplicated may differ in reality from those for other ILI ILI cases as well as for the treatment of ILI- such as RSV (this is a limitation in the use of related complications.12 A proportion of patients the data from Meier et al.;12 see Parameters who develop complications of ILI are assumed relating to the onset of influenza and other ILI, to require hospitalisation. The model assumes below). However, since the costs and effects that a proportion of complications will result in associated with other ILI are the same for each premature death. prophylaxis group, these do not affect the resulting estimates of cost-effectiveness. The decision model includes the administration • Prophylaxis using amantadine, oseltamivir and acquisition costs of influenza vaccination and and zanamivir are effective only against true prophylaxis, the costs of treatment of symptomatic influenza. ILI using NIs in at-risk groups, the costs of • Antiviral prophylaxis is effective in preventing consultation in primary and secondary care, the influenza only for the period over which costs of managing secondary complications of the patient is taking the drug. For seasonal influenza and ILI and the costs of hospitalisation prophylaxis, the model assumes that a 63

patient may be protected over a proportion • Patients who experience adverse events due to of the whole influenza season. However, it prophylaxis are likely to consult their GP for should be noted that monitoring of influenza advice. activity takes place at a national level and the • Adverse events due to oseltamivir and duration for which activity exceeds the national zanamivir are mild, self-limiting and have no threshold may not reflect influenza activity impact on a patient’s HRQoL. Adverse events at the local level. The importance of this due to amantadine prophylaxis may be more assumption is tested in the sensitivity analysis severe and may result in a reduction in the (see One-way/multiway sensitivity analysis patient’s quality of life. and scenario analysis, p. 90). For the sake of • Antiviral treatment of symptomatic simplicity, the model assumes that the risk influenza and ILI using zanamivir and of infection is constant for the period when oseltamivir is given in line with current NICE influenza is circulating; this is in line with the recommendations.116 The choice of NI for the previous models, reviewed in Systematic review treatment of symptomatic ILI is assumed to of existing cost-effectiveness evidence (p. 43). be independent of the prophylactic strategy • The joint benefit of vaccination followed by under consideration. Antiviral treatment is prophylaxis is assumed to be cumulative (the assumed to incur an additional cost in patients effectiveness of prophylaxis is applied to who have previously received prophylaxis. any remaining influenza cases which are not For example, if a patient is prescribed effectively protected by vaccination). oseltamivir prophylaxis, subsequently develops • The model assumes that amantadine, symptomatic ILI and is given oseltamivir oseltamivir and zanamivir would be used as treatment, a separate prescription of the drug prophylaxis when influenza is known to be is required. circulating in the community (the threshold is • All patients who develop complications due to currently set at 30 new ILI GP consultations influenza and other ILI present to a health- per 100,000 population).8 care professional for treatment. • The model assumes that the prescription • Patients who develop either uncomplicated or of seasonal prophylaxis and post-exposure complicated ILI may be prescribed antibiotics. prophylaxis of influenza requires a consultation • Patients who stop taking prophylaxis are with a GP. The possibility of multiple courses assumed to do so at the beginning of the of antiviral prophylaxis being prescribed to course and hence do not gain any additional an index case on behalf of other household protection over patients who do not receive contacts is explored in the sensitivity analysis. prophylaxis (the impact of assumptions The model assumes that prophylaxis is not regarding withdrawal rates are explored in given at the same time as influenza vaccination, the sensitivity analysis – see One-way/multiway hence a second visit is required. sensitivity analysis and scenario analysis, p. 90). • If an individual develops a secondary • The costs of diagnostic tests (blood tests, complication of ILI (whether or not this is due sputum tests, chest X-ray) for patients to influenza), the course of the complication presenting with respiratory complications are is unaffected by the prior use of prophylaxis. assumed to be included in the unit costs of GP Treatment of symptomatic influenza using consultation and A&E consultation. oseltamivir or zanamivir is assumed to reduce • Owing to limitations in the evidence base, the the incidence of complications in at-risk model assumes that only complicated ILI cases patients. If a patient has already developed a may result in hospitalisation and death. These complication while receiving prophylaxis, it is assumptions are explored in the sensitivity unlikely that antiviral treatment will provide analysis (see One-way/multiway sensitivity any additional benefit. Given the simple analysis and scenario analysis, p. 90). structure of the model, the analysis assumes • The model includes only those health benefits that patients who receive antiviral prophylaxis accrued by patients receiving influenza and subsequent treatment for symptomatic ILI prophylaxis; potential benefits accrued through develop complications after being prescribed decreased transmission of influenza as a result treatment. This assumption is likely to of the use of prophylaxis are not considered in favour prophylaxis as it increases the costs of the health economic model. treating symptomatic influenza. Assumptions • A proportion of influenza cases are assumed surrounding the use of antiviral treatment to be resistant to amantadine. Although there following prophylaxis are explored in the is some evidence of resistance for the NIs, 64 sensitivity analysis. these rates are low and are excluded from the DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

base-case analysis. The impact of resistance to the paediatric population. For the working-age oseltamivir is considered within the sensitivity adult and elderly populations, the attack rate was analysis (see One-way/multiway sensitivity taken from a pooled analysis of placebo group analysis and scenario analysis, p. 90). attack rates reported in five trials of post-exposure prophylaxis.46–49,72 It should be noted that patient- Model parameters level data were not available, hence these attack rates relate to populations that are mixed in terms Lists of all model parameters for the seasonal of subject age. Beta distributions were used to prophylaxis and post-exposure prophylaxis models characterise the uncertainty surrounding these by subgroup are presented in Appendix 7. attack rates. The attack rates are presented in Table 28. Event probabilities Baseline influenza attack rate Probability that an ILI is influenza The baseline influenza attack rate describes the The probability of developing ILI during the probability that an individual will develop influenza influenza season was not available from the over the influenza season. The model assumes literature. Instead, the model uses data provided that the probability of developing influenza differs by the RCGP concerning the probability that a among children, adults and elderly individuals. case of ILI is true influenza. Within the health Different attack rates are also assumed between economic model, this probability is divided by the the seasonal and post-exposure prophylaxis true influenza attack rate to provide an estimate models, as probability of influenza infection is of the broader ILI attack rate in each subgroup likely to be higher in an individual who has been (accounting for true influenza and other ILIs). in frequent close contact with an index case with Data relating to the probability that ILI is influenza symptomatic ILI in the household. In terms of was based on an analysis of swabs taken from seasonal prophylaxis, the clinical trials included individuals with symptomatic ILI collected during in this review do not represent a good basis for routine surveillance over the influenza seasons estimating the probability of developing influenza 2003–4 to 2006–7 (Dr Alex Elliott, RCGP, personal as they include different levels of exposure to communication). These data relate to those weeks influenza vaccination across each subgroup; one when influenza was known to be circulating in the would expect that this would result in lower attack community, as defined by the 30/100,000 ILI GP rates than in the unvaccinated population. For the consultation threshold;8 they are shown in Table 29. seasonal prophylaxis model, influenza attack rates were derived from a large meta-analysis of placebo arm groups of clinical trials of influenza vaccination Table 29 suggests that one would expect fewer versus no influenza vaccination reported by Turner influenza cases among the ILI cases when the et al.10 The model uses the actual patient numbers consultation rate falls to baseline levels. The presented in the summary of each meta-analysis to model assumes that the probability that ILI is true estimate the mean and distribution of the attack influenza is 0.50 across all subgroups (622/1256). rate. Beta distributions were used to describe the Uncertainty surrounding this parameter was uncertainty surrounding these parameters. modelled using a beta distribution.

This source does not, however, provide a useful Probability that influenza is influenza A basis for estimating attack rates for the post- The probability that a case of influenza is influenza exposure prophylaxis models, as individuals A is based on virological surveillance data provided eligible for post-exposure prophylaxis have, by by the HPA (Dr Piers Mook, HPA, personal definition, been exposed to an index case with communication). These data relate to 12 influenza symptomatic influenza or ILI. Consequently, one seasons from 1995–6 to 2006–7; they are shown in would expect the attack rate for these individuals Table 30. to be higher than the attack rate in an individual who has not been exposed to an index case. Attack The probability that influenza A is the dominant rates for the post-exposure prophylaxis options influenza strain during a given influenza season were sourced from the trials of post-exposure was calculated from the data shown in Table 30; this prophylaxis included in the systematic review (see gives a probability of 0.75 (influenza B is assumed Chapter 3). For the paediatric subgroup the attack to be dominant during the 2002–3 season). The rate was taken directly from the subgroup analysis probability that a case of influenza is influenza A reported by Hayden et al.,48 as this was the only was then modelled separately for those years where study which presented a subgroup analysis for influenza A is dominant and those where influenza 65

TABLE 28 Attack rates assumed within the model

Number of patients Number of patients Type of prophylaxis Age group with influenza at risk Attack rate Seasonal Children (0–15 years) 256 1469 0.174 Seasonal Adults (16–64 years) 104 1670 0.062 Seasonal Elderly (65+ years) 57 1098 0.052 Post-exposure Children (0–15 years) 21 111 0.189 Post-exposure Adults (16–64 years) 18 2051 0.088 Post-exposure Elderly (65+ years) 18 2051 0.088

TABLE 29 Influenza and influenza-like illness consultations when ILI consultations are above 30 per 100,000 population threshold

ILI consultation Number of Number Number Season Week rate swabs influenza A influenza B Total 2003–4 44 36.42 7 1 – 1 45 47.24 73 35 – 35 46 61.79 120 60 – 60 47 54.69 58 36 – 36 48 52.79 43 20 – 20 49 57.86 78 31 – 31 50 36.96 53 18 – 18 51 41.20 25 9 – 9 52 33.03 23 4 – 4 2004–5 1 38.91 15 5 – 5 2 34.89 27 13 – 13 3 33.26 16 4 – 4 4 30.45 29 14 1 15 5 34.26 27 15 2 17 6 32.28 31 14 1 15 2005–6 5 36.90 81 10 42 52 6 41.60 89 8 43 51 7 42.21 63 10 19 29 2006–7 6 37.64 120 69 1 70 7 43.85 153 82 – 82 8 38.17 125 55 – 55 All weeks/years 1256 513 109 622

B is dominant. For years in which influenza A is to characterise the uncertainty surrounding the dominant, the probability that an influenza case probability that influenza A is dominant and the is influenza A was estimated to be 0.86 (740/859). probability that an influenza case is influenza A For years in which influenza B is dominant, the given the dominant influenza strain during a given probability that an influenza case is influenza A was influenza season. These data are used to modify the estimated to be 0.30 (83/281). The overall mean effectiveness of amantadine which is effective only probability that a case of influenza is influenza A is against influenza A. estimated to be 0.72. Beta distributions were used

66 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

TABLE 30 Surveillance data relating to the probability that an influenza case is influenza A

Season Influenza A positive Influenza B positive Total number of swabs 2006–7 168 2 170 2005–6 28 85 113 2004–5 76 29 105 2003–4 124 0 124 2002–3 20 20 40 2001–2 39 1 40 2000–1 35 93 128 1999–2000 77 0 77 1998–9 49 17 66 1997–8 58 1 59 1996–7 74 69 143 1995–6 75 0 75

Duration of the influenza season Modelling the preventative The model assumes that individuals who are efficacy of vaccination effectively protected against influenza by The preventative efficacy of influenza vaccination vaccination are protected over the entire influenza for children, adults and the elderly was derived season. Individuals receiving influenza prophylaxis from meta-analyses of RCTs presented within are assumed to be protected over the period for three recent Cochrane reviews of influenza which they are taking the drug. Assuming the vaccination.117–119 The model assumes that influenza antivirals are prescribed when influenza is known vaccination and prophylaxis are effective against to be circulating, the preventative efficacies of true influenza but not ILI and that inactive the antivirals were adjusted according to the parenteral vaccines represent the mainstay of proportion of the influenza season for which the vaccination use in England and Wales. individual is taking the drug. Data relating to the duration of the influenza season (when the number The Cochrane reviews report the RR of of new GP ILI consultations is in excess of 30 per experiencing influenza for vaccination versus 100,000 population at the current threshold or 50 placebo to be 0.36 (95% CI 0.28–0.48) in healthy per 100,000 population at the previous threshold)8 children, 0.35 (95% CI 0.25–0.49) in healthy for influenza seasons 1987–8 to 2006–7 were made adults and 0.42 (95% CI 0.27–0.66) in elderly available to the assessment team by the RCGP (Dr populations. These preventative efficacy rates Alex Elliot, RCGP, personal communication). These are assumed to be the same for otherwise healthy data are shown in Table 31. and at-risk groups within each age band. The propagation of these RRs leads to a proportionate Based on the previously higher influenza threshold reduction in the probability of experiencing of 50 per 100,000 population, the mean duration secondary ILI complications and death within of the influenza season was estimated to be 10.77 vaccinated patients. It should be noted that the weeks. Using the current threshold of 30 new GP health economic analysis reported by Turner et consultations per 100,000 population, the mean al.10 assumed that influenza vaccination also had duration was estimated to be 5.71 weeks. Data an impact in terms of reducing the probability relating to the current threshold are assumed in of pneumonia, hospitalisation and mortality the base-case analysis; the impact of assuming the in adult and elderly patient groups, based on previous higher threshold is considered within a meta-analysis of influenza vaccination in the the sensitivity analyses (see One-way/multiway elderly reported by Gross et al.120 However, the sensitivity analysis and scenario analysis, p. 90). odds ratios for these end points appear to relate Uncertainty surrounding the duration of the to pneumonias, hospitalisations and deaths in influenza season was modelled using a gamma the intention-to-treat populations within trials distribution; a standard error of 7 days was of vaccination versus no vaccination; hence, assumed within the analysis. the inclusion of these effects is likely to result in double counting and an overestimate of the 67

TABLE 31 Duration of influenza epidemic period

Winter Epidemic weeks Consultation rate threshold used to estimate duration 1987–8 21 50 per 100,000 population 1988–9 10 50 per 100,000 population 1989–90 9 50 per 100,000 population 1990–1 11 50 per 100,000 population 1991–2 10 50 per 100,000 population 1992–3 10 50 per 100,000 population 1993–4 11 50 per 100,000 population 1994–5 12 50 per 100,000 population 1995–6 11 50 per 100,000 population 1996–7 13 50 per 100,000 population 1997–8 7 50 per 100,000 population 1998–9 8 50 per 100,000 population 1999–2000 7 50 per 100,000 population 2000–1 11 30 per 100,000 population 2001–2 7 30 per 100,000 population 2002–3 1 30 per 100,000 population 2003–4 9 30 per 100,000 population 2004–5 6 30 per 100,000 population 2005–6 3 30 per 100,000 population 2006–7 3 30 per 100,000 population

benefits of vaccination. Additional benefits of Modelling the preventative efficacy vaccination in terms of reducing pneumonias, of antiviral prophylaxis hospitalisations and mortality are thus not included Estimates of the preventative efficacy of in the Assessment Group model presented here. amantadine, oseltamivir and zanamivir in reducing It should also be noted that vaccination status is SLCI were derived from evidence included in the incorporated as a characteristic of the subgroups systematic review of clinical effectiveness presented included in the assessment; vaccination is not in Chapter 3. The model assumes that amantadine, considered as an option for this assessment. oseltamivir and zanamivir as seasonal prophylaxis are effective only for the period in which the The benefit of prior influenza vaccination is patient is taking the drug. In the absence of applied in the model to vaccinated subgroups evidence concerning the relationship between the by reducing the probability of developing point at which patients withdraw from prophylaxis influenza without prophylaxis. This is calculated and the protective benefits of prophylaxis in these as the probability of developing ILI minus the patients, the model assumes that patients who probability that ILI is influenza multiplied by withdraw from prophylaxis do so at the beginning 1 minus the RR of influenza for vaccination. of the prophylaxis course and receive no protective The preventative efficacy of prophylaxis is then benefit over individuals who do not receive applied to any remaining cases of influenza which prophylaxis. This assumption is in line with the are not effectively protected by vaccination (the previous modelling work reported by Turner et al.10 probability of developing other ILI is unaffected by vaccination). This approach appears to be the Preventative efficacy of most reasonable, given the inconsistent availability prophylaxis using amantadine of separate efficacy estimates for amantadine, The systematic review of clinical effectiveness oseltamivir and zanamivir prophylaxis in presented in Chapter 3 highlighted a paucity of vaccinated and unvaccinated subgroups. evidence relating to the efficacy of amantadine in

68 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

both the seasonal and post-exposure prophylaxis amantadine during the years 2004–7. Resistance settings. Two studies were available relating may occur in either strain; recent data suggest that to the seasonal prophylaxis of influenza using amantadine resistance is considerably higher in amantadine;57,58 data relating to the relative the H3N2 strain. Based on the data for the 2006–7 protective benefit of amantadine compared with influenza season, the model assumes that 37% placebo was available only from the study reported of influenza A cases are resistant to amantadine. by Reuman et al.57 This study included healthy This proportion is a crude estimate based on the adults who had not been vaccinated; a mean RR experience over a single influenza season and may of 0.40 (95% CI 0.08–2.03) was estimated from vary considerably as resistance levels and the ratio the event data reported within the clinical trial of H3N2 and H1N1 strains vary from year to year. publication. Owing to the absence of additional or alternative studies, this parameter estimate Preventative efficacy of was applied to all subgroups in the seasonal prophylaxis using oseltamivir prophylaxis model, hence the model assumes The systematic review of clinical effectiveness that the preventative efficacy of amantadine is presented in Chapter 3 identified a more independent of age and risk status. It should be substantial evidence base relating to the noted that the systematic searches did not identify effectiveness of oseltamivir in the prophylaxis of any direct evidence of the benefit of amantadine influenza. Two studies of seasonal prophylaxis in the paediatric population in line with licensed using oseltamivir were identified;64,66 one study66 indications (see Chapter 3); therefore we have recruited healthy adults (unvaccinated), while the extrapolated efficacy estimates from the adult other trial recruited at-risk elderly subjects in a population. residential home (> 80% of subjects vaccinated in intervention and control groups).64 The study The systematic review did not identify any clinical reported by Hayden et al.66 was applied to the trials of the effectiveness of amantadine in the post- otherwise healthy and at-risk paediatric and exposure prophylaxis setting within households working-age adult populations, while preventative (see Chapter 3). However, one study was identified efficacy estimates from the study reported by Peters which examined the efficacy of amantadine in et al.64 were applied to the otherwise healthy and outbreak control in healthy adolescents in a at-risk elderly populations. Based on event data boarding school over a period of 14 days.59 The reported by Hayden et al.,66 the RR of developing majority of subjects recruited within this study had influenza was estimated to be 0.24 (95% CI 0.10– been previously vaccinated for influenza. Prior 0.58). Analysis of event data reported by Peters et vaccination does not necessarily confound the al.64 suggested an RR of developing influenza of analysis of the efficacy of prophylaxis; however, it 0.08 (95% CI 0.01–0.63). It is unclear whether the is likely that the presence of effective vaccination difference between efficacy rates from these two would reduce the statistical power of the trial trials is a result of differences in terms of study comparison (as a result of lower attack rates in both population, underlying risk or another unknown prophylaxis and placebo groups). Efficacy estimates source of heterogeneity. within the outbreak control setting were assumed to be similar to those for amantadine when used Two studies were identified which evaluated as post-exposure prophylaxis, as the duration of the preventative efficacy of oseltamivir in the prophylaxis is similar (assuming post-exposure post-exposure prophylaxis of influenza.48,49 The prophylaxis using amantadine would be taken for preventative efficacy of oseltamivir for the healthy a duration of 10 days). Based on the event data adult group was based on a random-effects meta- reported in the clinical trial publication, the RR analysis of these two studies; the mean RR used of amantadine versus placebo was estimated to be in the model was estimated to be 0.19 (95% CI 0.10 (95% CI 0.03–0.34). Owing to a lack of any 0.08–0.45). Importantly, within the two trials alternative evidence, this RR was applied to all included in the meta-analysis one trial included subgroups in the model. paediatric and adult subjects48 while the other included only adult subjects.49 Owing to a paucity The model assumes that a proportion of patients of alternative evidence, this RR was applied to all develop amantadine-resistant disease; these otherwise healthy and at-risk adult populations. In patients are assumed to derive no prophylactic the paediatric population, the RR of developing benefit from amantadine. Surveillance data influenza following oseltamivir post-exposure (provided as academic-in-confidence) were prophylaxis was modelled on the subgroup analysis provided by the HPA regarding the proportion reported by Hayden et al.;48 the mean RR of of H1N1 and H3N2 isolates that were resistant to developing influenza for children was 0.36 (95% 69

CI 0.16–0.80). This RR was applied to both the is no trial evidence relating to the subgroup under otherwise healthy and at-risk paediatric subgroups. consideration, e.g. amantadine post-exposure prophylaxis in the elderly). In other instances, Preventative efficacy of where multiple sources exist, there are known prophylaxis using zanamivir heterogeneities between study populations (age, The systematic review identified two clinical trials risk status, level of prior vaccination), methods relating to the benefit of zanamivir for the seasonal of end-point measurement and duration of prophylaxis of influenza.70,75 The study reported prophylaxis. It is unclear whether differences by Monto et al.70 recruited healthy adults, the observed in these preventative efficacy estimates majority of whom were unvaccinated. The study are a result of one or a combination of these reported by La Force et al.74 recruited at-risk adults; known heterogeneities or some other underlying subjects recruited into this study had a higher level differences between the studies. The uncertainty of vaccination. Based on the event data reported surrounding all RRs of developing influenza for in the clinical trial paper, the RR of developing vaccination and prophylaxis was modelled using influenza in healthy adults was estimated to be 0.32 lognormal distributions; estimates of preventative (95% CI 0.17–0.63).70 This estimate was applied efficacy were sampled from a normal distribution to the otherwise healthy and at-risk children characterised by the logmean RR and the standard subgroups as well as to the healthy adult subgroup. error of the log of the RR. The reader should Similarly, the RR of developing influenza in at-risk be aware that there is likely to be a greater level adults was estimated to be 0.17 (95% CI 0.06–0.50); of uncertainty surrounding these effectiveness this RR was applied to the at-risk adult working age estimates than the uncertainty reflected in data subgroup.75 The RR for the elderly populations was from the studies included in the systematic review. based on a subgroup analysis reported by LaForce et al.;75 this RR was estimated to be 0.20 (95% CI Adverse events due to influenza 0.02–1.72). vaccination and prophylaxis The model includes the possibility of experiencing The review identified three trials which reported adverse events for patients receiving vaccination the clinical efficacy of zanamivir versus placebo and/or amantadine prophylaxis. The probability for the post-exposure prophylaxis of influenza in of experiencing adverse events due to vaccination adults72 and children and adults.46,47 The RR of was based on data reported by Turner et al.,76 developing influenza in all subgroups receiving sourced from an observational study of a 2-day zanamivir was estimated using a random-effects work absence per 100 healthy adults as a result meta-analysis of these three trials; the RR was of influenza vaccination.121 Although larger estimated to be 0.21 (95% CI 0.13–0.33). One surveillance data sources are available [e.g. the study did evaluate zanamivir as outbreak control vaccine adverse event reporting system (VAERS)], in largely at-risk elderly subjects;76 the model does these tend to be insensitive in the identification not use efficacy data from this study because of of minor adverse events. Adverse events due to differences in the duration of prophylaxis. The use vaccination are assumed to be self-limiting, to of the meta-analysis estimate for zanamivir in post- require no treatment and to have no impact on exposure prophylaxis in households represents a HRQoL. However, the model does assume that bias in favour of zanamivir in this subgroup. patients experiencing adverse events due to vaccination will consult their GP for advice. Relative risks and 95% CIs (shown in parentheses) used in the model are summarised in Table 32. Evidence concerning the incidence of adverse The footnotes detail whether each RR is based on events due to influenza prophylaxis is equivocal. trial evidence relating exclusively to the model In some instances, higher adverse event rates were subgroup, trial evidence that includes the subgroup reported in the placebo groups of the trials than or trial evidence relating to other subgroups. the intervention groups, while in other instances, rates were higher in the intervention groups (see It should be noted that the evidence surrounding Chapter 3). In most cases, it is unclear whether the effectiveness of amantadine, oseltamivir and adverse events are related to the prophylaxis or zanamivir within specific subgroups is not ideal, the clinical condition. This is further complicated and decisions regarding the appropriate inclusion by the poor reporting of the severity of adverse of specific preventative efficacy estimates are not events within the clinical trials. The evidence straightforward. For the most part, preventative does not allow for a robust comparison of adverse efficacy is assumed to be the same across a number event rates between amantadine, oseltamivir 70 of age and risk subgroups (even those where there and zanamivir. In the absence of more robust DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 (0.13–0.33) (0.02–1.72) (0.08–0.45) (0.01–0.63) (0.27–0.66) (0.08–2.03) (0.03–0.34) b b/c b c c c b (0.13–0.33) 0.21 (0.02–1.72) 0.20 (0.08–0.45) 0.19 (0.01–0.63) 0.08 (0.08–2.03) (0.03–0.34) 0.40 0.10 b/c b c c b b (0.13–0.33) 0.21 (0.06–0.50) 0.20 (0.03–0.34) (0.08–0.45) 0.10 0.19 (0.25–0.49) 0.42 (0.27–0.66) 0.42 (0.08–2.03) (0.10–0.58) 0.40 0.08 b b c a b a b (0.13–0.33) 0.21 (0.08–0.45) 0.19 (0.03–0.34) 0.10 (0.17–0.63) 0.17 (0.08–2.03) (0.10–0.58) 0.40 0.24 b a a b a b (0.13–0.33) 0.21 (0.03–0.34) 0.10 (0.17–0.63) 0.32 (0.28–0.48) (0.08–2.03) 0.35 (0.25–0.49) (0.10–0.58) 0.40 0.35 0.24 (0.16–0.80) 0.19 b c a c c b c (0.13–0.33) 0.21 (0.03–0.34) 0.10 (0.17–0.63) 0.32 (0.08–2.03) (0.10–0.58) 0.40 0.24 (0.16–0.80) 0.36 b c a c b c 0.36 (0.28–0.48) 0.36 0.32 Healthy children At-risk children Healthy adults At-risk adults Healthy elderly At-risk elderly Summary of relative risk (RR) estimates and 95% confidence intervals used in the model It is unclear whether elderly individuals were represented within the trials included in meta-analysis of zanamivir post-ex posure prophylaxis. RR based on clinical trial evidence relating exclusively to model subgroup. RR based on clinical trial evidence which includes model subgroup and other subgroups. RR based on clinical trial evidence from other model subgroups (equal effectiveness assumed). Vaccination Zanamivir (post-exposure) 0.21 Zanamivir (seasonal) Oseltamivir (post-exposure) 0.36 a b c NB Intervention Amantadine (seasonal)Amantadine (post-exposure)Oseltamivir (seasonal) 0.10 0.40 0.24

TABLE 32 TABLE 71

estimates from the trials included in the systematic rate was based on a European ILI surveillance review (see Chapter 3), assumptions regarding study reported by van Noort et al.104 This study the probability of adverse events for amantadine, used an internet-based approach to monitoring oseltamivir and zanamivir were drawn from the ILI symptoms and consultations in the general previous modelling work reported by Turner population in the Netherlands, Belgium and et al.10 In line with Turner et al.,10 the model Portugal. The study reported highly variable assumes that the adverse events associated with consultation rates for individuals with ILI ranging the NIs are self-limiting, incur no treatment from 25% to 67%. The model assumes that the true cost and have no impact on HRQoL. There is probability that an individual with symptomatic ILI evidence, however, that amantadine can result in will present is likely to be at the lower end of this severe neuropsychiatric adverse events including range. The model assumes a central estimate of behavioural changes, delirium, hallucinations, 0.25; uncertainty surrounding this parameter value agitations and seizures.10,14 In an attempt to capture was modelled using a beta distribution assuming these health effects, a utility decrement of 0.20 a subjectively large standard error (alpha = 5, is assumed per day of adverse events for a mean beta = 15). The probability of presentation with duration of 5 days, based on the analysis reported ILI is assumed to be the same for all subgroups by Turner et al.10 The model assumes that the included in the model. The impact of this probability of experiencing adverse events due to assumption is explored in the sensitivity analysis amantadine is 5%. The QALY loss associated with (see One-way/multiway sensitivity analysis and amantadine adverse events was characterised using scenario analysis, p. 90). a beta distribution, while the duration of adverse events was modelled using a gamma distribution. Probability of an individual presenting within 48 hours of Withdrawal rates for influenza prophylaxis symptomatic onset of ILI In the absence of better quality evidence identified Treatment using oseltamivir is currently from the clinical trials included in the systematic recommended only for those individuals who review (see Chapter 3), withdrawal rates from are considered to be at high risk of developing prophylaxis were based on those reported within complications who present within 48 hours of the previous modelling study reported by Turner et symptomatic onset.116 The probability of an al.10 The probability of withdrawal for amantadine individual presenting with ILI within 48 hours was assumed to be 5.7% in children and healthy of onset was derived from a study reported by adults, and 14.7% in at-risk adults and elderly Ross et al.123 The model assumes that half of individuals. The probability of withdrawal was those presenting on day 2 would be within the assumed to be 2% for oseltamivir and 1.3% 48-hour cut-off; this assumption is in line with for zanamivir across all model subgroups.10 the previous model reported by Turner et al.10 In Uncertainty surrounding withdrawal rates was this study, the probability of presentation within modelled using beta distributions. 48 hours was reported to be 52%, 16% and 11% in the paediatric, working-age adult and elderly Parameters relating to the onset of populations respectively. These probabilities are influenza and other influenza-like illnesses assumed to be the same in otherwise healthy and Probability of an individual with at-risk populations. The uncertainty surrounding ILI presenting symptomatically these parameters was modelled using beta There is considerable uncertainty surrounding the distributions based on the empirical data reported probability that an individual with ILI will consult by Ross et al.123 a health-care professional in either primary or secondary care. The model reported by Turner Probability that an individual et al.10 used evidence from a study of the excess presenting within 48 hours GP consultations reported by Fleming.112 The is prescribed an NI for use of these data implies the assumption that the treatment of ILI all excess GP consultations over the influenza In line with current recommendations from NICE season compared with the baseline rate are due concerning the use of NIs for the treatment of to influenza. The validity of this assumption is influenza and other ILI, the model assumes that questionable,122 as other ILIs such as RSV are oseltamivir and zanamivir are prescribed only for often more prevalent during the influenza season, patients who are at risk of secondary complications thus accounting for an unknown proportion of of ILI (including elderly patients over 65 years excess cases between the influenza season and of age). For the paediatric population who are 72 baseline periods. Instead, the ILI consultation eligible for treatment, the model assumes that DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

patients are treated using oseltamivir. For at-risk influenza is known to be circulating. A limitation adult populations, the model assumes that 89% of of these data, and their use in the model, is that patients receive oseltamivir, based on data reported the rates of complications resulting from other within the submission to NICE by Roche.20 The ILIs which are not influenza may not reflect remaining 11% of patients are assumed to receive complication rates due to influenza infection. treatment using zanamivir. Effectiveness of NIs for the treatment Probability of developing complications of symptomatic influenza due to influenza and other ILI The efficacy and safety of oseltamivir and The incidence of complications associated zanamivir for the treatment of influenza and other with influenza and ILI is not reported in detail ILI is beyond the scope of this assessment and within clinical trials of influenza prophylaxis is scheduled for reappraisal in 2008. However, (see Chapter 3). Instead, the probability of both zanamivir and oseltamivir are currently developing a complication of influenza or other recommended for treatment of symptomatic ILI was taken directly from a large UK-based influenza and ILI in at-risk individuals.116 Evidence observational study reported by Meier et al.12 This concerning the safety and efficacy of the NIs study collected and analysed data concerning the for the treatment of ILI was derived from the incidence, risk factors, clinical complications and earlier HTA report by Turner et al.10 The model drug utilisation associated with influenza and ILI assumes that oseltamivir and zanamivir reduce the using data collected in the GPRD in the period probability of experiencing complications due to 1991–6. A total of 141,293 patients in the database influenza and lead to a modest reduction in the were reported to have one or more diagnoses of impact of influenza on quality of life compared influenza or ILI. Data concerning the incidence of with best symptomatic care alone. The model specific complications, including exacerbations of assumes an odds ratio for all complications for underlying diseases and death due to influenza, zanamivir versus no treatment of 0.49 (95% CI were reported by age group (1–14 years, 15–49 0.23–1.04) in all at-risk populations, while the years, 50–64 years, and > 65 years) and by odds ratio for complications for oseltamivir versus presence of pre-existing chronic diseases. The rates no treatment is assumed to be 0.65 (95% CI 0.43, of specific complications reported by Meier et al.12 0.97) in the at-risk paediatric population and 0.40 are shown in Table 33. (95% CI 0.16–0.93) in at-risk adult and elderly populations.10 The model assumes that the NIs Data concerning complication rates for the are not effective in reducing complications due to predisposed group were assumed to represent the other ILIs which are not influenza. The odds ratios at-risk populations within the model. Complication derived from Turner et al.10 relate to reductions rates among the 15–49 year age group and the 50– in complications requiring antibiotics; owing to 64 year age group were combined to represent the the high rates of antibiotic use for the treatment working-age adult model populations. Uncertainty of ILI-related complications,12 and the absence surrounding the probability of experiencing a of alternative evidence, the model assumes that complication of influenza within each population these efficacy rates are applied to all ILI-related group was modelled using beta distributions, while complications. It is possible that this may overstate the multinomial probabilities of experiencing the benefit of zanamivir and oseltamivir in terms specific complications were modelled using of reducing complications due to influenza and Dirichlet distributions with minimally informative other ILI. A summary of treatment efficacy values priors based on the methods reported by Briggs assumed within the model is shown in Table 34. et al.124 The model assumes that the risk of developing complications is the same for influenza As noted in Model structure (above), the model and other ILI. assumes that the use of neuraminidase inhibitors for the treatment of symptomatic influenza is It should be noted that the use of this study is independent of the prophylactic strategy and flawed in that many of the ILIs reported by Meier requires a further prescription (any remaining NI et al. will be caused by viruses other than influenza. prophylaxis at the point of infection cannot be used This problem is compounded further as the as treatment at a higher dose). The impact of this study reported ILI complications over the whole assumption is explored in the sensitivity analysis year rather than the influenza season, hence the by excluding the possibility of NI treatment for proportion of episodes caused by other ILIs is patients who develop symptomatic ILI. likely to be higher than that for the period when 73

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Assessment of cost-effectiveness 1.09 49 11 12 23 59 97 936 114 171 346 256 754 7407 1019 1.07 5 9 67 21 21 981 110 195 457 106 273 819 65 years 1049 10,145 17,552 > 1.01 2 5 11 22 16 49 20 27 680 670 300 167 604 5402 1.02 4 7 12 81 46 16 52 141 722 309 1274 1252 1106 16,017 21,419 50–64 years 12 1.02 5 3 9 44 94 10 35 143 684 203 1502 1472 1337 1.02 5 4 21 85 171 454 646 185 748 5270 5185 3502 4530 69,23181,426 12,195 15–49 years 1.04 1 2 0 0 0 9 21 676 650 153 156 302 520 3695 1.05 0 2 0 17 17 29 701 113 2417 1470 20,896 17,201 1–14 years Healthy Predisposed Healthy Predisposed Healthy Predisposed Healthy Predisposed Incidence of influenza-like illness complications by subgroup based on Meier et al. Total cases in age in cases Total group Number in group CNS, central nervous system; GI, gastrointestinal; URTI, upper respiratory tract infection. Complications per patient Total Total complications Total patientsTotal 2311 Death GI bleeding Otitis media 684 Other Renal CNS Cardiac URTI Pneumonia Bronchitis Type of Type complication Respiratory tractRespiratory 1697

74 33 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

TABLE 34 Effectiveness of oseltamivir and zanamivir treatment in reducing complications (based on Turner et al.10)

Odds ratios (and 95% CIs) for reduction in complications

Population Odds ratio for zanamivir Odds ratio for oseltamivir Healthy children 0.70 (0.52–0.96) 0.65 (0.43–0.97) At-risk children 0.49 (0.23–1.04) 0.65 (0.43–0.97) Healthy adults 0.70 (0.52–0.96) 0.40 (0.16–0.93) At-risk adults 0.49 (0.23–1.04) 0.40 (0.16–0.93) Healthy elderly 0.70 (0.52–0.96) 0.40 (0.16–0.93) At-risk elderly 0.49 (0.23–1.04) 0.40 (0.16–0.93)

Probability of receiving antibiotics Furthermore, data relating to hospitalisation The model assumes that antibiotics may be rates were not available from the study by Meier prescribed for both patients who present with et al.12 Instead, the probability of hospitalisation uncomplicated ILI and those who present with was derived from hospitalisation rates for lower complicated ILI. The probability that an individual RTIs reported within a meta-analysis of 10 trials with or without complications is prescribed of oseltamivir for the treatment of symptomatic antibiotics was derived from the study reported influenza reported by Kaiser et al.99 The probability by Meier et al.12 The probability that a patient of hospitalisation for individuals with influenza- with uncomplicated influenza or ILI receives related complications was estimated from the antibiotics was estimated to be 0.28, 0.42 and 0.55 placebo arm data across the 10 included studies; in the paediatric, adult and elderly populations this probability was estimated to be 0.11 (5/46) in respectively. The probability that a patient with the otherwise healthy children and working-age complicated influenza or ILI receives antibiotics adult subgroups and 0.16 (15/95) in the at-risk was estimated to be 0.71, 0.80 and 0.74 in subgroups (including otherwise healthy elderly).99 the paediatric, adult and elderly populations The data presented in the study publication did respectively. Owing to a lack of evidence to the not allow for these estimates to be subdivided contrary, these values are assumed to be the further according to age group; this is unfortunate same for both the otherwise healthy and the at- as age is likely to affect the risk of hospitalisation. risk populations. Uncertainty surrounding these Uncertainty surrounding the probability probabilities was modelled using beta distributions of hospitalisation was modelled using beta based on the empirical data reported by Meier et distributions based on the empirical data reported al.,12 as shown in Table 35. by Kaiser et al.99

Probability of hospitalisation due A proportion of patients who are hospitalised to ILI-related complications may require ITU care with or without mechanical The model assumes that patients who experience ventilation. The previous model reported by ILI-related complications may require Turner et al.10 assumed that 4.9% (22/453) of hospitalisation. As noted above, the clinical trials patients undergo mechanical ventilation. No of influenza prophylaxis do not consistently report alternative evidence could be identified, hence the incidence of complications and as such do not the model uses these same parameter values. A provide any information regarding the probability beta distribution was used to characterise the that an individual requires hospitalisation. uncertainty surrounding this parameter.

TABLE 35 Probability of antibiotic use for influenza-like illness-related complications12

Patients without complications Patients with complications

Number receiving Number receiving Age group antibiotics Number in group antibiotics Number in group 1–14 years 2183 3093 4997 17,910 15–64 years 6983 8726 39,622 94,338 > 65 years 1527 2068 8544 15,620 75

Probability of death due to ILI- amantadine is given for a period of 6 weeks (42 related complications days) for patients who have not been previously The probability of death due to ILI-related vaccinated, and 3 weeks (21 days) for patients complications was taken from the population-based who have been previously vaccinated. The model study reported by Meier et al.12 The probability assumes that seasonal prophylaxis using oseltamivir of death due to influenza complications was is given for a period of 6 weeks (42 days). Seasonal observed to be very low in the paediatric and adult prophylaxis using zanamivir is assumed to be populations (< 1%); this probability was observed given for a period of 4 weeks (28 days). The model to be considerably higher in the elderly patients assumes that post-exposure prophylaxis using represented within the database (10–11%). The amantadine, oseltamivir and zanamivir is given for risk of death due to complications of ILI was a period of 10 days. The duration of treatment of observed to be slightly elevated in the predisposed symptomatic ILI using oseltamivir and zanamivir populations compared with the otherwise healthy is assumed to be 5 days. In line with licensed patients. As complications may be a result of true indications, the daily dosage of amantadine influenza or other ILI, the model assumes that the prophylaxis and zanamivir prophylaxis is assumed probability of death is the same for those patients to be 100 mg and 10 mg respectively for all who develop complications due to influenza and populations. The cost of prophylaxis and treatment for those patients who develop complications using oseltamivir for children assumes a mean body due to other ILI. Uncertainty surrounding this mass of between 23 kg and 40 kg. Unit costs for parameter was modelled using beta distributions amantadine, oseltamivir and zanamivir were taken based on the empirical data reported by Meier et from the BNF No. 54.14 Amantadine is available al.,12 as shown in Table 36. in both capsule and syrup form, and oseltamivir is available as capsules and as a suspension for Modelling resource use and costs reconstitution with water. The model assumes associated with influenza and other ILI that prophylaxis for adults is administered using The model includes the acquisition and capsules rather than syrup or suspension, as this administration costs for vaccination, antiviral allows for more reliable dosing (Dr Andrew Ross, prophylaxis and treatment, costs associated with RCGP, personal communication). The cost of each the management of adverse events, consultation prophylaxis course and treatment course includes costs, antibiotics, and hospitalisation costs for the possibility of wastage. Where multiple products managing severe ILI-related complications. As the were available, the least expensive is assumed. time horizon for the model is effectively 1 year in The costs of prophylaxis used in the model are duration, costs were not subjected to discounting. presented in Table 37.

Costs of prophylaxis and In the base-case analysis, the model assumes that treatment using amantadine, each prescription of prophylaxis requires a GP oseltamivir and zanamivir consultation. The model assumes also that the Prophylaxis and treatment were costed according administration of vaccination and the prescription to BNF list prices at the time of the assessment. of antiviral prophylaxis require separate The number of doses of prophylaxis required consultations. The impact of prescribing multiple using amantadine, oseltamivir and zanamivir was courses of prophylaxis for contact cases is explored calculated based on the dosages and durations in in the sensitivity analysis (see One-way/multiway line with licensed indications (see Table 27). The sensitivity analysis and scenario analysis, p. 90). model assumes that seasonal prophylaxis using

TABLE 36 Probability of death due to influenza and ILI-related complications12

Population Number of deaths Number of complications Probability of death Healthy children 0 2417 0.00 At-risk children 1 676 0.00 Healthy adults 33 6544 0.005 At-risk adults 16 2182 0.007 Healthy elderly 110 1049 0.1049 At-risk elderly 114 1019 0.112 76 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

TABLE 37 Acquisition cost per course of antiviral prophylaxis and treatment

Seasonal prophylaxis Post-exposure prophylaxis Treatment

Drug Adults Children Adults Children Adults Children Amantadine £14.40 £14.40 £4.80 £4.80 NA NA prophylaxis (unvaccinated) Amantadine £9.60 £9.60 £4.80 £4.80 NA NA prophylaxis (previously vaccinated) Oseltamivir £81.80 £73.65 £16.36 £16.36 £16.36 £16.36 prophylaxis Zanamivir £73.65 £73.65 £24.55 £24.55 £24.55 £24.55 prophylaxis

NA, not applicable.

Cost of vaccination Cost of ILI presentation The cost of influenza vaccination was estimated The model assumes that patients present with from list prices derived from BNF 54.14 Current symptomatic ILI either to their GP (in the surgery unit costs for influenza vaccine products range or at home) or at an A&E department. The from £4.98 to £6.59, including both proprietary probability that a patient with influenza or other and non-proprietary products (Table 38). ILI requires a home visit was derived from the Recommended influenza vaccines vary between study reported by Ross et al.123 Counts of patients influenza seasons; the mean vaccine price was with ILI who had home visits were reported in assumed within the model (£5.63). The model aggregate form for patients aged under 75 and assumes that influenza vaccination is administered those aged over 75. Further data regarding the by a GP; the cost of vaccination is assumed to proportion of consultations which took place at include the cost of a GP consultation based on home within each age group were provided by costs reported by Curtis and Netten.102 A GP the lead author of this study (Dr Andrew Ross, visit is assumed to cost £25. As these costs are RCGP, personal communication). The proportion common to all patients receiving vaccination, these of home visits was low in the paediatric and parameters have no impact on the incremental adult populations (5% and 8% respectively); the cost-effectiveness of influenza prophylaxis. proportion was considerably higher in the elderly

TABLE 38 Unit costs of inactivated influenza vaccines14

Product Type of vaccine Unit cost Inactivated influenza vaccinea Suspension of formaldehyde-inactivated influenza virus (split virion) £6.29 Inactivated influenza vaccinea Suspension of propiolactone-inactivated influenza virus (surface antigen) £3.98 Agrippal Suspension of formaldehyde-inactivated influenza virus (surface antigen) £5.03 Begrivac Suspension of formaldehyde-inactivated influenza virus (split virion) £5.03 Enzira Suspension of inactivated influenza virus (split virion) £6.59 Fluarix Suspension of formaldehyde-inactivated influenza virus (split virion) £4.49 Imuvac Suspension of formaldehyde-inactivated influenza virus (surface antigen) £6.59 Influvac subunit Suspension of formaldehyde-inactivated influenza virus (surface antigen) £5.22 Mastaflu Suspension of formaldehyde-inactivated influenza virus (surface antigen) £6.50 Viroflu Suspension of inactivated influenza virus (surface antigen, virosome) £6.59

a Non-proprietary vaccine product. 77

population (38%). Beta distributions were used oseltamivir and zanamivir are mild, self-limiting to characterise the uncertainty surrounding this and incur no additional medical costs. parameter based on the empirical data provided by Dr Ross of the RCGP. The proportion of all ILI Cost of hospitalisation due presentations that take place in A&E departments to serious complications of was based on clinical opinion (Professor influenza and other ILI Robert Read, University of Sheffield, personal The cost of hospitalisation for serious communication); the model assumes that 3% of complications was taken from the NHS reference patients present to A&E (range 1–5%). A beta costs 2005–2006.125 The unit cost for lobar, atypical distribution was used to capture the uncertainty or viral pneumonia (D14) without complications surrounding this quantity. This parameter was was assumed; this was divided by the mean assumed to be the same for otherwise healthy and length of stay to derive an estimate of the daily at-risk paediatric, adult and elderly populations. cost of hospitalisation. The standard error for this parameter was estimated by dividing the Unit costs for GP surgery consultations and home interquartile range by 1.349 and dividing this by visits were derived from the PSSRU102 while the cost the square root of the number of submissions. This of an A&E consultation was derived from the NHS cost was then multiplied by the assumed duration reference costs.125 The model assumes that a GP of inpatient stay within each population group surgery consultation costs £25,102 a home visit costs reported by Turner et al.10 £69102 and an A&E attendance costs £95.56 (first attendance data code 180F).125 The unit costs for Mean lengths of hospitalisation stay due to A&E attendances are assumed to include the costs ILI-related complications were taken from of diagnostic tests (e.g. blood and sputum tests, Turner et al.;10 these are assumed to differ lung function tests, etc.). Based on the information substantially between the paediatric, adult and reported above, the model assumes a mean cost of elderly population subgroups. Turner et al.10 presentation with symptomatic ILI of £29.52 for did not include any uncertainty surrounding children, £30.73 for working-age adults and £43.20 these estimates, hence the degree of uncertainty for elderly individuals. surrounding these mean values has been subjectively modelled using gamma distributions. Cost of antibiotics for the treatment These data are shown in Table 39. of ILI-related complications The model assumes that antibiotics are prescribed A proportion of patients with particularly for individuals presenting with uncomplicated severe complications may require ITU care and ILI as well as those presenting with influenza and mechanical ventilation; Turner et al.10 note that ILI-related complications. The precise antibiotic the proportion of cases requiring mechanical prescribed depends on the type of complication; ventilation is not known. The model uses the same for simplicity, the model assumes that the preferred value reported by Turner et al.10 (probability of antibiotic for the treatment of symptomatic ILI ITU care = 0.05). The typical duration of intensive and related complications is co-amoxiclav. In its care required for severely complicated cases was non-proprietary tablet form, the unit cost for co- derived from a descriptive study of pneumonia amoxiclav is £6.80 for a 21-tablet course.14 management in the US reported by Oliveira et al.126 Oliveira et al. report a mean duration of Cost of managing adverse events intensive care unit (ICU) stay of 28 days ± 26 days resulting from vaccination (10 patients). It should be noted, however, that and prophylaxis this study may not reflect UK treatment patterns. The model assumes that adverse events resulting Uncertainty surrounding this parameter was from vaccination and prophylaxis (amantadine modelled using a lognormal distribution. The cost only) incur additional costs due to additional GP per intensive care day was taken from the NHS attendances. As noted above, the cost of a GP reference costs 2005–2006.125 The cost per critical attendance was assumed to be £25.102 It should care day was assumed to be £1345.39 (Critical care be noted that not all patients who experience level 2 code TCCS CC1L2). adverse events will consult their GP, hence it is possible that the costs of managing adverse events Modelling the impact of influenza and is overestimated in the model, although the impact ILI on health-related quality of life of this bias on cost-effectiveness outcomes is minor. The model estimates the number of QALYs The model assumes that adverse events due to lost due to adverse events of prophylaxis 78 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

TABLE 39 Mean length of hospital stay assumed for patients experiencing ILI-related complications

Population Mean length of stay (days) Assumed standard error Healthy children 2.3 3 At-risk children 2.3 3 Healthy adults 11.9 3 At-risk adults 11.9 3 Healthy elderly 15 3 At-risk elderly 15 3

(amantadine only), influenza and ILI episodes, QALY loss due to an episode of influenza was complications resulting from influenza and other estimated using data collected in five clinical trials ILI, and premature death as a result of secondary of oseltamivir for the treatment of influenza in complications of ILI. In contrast to conventional healthy adults and at-risk and elderly populations. methods for deriving the number of QALYs gained Within these studies, a 10-point Likert scale was by the typical patient receiving a given health completed daily for up to 21 days by patients intervention, the model operates in terms of the receiving oseltamivir treatment and patients number of QALYs lost over the influenza season receiving placebo. The scale employed was similar including an estimate of the impact of premature to a VAS, using a lower anchor which had a score death due to ILI complications. The difference in of 0 describing ‘worst possible health’ and an QALYs lost between one prophylactic option and upper anchor which had a score of 10 describing its best comparator gives an estimate of the number ‘normal health for someone your age’. As the of QALYs saved, ceteris paribus. It should be noted upper anchor on the rating scale did not describe from the outset that the clinical trials of influenza a notional state of ‘best possible health’, Turner prophylaxis did not include direct evaluation of et al.10 recalibrated the upper anchor to represent the impact of the prophylaxis or disease on health mean utility scores for each age group using data utility using a preference-based valuation method. from the Measurement and Valuation of Health This problem is compounded by the paucity of (MVH) study.105 The VAS equivalent data were reliable health utility estimates indirectly available then converted into TTO utility scores based on within the literature. As such, the estimates of a VAS–TTO transformation algorithm reported HRQoL employed within the model should be by the MVH group.105 Turner et al.10 assumed treated with caution. that missing values resulted from the respondent having returned to normal health; missing values QALYs lost due to influenza were therefore imputed as ‘normal health’ utility and ILI episodes scores. The number of QALYs gained over the Previous evaluations of influenza and its prevention 21-day period was estimated for the healthy adult and treatment have used health utility scores and at-risk and elderly populations for oseltamivir derived using the EQ-5D127 or the Health Utilities and placebo. The number of QALYs lost due to an Index, mark III (HUI3)128 based on general influenza episode was calculated as the expected population valuations or retrospective valuations QALYs gained in the non-influenza population from individuals with a history of virologically- over 21 days minus the QALYs lost due to influenza confirmed influenza. These studies were based over 21 days. For example, assuming a baseline on small numbers of subjects (n < 25). The study utility of 0.90 without influenza, and a mean 21- reported by Griffin127 reported an extreme value day QALY loss of 0.041 with influenza, the number for the utility associated with influenza infection of QALYs lost due to influenza is calculated as which is valued as a state worse than death (0.90 × 21) – (0.041 × 365)/365. (utility = –0.066).127 It is likely that the impact of influenza on quality of life will be greatest when the As equivalent data were not available from the illness is at its peak, and that it will have a lesser zanamivir trials, the model assumes that the impact impact in the first and last days of illness. of zanamivir treatment on HRQoL is equivalent to that for oseltamivir. Data were not available for The methodology reported by Turner et al.10 was the paediatric population; therefore, the model used to generate QALY loss estimates for cases of assumes the same QALY loss as in the healthy influenza and other ILI (see Review of exisiting adult population. The model also assumes that the economic evaluation studies, p. 43). The expected QALY loss for an uncomplicated influenza episode 79

is the same as that for an uncomplicated ILI QALYs lost due to ILI- episode. Mean QALY gains over 21 days used in related complications the model are presented in Table 40. In their earlier In principle, the Likert scale data collected within report, Turner et al.10 modelled the uncertainty the oseltamivir trials should have included quality in the data, but did not account for additional of life valuations for individuals who experienced uncertainty resulting from the process of mapping serious complications of influenza (or at least from Likert data collected in the trials to a VAS and those occurring within the 21-day evaluation subsequently to TTO utilities. In order to better period). However, it should be noted that beyond reflect this uncertainty, the model uses the mean the first 7 days, the number of respondents in QALY scores and an assumed level of additional the treatment and placebo groups declined uncertainty (subjectively assigned). These considerably. The model assumes that serious parameters were modelled using beta distributions. complications such as respiratory illness and the exacerbation of underlying health problems are QALYs lost due to adverse not captured within these valuations, and that such events due to prophylaxis complications result in a further reduction in a The model assumes that adverse events due to patient’s HRQoL. amantadine impact upon a patient’s health- related quality of life. The model assumes a utility Systematic searches were undertaken to identify decrement of 0.20 for a mean duration of 5 days studies reporting preference-based valuations based on the previous work reported by Turner of the impact of influenza, ILI and related et al.10 Uncertainty surrounding the disutility complications on HRQoL (see Appendix 1). The of adverse events was modelled using a beta searches did not identify any published studies distribution, whilst uncertainty surrounding the that reported preference-based valuations of the duration of adverse events was modelled using a impact of the range of ILI complications associated gamma distribution, assuming a standard error of with influenza and ILI (bronchitis, pneumonia, 1 day. otitis media and exacerbation of an underlying

TABLE 40 Mean quality-adjusted life-year (QALY) gains over 21-day period

Population Oseltamivir mean QALY Placebo mean QALY Healthy children 0.042 0.041 At-risk children 0.030 0.028 Healthy adults 0.042 0.041 At-risk adults 0.030 0.028 Healthy elderly 0.030 0.028 At-risk elderly 0.030 0.028

TABLE 41 Utility scores associated with ILI-related complications

Committee HUI Mean decrement Assumed lower 95% Assumed upper Parameter values from baseline CI 95% CI Baseline utility score 0.90 – – –

Utility – moderate 0.75 0.15 0.05 0.25 to severe respiratory illness Utility – exacerbation 0.53 0.37 0.27 0.47 of cardiac/asthma complication Utility – other 0.53 0.37 0.27 0.47 complications

HUI, Health Utilities Index. 80 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

condition, e.g. asthma). Instead, health utility QALYs lost due to premature death decrements for secondary complications were resulting from ILI complications derived from a modelling study of vaccination The expected number of QALYs lost due to against a variety of diseases.129 Within this study, premature death resulting from secondary committee HUI (mark II) scores were derived for complications of ILI was also based on the methods a number of health states associated with influenza reported by Turner et al.10 Crude estimates of and ILI (Table 41). These utility estimates represent the mean age of death due to influenza for the the consensus of the committee who undertook the paediatric, adult and elderly populations were valuation exercise and as such do not include any derived from data reported by the Office for estimates of uncertainty. Wide standard errors were National Statistics (ONS; DH2).130 Interim life assumed within the probabilistic sensitivity analysis tables for England and Wales were then used to based on lognormal distributions. calculate the expected number of life-years lost due to premature death for each age group based The duration over which these utility decrements on the mean age of death. Life-years lost were are applied was based on clinical trial data weighted by general population utility scores presented within the Roche submission,20 derived from Kind et al.131 to generate estimates of sourced from clinical trials of oseltamivir. The the number of QALYs lost within each age group. duration of each illness was derived simply by Expected QALYs lost were discounted at a rate calculating the number of days between the onset of 3.5%. It should be noted that while the risk of of the complication and its resolution (Gavin death due to ILI complications is higher in the at- Lewis, Roche, personal communication). The risk groups, the estimate of the number of QALYs submission contained data relating to the duration lost is assumed to be the same for the healthy of pneumonia, bronchitis and otitis media in and at-risk populations; this assumption may be children, healthy adults and at-risk groups. The biased in favour of prophylaxis within the at-risk mean duration of disutility for any respiratory population subgroups. Table 43 shows the modelled complication was estimated by weighting the estimates of the expected discounted QALYs for durations observed in the clinical trials by the each population group.96 ratio of pneumonia : bronchitis in each age group, as reported by Meier et al.12 In the absence of Calculation of cost-effectiveness any alternative evidence, the duration of other respiratory complications was assumed to follow The central estimates of cost-effectiveness are this same pattern. The uncertainty analysis assumes based on the expected costs and QALYs lost for a large standard error of 3 days for each subgroup; each option, as calculated from the results of uncertainty surrounding these quantities was the stochastic model. This approach is intended modelled using gamma distributions. Owing to a to capture any non-linearities in the model lack of alternative evidence, the duration of other parameter distributions. The calculation of cost- non-respiratory complications is assumed to be the effectiveness is fully incremental, whereby each same as that for respiratory complications. Table 42 prophylactic strategy is compared against its next shows the assumed durations for these reductions best comparator. Prophylactic strategies which are in HRQoL. dominated (simple or extended) are ruled out of the analysis.

TABLE 42 Assumed duration of utility reductions

Respiratory and other complications Otitis media

Mean duration Assumed standard Mean duration Assumed standard Population (days) error (days) error Healthy children 7.89 3.00 9.36 3.00 At-risk children 8.07 3.00 9.36 3.00 Healthy adults 9.23 3.00 9.36 3.00 At-risk adults 10.65 3.00 9.36 3.00 Healthy elderly 10.88 3.00 9.36 3.00 At-risk elderly 10.87 3.00 9.36 3.00 81

TABLE 43 Expected QALYs potentially lost resulting from death due to influenza from the stochastic model. The second scenario presents the cost-effectiveness results based on the Expected QALYs deterministic model. Population subgroup (discounted at 3.5%) Sensitivity analysis 3: cost-effectiveness Children 24.74 of oseltamivir given in suspension form Adults 13.37 The base-case analysis assumes that seasonal Elderly 2.95 prophylaxis using oseltamivir is prescribed in capsule form to all adult populations, as this is QALY, quality-adjusted life-year. likely to ensure more accurate dosing. However, in principle, oseltamivir given as suspension may allow for less wastage than in capsule form, thus Uncertainty analysis leading to a reduction in the cost of the drug. A One-way sensitivity analysis 56-cap pack of oseltamivir provides 10 × 75 mg and scenario analysis tablets providing 750 mg of the drug (10 doses) Simple one-way sensitivity analysis and scenario while a 75 ml bottle (60 mg/5 ml) of oseltamivir in analysis were undertaken to examine the impact of suspension form provides a total of 900 mg of the changing model assumptions on the incremental drug (12 doses of 75 mg). While both products cost cost-effectiveness of alternative prophylaxis options £16.36 per unit, the use of suspension could, in (the results of these analyses are presented in principle, offer savings over oseltamivir capsules. One-way/multiway sensitivity analysis and scenario analysis, p. 90). Details of these sensitivity analyses Sensitivity analysis 4: are detailed below. multiple prescriptions The base-case model assumes that each Sensitivity analysis 1: proposed prescription of prophylaxis requires a GP price reduction for zanamivir consultation; for vaccinated patients, the model In November 2007, the manufacturer of assumes that prophylaxis can be given during the zanamivir (GSK) applied to the Department of same consultation as the influenza vaccine. The Health for a price modulation of two of their Roche model assumed that four prescriptions drugs, one of which was zanamivir. The current of prophylaxis could be obtained per GP list price for zanamivir is £24.55 (five disks, attendance. This scenario analysis assumes that four blisters per disk); the new proposed price four prescriptions may be obtained per individual, for zanamivir is £16.36 (Toni Maslen, Health resulting in a reduction in the cost of GP Outcomes Programme Leader, GSK, personal attendances for unvaccinated patients.20 communication). This proposed price reduction for zanamivir was approved by the Department Sensitivity analyses 5 and 6: of Health with effect from 1 February 2008 but reduced vaccine efficacy was not listed in the BNF (No. 54)14 at the time Sensitivity analysis was undertaken assuming a of submission. This scenario analysis presents the lower efficacy rate for vaccination to capture the central estimates of cost-effectiveness of influenza potential impact of a mismatch between vaccine prophylaxis including this proposed price and circulating strains of influenza. Scenario 5 reduction for zanamivir. All other parameter values assumes an RR for vaccination of 0.50, while and assumptions in this analysis are the same as scenario 6 assumes an RR of 0.75. those in the base-case analysis presented in Central estimates of cost-effectiveness (see below). The Sensitivity analysis 7: protection reader should note that where zanamivir remains over entire influenza season dominated by another prophylaxis option despite The base-case analysis assumes that patients the price change, the slight differences in the cost- receiving seasonal prophylaxis are at risk of effectiveness of the remaining prophylactic options infection when they stop taking the drug. This from the base case results are due to sampling scenario assumes that the patient is protected over errors in the stochastic model. the entire influenza season.

Sensitivity analysis 2: deterministic Sensitivity analysis 8: no antiviral estimates of cost-effectiveness treatment for symptomatic influenza The base-case health economic analysis is based This sensitivity analysis assumes that patients who upon the expected (mean) costs and health develop symptomatic ILI do not receive antiviral 82 outcomes for each prophylactic option, drawn treatment using oseltamivir or zanamivir. DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Sensitivity analysis 9: equivalent Sensitivity analysis 19: use of a higher efficacy for oseltamivir and threshold for influenza activity zanamivir prophylaxis The base-case analysis assumes that seasonal There is uncertainty surrounding the relative prophylaxis will be used when the GP consultation efficacy of oseltamivir and zanamivir for the rate for ILI is in excess of 30 per 100,000 prophylaxis of influenza. The Roche model population.8 This scenario analysis examines the assumed that oseltamivir and zanamivir had potential impact of using the previous influenza equivalent efficacy. This scenario assumes that threshold of 50 consultations per 100,000 oseltamivir and zanamivir are equivalent, and uses population on the cost-effectiveness of prophylaxis. the most favourable efficacy estimate for NIs within This analysis draws on parameter values reported the model subgroup under evaluation. by Turner et al.10 which was undertaken when the previous influenza threshold was implemented. Sensitivity analysis 10: no adverse events Sensitivity analysis 20: lower There is uncertainty regarding the cost and health GP consultation rate impact of adverse events associated with influenza The base-case model assumes that the probability prophylaxis. The base-case model assumes that that an individual with symptomatic ILI consults individuals receiving prophylaxis may experience a health-care professional is 0.25; however, this adverse events that may lead to additional medical is based on a single survey and is associated with care costs and a further loss of quality of life for considerable uncertainty. This sensitivity analysis amantadine. This scenario explores the impact of assumes that the probability that an individual with assuming no costs or health impacts associated with symptomatic ILI consults their GP is half the base- adverse events. case value.

Sensitivity analysis 11: no Sensitivity analysis 21: higher withdrawals from prophylaxis GP consultation rate The model assumes that a proportion of patients This sensitivity analysis assumes that the probability withdraw from prophylaxis, and that patients that an individual with symptomatic ILI consults who withdraw gain no protective benefit against their GP is double the base-case value. influenza. This scenario assumes a withdrawal probability of 0. Sensitivity analysis 22: alternative mapping function Sensitivity analyses 12–16: for influenza QALY loss resistance against oseltamivir The base-case model uses rating scale data from The base-case model assumes that resistance clinical trials, mapped to a VAS, and subsequently to oseltamivir is 0. These scenarios explore the mapped to TTO to generate QALY losses for the impact of oseltamivir resistance on resulting cost- period in which an individual has influenza. This effectiveness estimates. Levels of resistance against sensitivity analysis uses an alternative mapping amantadine are assumed to be the same as the function, converting VAS data into EQ-5D utilities. base-case value for each scenario. Sensitivity analysis 23: lower Sensitivity analysis 17: QALY losses for at-risk groups lower attack rates The base-case model assumes that the likely Previous models of influenza prophylaxis have reduction in expected QALYs lost due to premature reported that cost-effectiveness estimates are highly death as a result of influenza complications is the sensitive to the true influenza attack rate. This same in healthy and at-risk populations. This scenario assumes that the attack rate is half that of analysis assumes that the expected QALY loss in the base case in each model subgroup. the at-risk group is half the value used in the base case. Sensitivity analysis 18: higher attack rates Sensitivity analysis 24: complication This scenario assumes that the attack rate is double utility decrements halved that of the base case in each model subgroup. The evidence concerning the impact of ILI complications on health outcomes is scarce and

subject to considerable uncertainty. This analysis Cost-effectiveness results assumes a 50% reduction in utility decrements associated with ILI complications. This section presents the results of the cost- effectiveness analysis of amantadine, oseltamivir Sensitivity analysis 25: impact of and zanamivir for the prevention of influenza. The assumptions regarding hospitalisation central estimates of cost-effectiveness for each of in uncomplicated cases the six model subgroups with and without previous The base-case model assumes that uncomplicated influenza vaccination are presented below. As noted ILI cases do not result in hospitalisation or death. in Calculation of cost-effectiveness (see above), all Scenario 25 assumes that 10% of uncomplicated central estimates of cost-effectiveness are based cases result in hospitalisation. on expected costs and health outcomes generated by the stochastic model. The next section, One- Sensitivity analysis 26: undiscounted way/multiway sensitivity analysis and scenario cost-effectiveness estimates analysis (see p. 90), presents the results of the Within the base-case model analysis, health simple sensitivity analysis and scenario analysis to outcomes were discounted at a rate of 3.5%. This identify key determinants of the cost-effectiveness analysis presents cost-effectiveness estimates of amantadine, oseltamivir and zanamivir for the without discounting. prevention of influenza. The subsequent section, Probabilistic sensitivity analysis results, presents the Probabilistic sensitivity analysis results of the probabilistic sensitivity analysis using Comprehensive probabilistic sensitivity analysis CEACs. was undertaken to explore the joint uncertainty in model parameters on the cost-effectiveness Central estimates of of each prophylaxis option. Uncertainty in cost-effectiveness model parameters was propagated through the Seasonal prophylaxis model results model using Monte Carlo sampling techniques (5000 samples) to generate information on the Tables 44–49 present the central estimates of probability that each prophylactic option is optimal cost-effectiveness for seasonal prophylaxis using (i.e. that it produces the greatest amount of net amantadine, oseltamivir and zanamivir for the six benefit). The results of the probabilistic sensitivity model subgroups. The reader should note that analysis are presented as incremental cost- these central estimates are based on the BNF prices effectiveness acceptability curves [see Probabilistic of amantadine, oseltamivir and zanamivir at the sensitivity analysis results (p.102), Appendix 10 and time of the assessment. Appendix 11]. Group 1: healthy children Model validation The model results presented in Table 44 suggest The validity of the model was tested extensively. that the most effective seasonal prophylaxis option The model structure was reviewed throughout the for healthy children is oseltamivir, irrespective model development process; the validity of key of vaccination status. Oseltamivir is expected model assumptions was reviewed by clinical experts to produce a small improvement in terms of and compared with assumptions used in previous QALY losses avoided compared with the other health economic models of influenza prophylaxis. prophylactic strategies; however, this is not the At the end of the model development process, the most expensive prophylactic option. Zanamivir is logical consistency of the model structure and the less effective and more expensive than oseltamivir, handling of model parameters were checked by the irrespective of vaccination status, hence it is ruled lead modeller and also by a second modeller who out by simple dominance and is not included in was not involved in the assessment. In addition, this analysis. For healthy children who have not every model parameter and its distributional been previously vaccinated against influenza, characteristics were checked against the source data amantadine is expected to be ruled out by that were used to inform it. Finally, the expectation extended dominance, as oseltamivir has a more of probabilistic samples of each model parameter favourable incremental cost-effectiveness ratio. was checked against its parameter mean to identify For healthy children who have been previously any programming errors and any areas of non- vaccinated, amantadine is expected to be linearity introduced through the model structure. dominated by no prophylaxis. For unvaccinated children, the incremental cost-effectiveness of 84 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

TABLE 44 Cost-effectiveness of seasonal prophylaxis – healthy children

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £17.72 0.0043 – – – Amantadine £56.23 0.0040 – – Extendedly dominated Zanamivir £112.15 0.0033 – – Dominated Oseltamivir £85.51 0.0028 £67.79 0.0015 £44,007

Previously vaccinated individuals Amantadine £78.64 0.0030 – – Dominated No prophylaxis £43.23 0.0030 – – Dominates Zanamivir £140.36 0.0026 – – Dominated Oseltamivir £115.05 0.0024 £71.81 0.0006 £129,357

TABLE 45 Cost-effectiveness of seasonal prophylaxis – at-risk children

Incremental Incremental Incremental cost per QALY Option Costs QALYs lost cost QALYs gained

Unvaccinated individuals No prophylaxis £29.89 0.0109 – – – Amantadine £66.92 0.0097 – – Extendedly dominated Zanamivir £121.56 0.0083 – – Dominated Oseltamivir £93.57 0.0071 £63.68 0.0038 £16,630

Previously vaccinated individuals No prophylaxis £51.71 0.0075 – – – Amantadine £86.84 0.0073 – – Extendedly dominated Zanamivir £147.86 0.0065 – – Dominated Oseltamivir £122.06 0.0061 £70.34 0.0014 £51,069

oseltamivir versus no prophylaxis is expected to of whether or not they have been previously be around £44,000 per QALY gained. For healthy vaccinated. Again, zanamivir is expected to be less children who have received prior vaccination, effective and more expensive than oseltamivir, the incremental cost-effectiveness of oseltamivir hence it is ruled out of the analysis by simple compared with no prophylaxis is estimated to be dominance. Amantadine is expected to be ruled approximately £129,000 per QALY gained. out of the analysis by extended dominance (again oseltamivir has a more favourable cost-effectiveness Group 2: at-risk children ratio). The incremental cost-effectiveness of oseltamivir compared with no prophylaxis is The model results presented in Table 45 suggest estimated to be approximately £17,000 per QALY that the most effective seasonal prophylaxis option gained in unvaccinated at-risk children and for at-risk children is oseltamivir irrespective £51,000 per QALY gained in at-risk children who have previously been vaccinated against influenza. 85

TABLE 46 Cost-effectiveness of seasonal prophylaxis – healthy adults

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £6.63 0.0020 – – – Amantadine £46.49 0.0019 – – Extendedly dominated Zanamivir £103.70 0.0015 – – Extendedly dominated Oseltamivir £111.09 0.0013 £104.45 0.0007 £147,505

Previously vaccinated individuals Amantadine £71.34 0.0014 – – Dominated No prophylaxis £35.64 0.0014 – – Dominates Zanamivir £133.74 0.0012 – – Extendedly dominated Oseltamivir £141.6 0.0011 £105.9 0.0002 £427,184

TABLE 47 Cost-effectiveness of seasonal prophylaxis – at-risk adults

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £13.57 0.0046 – – – Amantadine £52.74 0.0042 – – Extendedly dominated Zanamivir £108.33 0.0033 – – Extendedly dominated Oseltamivir £115.63 0.0030 £102.06 0.0016 £63,552

Previously vaccinated individuals Amantadine £75.94 0.0032 – – Dominated No prophylaxis £40.39 0.0031 – – Dominates Zanamivir £137.67 0.0027 – – Extendedly dominated Oseltamivir £145.53 0.0025 £105.14 0.0006 £186,651

Group 3: healthy adults amantadine is ruled out of the analysis by extended dominance, while for vaccinated healthy adults The results presented in Table 46 suggest that amantadine is expected to be dominated by no oseltamivir is expected to be the most effective prophylaxis. The incremental cost-effectiveness option for seasonal prophylaxis of influenza of oseltamivir compared with no prophylaxis in healthy adults. This analysis suggests that is estimated to be approximately £148,000 per zanamivir is expected to be slightly less expensive QALY gained in unvaccinated healthy adults and than oseltamivir, but is ruled out by extended £427,000 per QALY gained in healthy adults who dominance. For unvaccinated healthy adults have previously been vaccinated. 86 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Group 4: at-risk adults by extended dominance, while for vaccinated individuals, amantadine is expected to be less Table 47 suggests that oseltamivir is expected to be effective and more expensive than a policy of no the most effective option for seasonal prophylaxis prophylaxis. The incremental cost-effectiveness in at-risk adults. As with the healthy adult model, of oseltamivir compared with no prophylaxis is zanamivir is expected to be ruled out by extended estimated to be approximately £64,000 per QALY dominance as oseltamivir has a lower incremental gained in unvaccinated individuals and £187,000 cost-effectiveness ratio. For unvaccinated at-risk per QALY gained in at-risk adults who have adults, amantadine is expected to be ruled out previously been vaccinated against influenza.

TABLE 48 Cost-effectiveness of seasonal prophylaxis – healthy elderly

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £10.43 0.0048 – – – Amantadine £49.93 0.0044 – – Extendedly dominated Zanamivir £106.16 0.0035 – – Extendedly dominated Oseltamivir £112.80 0.0028 £102.38 0.0021 £49,742

Previously vaccinated individuals Amantadine £74.16 0.0035 – – Dominated No prophylaxis £38.59 0.0035 – – Dominates Zanamivir £136.02 0.0029 – – Extendedly dominated Oseltamivir £143.54 0.0026 £104.95 0.0009 £121,728

TABLE 49 Cost-effectiveness of seasonal prophylaxis – at-risk elderly

Incremental Incremental Incremental cost per QALY Option Costs QALYs lost cost QALYs gained

Unvaccinated individuals No prophylaxis £13.45 0.0062 – – – Amantadine £52.63 0.0057 – – Extendedly dominated Zanamivir £108.39 0.0045 – – Extendedly dominated Oseltamivir £114.54 0.0036 £101.09 0.0027 £38,098

Previously vaccinated individuals No prophylaxis £40.75 0.0045 – – – Amantadine £76.25 0.0044 – – Extendedly dominated Zanamivir £137.84 0.0037 – – Extendedly dominated Oseltamivir £145.15 0.0033 £104.40 0.0011 £93,763 87

Group 5: healthy elderly Post-exposure prophylaxis model results Tables 50–55 present the central estimates of The cost-effectiveness results presented in Table 48 cost-effectiveness for post-exposure prophylaxis suggest that oseltamivir is expected to be the most of influenza using amantadine, oseltamivir and effective seasonal prophylaxis option for elderly zanamivir for the six model subgroups. adults who are otherwise healthy. As with the working-age adult models, zanamivir is expected to Group 1: healthy children be ruled out by extended dominance. Amantadine is expected to be ruled out by extended dominance The model results presented in Table 50 suggest for unvaccinated individuals, and is dominated that zanamivir is expected to be the most effective by no prophylaxis in vaccinated populations. option for the post-exposure prophylaxis of The incremental cost-effectiveness of oseltamivir influenza in otherwise healthy children. In this compared with no prophylaxis is estimated to be instance, oseltamivir and amantadine are ruled around £50,000 per QALY gained in unvaccinated out of the analysis by extended dominance. The healthy elderly adults and around £122,000 per incremental cost-effectiveness of zanamivir versus QALY gained in healthy elderly adults who have no prophylaxis is estimated to be £23,000 per previously been vaccinated. QALY gained for unvaccinated healthy children and around £72,000 in vaccinated healthy children. Group 6: at-risk elderly The reader should note that oseltamivir is the only The results presented in Table 49 suggest that licensed prophylactic in children under the age of oseltamivir is expected to be the most effective 5 years; the incremental cost-effectiveness ratio for seasonal prophylaxis option for at-risk elderly oseltamivir versus no prophylaxis is expected to adults. Zanamivir and amantadine are both ruled be around £24,000 per QALY gained and £74,000 out of the analysis by extended dominance. The per QALY gained in unvaccinated and vaccinated incremental cost-effectiveness of oseltamivir groups respectively. compared with amantadine is estimated to be around £38,000 per QALY gained in unvaccinated Group 2: at-risk children at-risk elderly individuals and £94,000 per QALY gained in at-risk elderly adults who have previously The cost-effectiveness results presented in Table 51 been vaccinated. suggest that zanamivir is expected to be the most

TABLE 50 Cost-effectiveness of post-exposure prophylaxis – healthy children

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £18.96 0.0047 – – – Amantadine £46.40 0.0039 – – Extendedly dominated Oseltamivir £54.35 0.0032 – – Extendedly dominated Zanamivir £61.18 0.0029 £42.22 0.0018 £23,225

Previously vaccinated individuals No prophylaxis £44.09 0.0032 – – – Amantadine £73.84 0.0030 – – Extendedly dominated Oseltamivir £83.30 0.0027 – – Extendedly dominated Zanamivir £91.00 0.0026 £46.91 0.0007 £71,648 88 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

TABLE 51 Cost-effectiveness of post-exposure prophylaxis – at-risk children

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £32.56 0.0118 – – – Amantadine £57.55 0.0097 – – Extendedly dominated Oseltamivir £63.97 0.0082 – – Extendedly dominated Zanamivir £69.76 0.0073 £37.20 0.0045 £8233

Previously vaccinated individuals No prophylaxis £53.57 0.0081 – – – Amantadine £82.44 0.0074 – – Extendedly dominated Oseltamivir £91.35 0.0068 – – Extendedly dominated Zanamivir £98.67 0.0065 £45.10 0.0016 £27,684

effective option for the post-exposure prophylaxis £104,000 per QALY gained for unvaccinated of influenza in at-risk children. Oseltamivir and healthy adults. amantadine are expected to be ruled out of the analysis by extended dominance for unvaccinated Group 4: at-risk adults and vaccinated subgroups. The incremental cost- effectiveness of zanamivir versus no prophylaxis is Table 53 suggests that oseltamivir is expected estimated to be around £8000 per QALY gained in to be the most effective option for the post- unvaccinated at-risk children and approximately exposure prophylaxis of influenza in at-risk adults. £28,000 per QALY gained in vaccinated at-risk Again, zanamivir is expected to be dominated children. by oseltamivir irrespective of vaccination status. Amantadine is again expected to be ruled out For at-risk children under the age of 5 years, the by extended dominance. The incremental cost- incremental cost-effectiveness of oseltamivir versus effectiveness of oseltamivir versus no prophylaxis is no prophylaxis is expected to be around £9000 per estimated to be around £13,000 per QALY gained QALY gained for unvaccinated at-risk children and for unvaccinated at-risk adults and £44,000 per around £29,000 per QALY gained for vaccinated QALY gained for previously vaccinated at-risk at-risk children. adults.

Group 3: healthy adults Group 5: healthy elderly

The cost-effectiveness estimates presented in Table 54 suggests that oseltamivir is expected to Table 52 suggest that oseltamivir is expected to be be the most effective option for the post-exposure the most effective option for the post-exposure prophylaxis of influenza in otherwise healthy prophylaxis of influenza in healthy adults. elderly adults. Zanamivir is again expected to Within this subgroup, zanamivir is expected be dominated by oseltamivir and is hence ruled to be dominated by oseltamivir irrespective of out of the analysis. Amantadine is expected to be vaccination status. Amantadine is expected to be ruled out of the analysis by extended dominance. ruled out by extended dominance. The incremental The incremental cost-effectiveness of oseltamivir cost-effectiveness of oseltamivir versus no versus no prophylaxis is estimated to be around prophylaxis is estimated to be £34,000 per QALY £11,000 per QALY gained for unvaccinated healthy gained for vaccinated healthy adults and around elderly individuals and around £28,000 per QALY

TABLE 52 Cost-effectiveness of post-exposure prophylaxis – healthy adults

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £9.17 0.0028 – – – Amantadine £38.48 0.0024 – – Extendedly dominated Zanamivir £55.19 0.0017 – – Dominated Oseltamivir £46.94 0.0017 £37.77 0.0011 £34,181

Previously vaccinated individuals No prophylaxis £37.36 0.0019 – – – Amantadine £67.80 0.0019 – – Extendedly dominated Zanamivir £85.67 0.0015 – – Dominated Oseltamivir £77.46 0.0015 £40.10 0.0004 £103,706

TABLE 53 Cost-effectiveness of post-exposure prophylaxis – at-risk adults

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £19.34 0.0064 – – – Amantadine £47.10 0.0055 – – Extendedly dominated Zanamivir £61.49 0.0040 – – Dominated Oseltamivir £53.18 0.0039 £33.85 0.0025 £13,459

Previously vaccinated individuals No prophylaxis £44.32 0.0044 – – – Amantadine £74.21 0.0041 – – Extendedly dominated Zanamivir £91.27 0.0035 – – Dominated Oseltamivir £83.04 0.0035 £38.73 0.0009 £43,970

gained for at-risk elderly who have previously been no prophylaxis is estimated to be around £8000 vaccinated against influenza. per QALY for vaccinated at-risk elderly individuals and around £22,000 per QALY gained for at- Group 6: at-risk elderly risk elderly individuals who have previously been vaccinated. The model results presented in Table 55 suggest that oseltamivir is expected to be the most effective One-way/multiway sensitivity option for the post-exposure prophylaxis of analysis and scenario analysis influenza in at-risk elderly individuals. Zanamivir is expected to be dominated by oseltamivir and is This section presents one-way and multiway ruled out of the analysis. Amantadine is expected sensitivity analysis to explore the impact of to be ruled out by extended dominance. The changing parameter assumptions on the incremental cost-effectiveness of oseltamivir versus incremental cost-effectiveness of amantadine, 90 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

TABLE 54 Cost-effectiveness of post-exposure prophylaxis – healthy elderly

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £17.75 0.0082 – – – Amantadine £45.76 0.0069 – – Extendedly dominated Zanamivir £60.50 0.0051 – – Dominated Oseltamivir £52.17 0.0050 £34.42 0.0032 £10,716

Previously vaccinated individuals No prophylaxis £43.82 0.0059 – – – Amantadine £73.59 0.0054 – – Extendedly dominated Zanamivir £90.52 0.0045 – – Dominated Oseltamivir £82.27 0.0045 £38.45 0.0014 £28,473

TABLE 55 Cost-effectiveness of post-exposure prophylaxis – at-risk elderly

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £22.88 0.0106 – – – Amantadine £50.05 0.0089 – – Extendedly dominated Zanamivir £63.68 0.0065 – – Dominated Oseltamivir £55.33 0.0065 £32.45 0.0041 £7866

Previously vaccinated individuals No prophylaxis £47.50 0.0076 – – – Amantadine £76.92 0.0070 – – Extendedly dominated Zanamivir £93.37 0.0059 – – Dominated Oseltamivir £85.11 0.0058 £37.60 0.0017 £21,608

oseltamivir and zanamivir for the prevention of subject to a small degree of Monte Carlo sampling influenza. Descriptions of these scenarios are error. presented in Uncertainty analysis (p. 82). Seasonal prophylaxis Sensitivity analysis – cost-effectiveness Results for seasonal prophylaxis are presented in results including proposed reduction Tables 56–61. in the price of zanamivir Tables 56–67 present the results of the model Post-exposure prophylaxis incorporating the proposed price reduction for Results for post-exposure prophylaxis are zanamivir. The reader should note that as these presented in Tables 62–67. results are based on the stochastic model, they are

TABLE 56 Cost-effectiveness of seasonal prophylaxis – healthy children

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £17.71 0.0043 – – – Amantadine £56.20 0.0040 – – Extendedly dominated Zanamivir £87.59 0.0033 – – Dominated Oseltamivir £85.49 0.0028 £67.78 0.0015 £43,870

Previously vaccinated individuals Amantadine £78.64 0.0030 – – Dominated No prophylaxis £43.22 0.0030 – – Dominates Zanamivir £115.80 0.0026 – – Dominated Oseltamivir £115.05 0.0024 £71.82 0.0006 £129,888

TABLE 57 Cost-effectiveness of seasonal prophylaxis – at-risk children

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £29.62 0.0109 – – – Amantadine £66.68 0.0097 – – Extendedly dominated Zanamivir £96.83 0.0084 – – Dominated Oseltamivir £93.38 0.0071 £63.76 0.0038 £16,598

Previously vaccinated individuals No prophylaxis £51.53 0.0075 – – – Amantadine £86.66 0.0074 – – Extendedly dominated Zanamivir £123.14 0.0066 – – Dominated Oseltamivir £121.90 0.0061 £70.37 0.0014 £50,902

Table 68 summarises the ICERs presented in per QALY gained for these comparisons. In terms the base-case analysis and those including the of the post-exposure prophylaxis of influenza, the proposed reduction in the price of zanamivir. price reduction has no impact on the adult and elderly subgroup analyses, as zanamivir consistently The summary of cost-effectiveness results remains dominated by oseltamivir. The proposed presented in Table 68 shows that the proposed price reduction is, however, expected to lead to an price reduction has no impact on the majority of improvement in the cost-effectiveness of zanamivir economic comparisons presented in the base-case for otherwise healthy and at-risk children. For analysis. In terms of seasonal prophylaxis, the cost- unvaccinated healthy children, the reduction in effectiveness of zanamivir is no longer ruled out by the price of zanamivir is expected to result in a extended dominance in at-risk adults; however, the reduction in the cost-effectiveness of zanamivir incremental cost-effectiveness ratio for zanamivir versus no prophylaxis from £23,000 per QALY 92 versus no prophylaxis remains in excess of £50,000 gained to £19,000 per QALY gained. The cost- DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

TABLE 58 Cost-effectiveness of seasonal prophylaxis – healthy adults

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £6.57 0.0020 – – – Amantadine £46.40 0.0019 – – Extendedly dominated Zanamivir £79.09 0.0015 – – Extendedly dominated Oseltamivir £111.04 0.0013 £104.46 0.0007 £147,083

Previously vaccinated individuals Amantadine £71.26 0.0014 – – Dominated No prophylaxis £35.58 0.0014 – – Dominates Zanamivir £109.11 0.0012 – – Extendedly dominated Oseltamivir £141.56 0.0011 £105.98 0.0002 £427,802

TABLE 59 Cost-effectiveness of seasonal prophylaxis – at-risk adults

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £13.70 0.0046 – – – Amantadine £52.83 0.0042 – – Extendedly dominated Zanamivir £83.85 0.0033 £70.15 0.0013 £53,159 Oseltamivir £115.69 0.0030 £31.84 0.0003 £108,379

Previously vaccinated individuals Amantadine £76.03 0.0031 – – Dominated No prophylaxis £40.47 0.0031 – – Dominates Zanamivir £113.17 0.0026 £72.70 0.0005 £157,216 Oseltamivir £145.58 0.0025 £32.41 0.0001 £313,592

effectiveness of zanamivir in vaccinated, otherwise One-way sensitivity analysis healthy children is expected to be in excess of and scenario analysis results £59,000 per QALY gained. For unvaccinated at-risk Healthy children children, the lower price for zanamivir is expected The results of the simple sensitivity analysis for the to lead to an improvement in the cost-effectiveness healthy children subgroup are presented in Table of zanamivir versus no prophylaxis from £8000 69. per QALY gained to £6000 per QALY gained. For vaccinated at-risk children, the cost-effectiveness The simple sensitivity analysis results presented of zanamivir is improved from £28,000 per QALY in Table 69 suggest that the base-case seasonal gained to £23,000 per QALY gained. prophylaxis cost-effectiveness estimates are

TABLE 60 Cost-effectiveness of seasonal prophylaxis – healthy elderly

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £10.48 0.0048 – – – Amantadine £49.98 0.0044 – – Extendedly dominated Zanamivir £81.63 0.0035 – – Extendedly dominated Oseltamivir £112.82 0.0028 £102.34 0.0021 £49,590

Previously vaccinated individuals Amantadine £74.21 0.0035 – – Dominated No prophylaxis £38.63 0.0035 – – Dominates Zanamivir £111.48 0.0029 – – Extendedly dominated Oseltamivir £143.55 0.0026 £104.92 0.0009 £120,292

TABLE 61 Cost-effectiveness of seasonal prophylaxis – at-risk elderly

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £13.46 0.0062 – – – Amantadine £52.64 0.0057 – – Extendedly dominated Zanamivir £83.81 0.0045 – – Extendedly dominated Oseltamivir £114.53 0.0036 £101.07 0.0027 £37,968

Previously vaccinated individuals No prophylaxis £40.75 0.0045 – – – Amantadine £76.26 0.0044 – – Extendedly dominated Zanamivir £113.26 0.0037 – – Extendedly dominated Oseltamivir £145.15 0.0033 £104.40 0.0011 £93,581

sensitive to assumptions regarding influenza attack sensitive to the influenza attack rate, the use rates, the level of resistance against oseltamivir, of multiple prescriptions of prophylaxis at a vaccine efficacy, the threshold used to describe single GP visit, vaccine efficacy, assumptions when influenza is circulating in the community regarding the relative effectiveness of oseltamivir (particularly the duration of the influenza season), and zanamivir and the risk of hospitalisation in the risk of hospitalisation in uncomplicated cases uncomplicated cases. Amantadine and oseltamivir and the discount rate. Amantadine and zanamivir as post-exposure prophylaxis remain dominated or as seasonal prophylaxis remain dominated extendedly dominated by zanamivir in the majority across almost all scenarios. The cost-effectiveness of the scenarios presented for healthy children. estimates for post-exposure prophylaxis are 94 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

TABLE 62 Cost-effectiveness of post-exposure prophylaxis – healthy children

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £18.92 0.0047 – – – Amantadine £46.38 0.0040 – – Extendedly dominated Oseltamivir £54.34 0.0032 – – Dominated Zanamivir £52.98 0.0029 £34.06 0.0018 £18,717

Previously vaccinated individuals No prophylaxis £44.04 0.0032 – – – Amantadine £73.81 0.0030 – – Extendedly dominated Oseltamivir £83.28 0.0027 – – Dominated Zanamivir £82.79 0.0026 £38.75 0.0007 £59,412

TABLE 63 Cost-effectiveness of post-exposure prophylaxis – at-risk children

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £32.38 0.0119 – – – Amantadine £57.38 0.0098 – – Extendedly dominated Oseltamivir £63.82 0.0082 – – Dominated Zanamivir £61.45 0.0073 £29.07 0.0045 £6390

Previously vaccinated individuals No prophylaxis £53.42 0.0081 – – – Amantadine £82.29 0.0075 – – Extendedly dominated Oseltamivir £91.22 0.0068 – – Dominated Zanamivir £90.37 0.0065 £36.96 0.0016 £22,663

At-risk children and the discount rate. Amantadine and zanamivir The results of the simple sensitivity analysis for the remain dominated by oseltamivir in almost every at-risk children subgroup are presented in Table 70. scenario in this subgroup. The cost-effectiveness estimates for post-exposure prophylaxis are also The simple sensitivity analysis results presented sensitive to the influenza attack rate, the use of in Table 70 suggest that the base-case seasonal multiple prescriptions of prophylaxis at a single GP prophylaxis cost-effectiveness estimates for at- visit, vaccine efficacy, assumptions regarding the risk children are also sensitive to influenza attack relative effectiveness of oseltamivir and zanamivir rates, the level of resistance against oseltamivir, and the risk of hospitalisation in uncomplicated vaccine efficacy, the threshold used to describe cases. Amantadine and oseltamivir post-exposure when influenza is circulating in the community, prophylaxis are generally dominated or extendedly the risk of hospitalisation in uncomplicated cases 95

TABLE 64 Cost-effectiveness of post-exposure prophylaxis – healthy adults

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £9.23 0.0028 – – – Amantadine £38.54 0.0024 – – Extendedly dominated Zanamivir £47.03 0.0017 – – Dominated Oseltamivir £46.96 0.0017 £37.73 0.0011 £34,099

Previously vaccinated individuals No prophylaxis £37.40 0.0019 – – – Amantadine £67.84 0.0019 – – Extendedly dominated Zanamivir £77.51 0.0015 – – Dominated Oseltamivir £77.49 0.0015 £40.09 0.0004 £103,573

TABLE 65 Cost-effectiveness of post-exposure prophylaxis – at-risk adults

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £19.18 0.0064 – – – Amantadine £46.94 0.0055 – – Extendedly dominated Zanamivir £53.20 0.0040 – – Dominated Oseltamivir £53.09 0.0039 £33.92 0.0025 £13,539

Previously vaccinated individuals No prophylaxis £44.20 0.0044 – – – Amantadine £74.10 0.0041 – – Extendedly dominated Zanamivir £82.99 0.0035 – – Dominated Oseltamivir £82.96 0.0035 £38.75 0.0009 £44,163

dominated by zanamivir within the at-risk children influenza is circulating in the community, the risk subgroup. of hospitalisation in uncomplicated cases and the discount rate. The post-exposure prophylaxis Healthy adults healthy adult model is sensitive to the influenza The results of the simple sensitivity analysis for the attack rate, the use of multiple prescriptions of healthy adult subgroup are presented in Table 71. prophylaxis at a single GP visit, vaccine efficacy and the risk of hospitalisation in uncomplicated The results presented in Table 71 suggest that cases. the cost-effectiveness estimates for seasonal prophylaxis in healthy adults are sensitive to At-risk adults assumptions regarding influenza attack rates, The results of the simple sensitivity analysis for the the level of resistance against oseltamivir, vaccine at-risk adult subgroup are presented in Table 72. efficacy, the threshold used to describe when 96 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

TABLE 66 Cost-effectiveness of post-exposure prophylaxis – healthy elderly

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £17.70 0.0082 – – – Amantadine £45.74 0.0069 – – Extendedly dominated Zanamivir £52.28 0.0051 – – Dominated Oseltamivir £52.14 0.0050 £34.44 0.0032 £10,734

Previously vaccinated individuals No prophylaxis £43.78 0.0059 – – – Amantadine £73.56 0.0054 – – Extendedly dominated Zanamivir £82.30 0.0045 – – Dominated Oseltamivir £82.24 0.0045 £38.46 0.0013 £28,608

TABLE 67 Cost-effectiveness of post-exposure prophylaxis – at-risk elderly

Incremental Incremental cost per QALY Option Costs QALYs lost Incremental cost QALYs gained

Unvaccinated individuals No prophylaxis £22.75 0.0106 – – – Amantadine £49.95 0.0089 – – Extendedly dominated Zanamivir £55.39 0.0065 – – Dominated Oseltamivir £55.24 0.0064 £32.49 0.0041 £7892

Previously vaccinated individuals No prophylaxis £47.41 0.0075 – – – Amantadine £76.84 0.0069 – – Extendedly dominated Zanamivir £85.10 0.0058 – – Dominated Oseltamivir £85.04 0.0058 £37.63 0.0017 £21,749

The results presented in Table 72 suggest that vaccine efficacy and the risk of hospitalisation in the cost-effectiveness estimates for seasonal uncomplicated cases. prophylaxis in at-risk adults again are sensitive to assumptions regarding influenza attack rates, Healthy elderly the level of resistance against oseltamivir, vaccine The results of the simple sensitivity analysis for the efficacy, the threshold used to describe when healthy elderly subgroup are presented in Table 73. influenza is circulating in the community, the relative effectiveness of oseltamivir and zanamivir, Table 73 suggests that the cost-effectiveness the risk of hospitalisation in uncomplicated estimates are sensitive to assumptions regarding cases and the discount rate. The post-exposure influenza attack rates, the level of resistance prophylaxis healthy adult model is sensitive to against oseltamivir, vaccine efficacy, the threshold the influenza attack rate, the use of multiple used to describe when influenza is circulating prescriptions of prophylaxis at a single GP visit, in the community, the risk of hospitalisation in 97

TABLE 68 Summary of incremental cost-effectiveness ratios for influenza prophylaxis (base-case and secondary analysis including proposed price reduction for zanamivir)

Base case (incremental cost per QALY Price reduction for zanamivir (incremental gained) cost per QALY gained)

Population Amantadine Zanamivir Oseltamivir Amantadine Zanamivir Oseltamivir

Seasonal prophylaxis Healthy children Unvaccinated Ext dom Dom £44,007 Ext dom Dom £43,870 Vaccinated Dom Dom £129,357 Dom Dom £129,888 At-risk children Unvaccinated Ext dom Dom £16,630 Ext dom Dom £16,598 Vaccinated Ext dom Dom £51,069 Ext dom Dom £50,902 Healthy adults Unvaccinated Ext dom Ext dom £147,505 Ext dom Ext dom £147,083 Vaccinated Dom Ext dom £427,184 Dom Ext dom £427,802 At-risk adults Unvaccinated Ext dom Ext dom £63,552 Ext dom £53,159 £108,379 Vaccinated Dom Ext dom £186,651 Dom £157,216 £313,592 Healthy elderly Unvaccinated Ext dom Ext dom £49,742 Ext dom Ext dom £49,590 Vaccinated Dom Ext dom £121,728 Dom Ext dom £120,292 At-risk elderly Unvaccinated Ext dom Ext dom £38,098 Ext dom Ext dom £37,968 Vaccinated Ext dom Ext dom £93,763 Ext dom Ext dom £93,581

Post-exposure prophylaxis Healthy children Unvaccinated Ext dom £23,225 Ext dom Ext dom £18,717 Dom Vaccinated Ext dom £71,648 Ext dom Ext dom £59,412 Dom At-risk children Unvaccinated Ext dom £8233 Ext dom Ext dom £6390 Dom Vaccinated Ext dom £27,684 Ext dom Ext dom £22,663 Dom Healthy adults Unvaccinated Ext dom Dom £34,181 Ext dom Dom £34,099 Vaccinated Ext dom Dom £103,706 Ext dom Dom £103,573 At-risk adults Unvaccinated Ext dom Dom £13,459 Ext dom Dom £13,539 Vaccinated Ext dom Dom £43,970 Ext dom Dom £44,163 Healthy elderly Unvaccinated Ext dom Dom £10,716 Ext dom Dom £10,734 Vaccinated Ext dom Dom £28,473 Ext dom Dom £28,608 At-risk elderly Unvaccinated Ext dom Dom £7866 Ext dom Dom £7892 Vaccinated Ext dom Dom £21,608 Ext dom Dom £21,749

Dom, dominated; Ext dom, extendedly dominated. 98 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued £57,672 £88,526 £124,523 £124,523 £124,523 £124,523 £121,952 £138,807 £156,663 £179,620 £129,357 £129,888 £124,523 £124,523 £124,523 Dom Dom Dom Dom Dom Dom Dom Dom £1,599,296£332,782 £210,229 £253,083 Dom Dom Dom Dom Dom Dom Dom Ext dom Dom Dom Ext dom Dom Dom Dom Dom Dom Dom Ext dom Dom Dom Dom Dom Dom Dom Vaccinated £42,244 £42,244 £42,244 £42,244 £41,319 £47,387 £53,815 £62,079 £42,244 £44,007 £43,870 £42,244 £42,244 £42,244 £42,244 Dom Dom Dom Dom Dom Dom Dom Dom £573,163£117,218 £73,099 £88,526 Dom Dom Dom Dom Dom Dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Amantadine ZanamivirExt dom Oseltamivir Amantadine Zanamivir Oseltamivir Unvaccinated Ext dom Ext dom Ext dom Ext dom Sensitivity analysis – healthy children 7. 100% protection over influenza season Ext dom 8. No antiviral treatment 9. Best-case efficacy for NIs 10. No adverse events 11. No withdrawals 12. 10% resistance for oseltamivir13. 20% resistance for oseltamivir14. 30% resistance for oseltamivir Ext dom 15. 40% resistance for oseltamivir Ext dom 16. 50% resistance for oseltamivir Ext dom Ext dom Ext dom 6. Vaccine efficacy = 25% 6. Vaccine Seasonal prophylaxis Base case (stochastic model) Scenario reduction zanamivir 1. Price 2. Base-case deterministic model3. Oseltamivir as suspension 4. Multiple prescriptions efficacy = 50% Ext dom 5. Vaccine

TABLE 69 TABLE 99

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Assessment of cost-effectiveness £253,083 £60,243 £202,944 £124,839 £123,891 £114,902 £124,523 £127,052 £104,791 £103,495 Ext dom Dom Ext dom Ext dom £38,627 Ext dom Ext dom Ext dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom £71,648 £59,412 £71,668 £71,668 £61,717 £50,471 £32,302 £71,668 Dom Ext dom Dom Dom Dom Dom Dom Dom Dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Vaccinated £88,526 £19,104 £70,476 £42,560 £41,613 £38,980 £42,244 £43,102 £22,513 £35,111 Ext dom Dom Ext dom Ext dom £11,322 Ext dom Ext dom Ext dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom £23,225 £18,717 £23,217 £23,217 £19,634 £23,217 £23,217 £23,217 AmantadineExt dom Zanamivir Oseltamivir Amantadine Zanamivir Oseltamivir Unvaccinated Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Sensitivity analysis – healthy children (continued) 17. Attack rates halved Scenario 18. Attack rates doubled 19. Higher influenza threshold 20. GP consultation rates halved 21. GP consultation rates doubled to EQ-5D mapping function22. VAS loss for at-risk halved 23. QALY Ext dom 24. Complication disutilities halved Ext dom 25. 10% uncomplicated hospitalised26. Undiscounted Ext dom Ext dom prophylaxis Post-exposure Base case (stochastic model) reduction zanamivir 1. Price 2. Base-case deterministic model3. Oseltamivir as suspension 4. Multiple prescriptions efficacy = 50% Ext dom 5. Vaccine efficacy = 25% 6. Vaccine 7. 100% protection over influenza season Ext dom

100 69 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 £71,668 Ext dom £71,668 Ext dom £70,684 Ext dom £71,668 Ext dom £71,668 Ext dom £71,668 Ext dom £71,668 Ext dom £71,668 Ext dom £33,816 Ext dom £71,668 Ext dom £71,984 Ext dom £71,037 Ext dom £66,131 Ext dom £71,668 Ext dom £73,124 Ext dom £51,937 Ext dom £59,566 Ext dom £147,374 Ext dom £1,759,576 £59,607 Ext dom Vaccinated Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £9590 Ext dom £3485 Dom £23,217 Ext dom £23,217 Ext dom £22,863 Ext dom £23,217 Ext dom £23,217 Ext dom £23,217 Ext dom £23,217 Ext dom £23,217 Dom £50,471 Ext dom £23,217 Ext dom £23,533 Ext dom £22,585 Ext dom £21,423 Ext dom £23,217 Ext dom £23,688 Ext dom £19,296 Ext dom £630,864 £18,875 Unvaccinated AmantadineExt dom Zanamivir Oseltamivir Amantadine Zanamivir Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Scenario 8. No antiviral treatment 9. Best-case efficacy for NIs 10. No adverse events 11. No withdrawals 12. 10% resistance for oseltamivir Ext dom 13. 20% resistance for oseltamivir Ext dom 14. 30% resistance for oseltamivir Ext dom 15. 40% resistance for oseltamivir Ext dom 16. 50% resistance for oseltamivir Ext dom 17. Attack rates halved 18. Attack rates doubled 19. Higher influenza threshold 20. GP consultation rates halved 21. GP consultation rates doubled Ext dom 22. VAS to EQ-5D mapping function22. VAS Ext dom 23. QALY loss for at-risk halved 23. QALY 24. Complication disutilities halved Ext dom 25. 10% uncomplicated hospitalised Dom 26. Undiscounted Dom, dominated; EQ-5D, EuroQol-5D; Ext dom, extendedly dominated; GP, general practitioner; NI, neuraminidase inhibitor; QALY, quality-adjusted life-year; VAS, visual analogue life-year; VAS, quality-adjusted general practitioner; NI, neuraminidase inhibitor; QALY, Dom, dominated; EQ-5D, EuroQol-5D; Ext dom, extendedly GP, scale. 101

uncomplicated cases and the discount rate. The Uncertainty analysis results: proposed post-exposure prophylaxis healthy elderly model price reduction for zanamivir is sensitive to the influenza attack rate, the use of Table 76 presents the probability that each multiple prescriptions of prophylaxis at a single GP prophylactic option produces the greatest level visit, vaccine efficacy and the risk of hospitalisation of net benefit at thresholds of £20,000 per in uncomplicated cases. QALY gained and £30,000 per QALY gained, incorporating the proposed reduction in the price Healthy elderly of zanamivir. The option which is most likely Table 74 presents the results of the simple sensitivity to produce the greatest level of net benefit is analysis for the at-risk elderly subgroup. highlighted in bold for each comparison.

Table 74 suggests that the cost-effectiveness estimates are sensitive to assumptions regarding Budget impact analysis influenza attack rates, the level of resistance against oseltamivir, vaccine efficacy, the threshold This section presents estimates of the budget used to describe when influenza is circulating impact of a positive recommendation for each in the community, the risk of hospitalisation in prophylactic option within each model subgroup uncomplicated cases and the discount rate. The in the light of current NICE recommendations. post-exposure prophylaxis at-risk elderly model The analysis is based upon the expected cost of is sensitive to the influenza attack rate, the use of each prophylaxis strategy, including potential cost multiple prescriptions of prophylaxis at a single GP savings associated with the avoidance of influenza visit, vaccine efficacy, and the risk of hospitalisation and other ILIs. Separate budget impact analyses in uncomplicated cases. are presented for seasonal prophylaxis and post- exposure prophylaxis. NICE currently recommends Probabilistic sensitivity the use of oseltamivir as post-exposure prophylaxis analysis results in at-risk individuals aged over 13 years; this is taken to be the baseline cost, against which the Probabilistic sensitivity analysis was undertaken for incremental cost of each prophylactic option is the use of seasonal prophylaxis and post-exposure compared. prophylaxis using amantadine, oseltamivir and zanamivir in each of the six subgroups, for The population of England and Wales is currently vaccinated and unvaccinated patients. Cost- estimated to be around 53,728,600, based on effectiveness acceptability curves for these 24 base data from the ONS. Of this figure, approximately case health economic comparisons are presented in 11,295,800 are aged under 16, 33,822,300 are Appendix 8. Probability sensitivity analysis was also working-age adults and 8,610,500 are elderly. The undertaken for all health economic comparisons previous assessment by Turner et al.10 suggested incorporating the proposed reduction in the that approximately 12%, 25% and 42% of children, price of zanamivir. Cost-effectiveness acceptability adults and elderly individuals respectively would be curves for these comparisons are presented in considered high risk. Recent evidence suggests that Appendix 9. For clarity of reporting, the results of uptake of influenza vaccination is approximately the probabilistic sensitivity analysis are presented 79% in individuals over the age of 65 years and in tabular form in Tables 75 and 76. These tables around 42% in high-risk individuals who are under show the probability that each prophylactic option the age of 65. Data from the Department of Health produces the greatest incremental net benefit suggest that the residential care home population assuming cost-effectiveness thresholds of £20,000 in England and Wales is around 545,000 persons. per QALY gained and £30,000 per QALY gained. These data were synthesised to crudely estimate the number of individuals who fall into each of the Uncertainty analysis results: model subgroups (Table 77). base-case scenario Table 75 presents the probability that each For the seasonal prophylaxis budget impact model, prophylactic option produces the greatest level any individual within each subgroup could be of net benefit at thresholds of £20,000 per QALY potentially eligible to receive prophylaxis provided gained and £30,000 per QALY gained for the he or she is over the age specified within the base-case analysis. The option which is most likely licensed indications for each prophylaxis drug. to produce the greatest level of net benefit is The proportion of children who would be eligible highlighted in bold for each comparison. for prophylaxis using amantadine, oseltamivir 102 and zanamivir was estimated using data from the DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued £23,114 £51,069 £50,902 £48,943 £48,943 £48,943 £34,479 £22,081 £48,943 £48,118 £48,943 £48,943 £47,910 £54,683 £61,857 £71,082 £83,381 £100,601 £100,601 Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom £641,536 £132,625 Ext dom Dom Vaccinated Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £6583 £34,479 £16,630 £16,598 £15,882 £15,882 £15,882 £15,882 £15,882 £15,882 £15,595 £15,882 £15,882 £15,510 £17,948 £20,531 £23,852 £42,085 Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom £229,215£46,007 £28,280 Ext dom Ext dom Unvaccinated Amantadine ZanamivirExt dom Ext dom OseltamivirExt dom Ext dom Ext dom AmantadineExt dom Ext dom ZanamivirExt dom Ext dom Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £29,840 Sensitivity analysis – at-risk children 18. Attack rates doubled 17. Attack rates halved Seasonal prophylaxis Base case (stochastic model) Scenario 1. Price reduction zanamivir 1. Price 2. Base-case deterministic model 3. Oseltamivir as suspension 4. Multiple prescriptions efficacy = 50% 5. Vaccine efficacy = 25% 6. Vaccine 7. 100% protection over influenza season 8. No antiviral treatment 9. Best-case efficacy for NIs 10. No adverse events 11. No withdrawals 12. 10% resistance for oseltamivir 13. 20% resistance for oseltamivir 14. 30% resistance for oseltamivir 15. 40% resistance for oseltamivir 16. 50% resistance for oseltamivir

TABLE 70 TABLE 103

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Assessment of cost-effectiveness Ext dom Ext dom Ext dom Ext dom Ext dom £14,428 Ext dom Ext dom Dom Ext dom £35,925 £41,402 £49,435 £54,920 £52,179 £49,538 £48,653 £80,454 £705,940£27,705 £22,858 £27,226 £27,705 £11,887 £19,187 £23,706 £27,705 £27,705 £22,663 £27,684 Dom Dom Dom Dom Dom Dom Dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Vaccinated Ext dom £8341 £11,658 £16,041 £17,821 £16,932 £15,921 £15,863 £27,226 Ext dom Ext dom Ext dom Ext dom Ext dom £4075 Ext dom Ext dom Dom Ext dom £252,401£8236 £6491 £8073 £8236 £8236 £8236 £6797 £8236 £8236 £6390 £8233 Dom Dom Dom Dom Dom Dom Dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £2991 Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Unvaccinated AmantadineExt dom Zanamivir Oseltamivir Amantadine Zanamivir Oseltamivir Sensitivity analysis – at-risk children (continued) 9. Best-case efficacy for NIs 10. No adverse events 8. No antiviral treatment 7. 100% protection over influenza season 6. Vaccine efficacy = 25% 6. Vaccine 5. Vaccine efficacy = 50% 5. Vaccine 4. Multiple prescriptions 3. Oseltamivir as suspension 2. Base-case deterministic model 1. Price reduction zanamivir 1. Price Post-exposure prophylaxis Post-exposure Base case (stochastic model) 26. Undiscounted 25. 10% uncomplicated hospitalised 24. Complication disutilities halved 23. QALY loss for at-risk halved 23. QALY 22. VAS to EQ-5D mapping function 22. VAS 21. GP consultation rates doubled 20. GP consultation rates halved Scenario 19. Higher influenza threshold

104 70 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom £20,336 £20,165 £27,983 £31,088 £29,537 £27,943 £27,589 £27,705 £12,495 £58,125 £27,705 £27,705 £27,705 £27,705 £27,705 £27,310 Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Vaccinated Ext dom Ext dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom £6045 £696 £8319 £9242 £8781 £8147 £8280 £8236 £2761 £19,187 £8236 £8236 £8236 £8236 £8236 £8094 Ext dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Unvaccinated AmantadineExt dom Zanamivir Oseltamivir Amantadine Zanamivir Oseltamivir Dom, dominated; EQ-5D, EuroQol-5D; Ext dom, extendedly dominated; GP, general practitioner; NI, neuraminidase inhibitor; QALY, quality-adjusted life-year; VAS, visual analogue life-year; VAS, quality-adjusted general practitioner; NI, neuraminidase inhibitor; QALY, Dom, dominated; EQ-5D, EuroQol-5D; Ext dom, extendedly GP, scale. 26. Undiscounted 25. 10% uncomplicated hospitalised 24. Complication disutilities halved 23. QALY loss for at-risk halved 23. QALY 22. VAS to EQ-5D mapping function 22. VAS 21. GP consultation rates doubled 20. GP consultation rates halved 19. Higher influenza threshold 18. Attack rates doubled 17. Attack rates halved 16. 50% resistance for oseltamivir 15. 40% resistance for oseltamivir 14. 30% resistance for oseltamivir 13. 20% resistance for oseltamivir 12. 10% resistance for oseltamivir 11. No withdrawals Scenario 105

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Assessment of cost-effectiveness Dom Dom £427,184 £427,802 £410,832 £347,397 £410,832 £286,598 £189,972 £410,832 £410,832 £410,832 £410,832 £402,550 £456,845 £514,360 £588,309 £824,945 £203,776 Ext dom Ext dom Ext dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £607,181 £607,181 Ext dom Ext dom Vaccinated Amantadine Zanamivir Oseltamivir Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Ext dom Dom Dom Dom Dom Dom Dom Dom Dom £147,505 £147,083 £141,659 £119,456 £141,659 £141,659 £141,659 £141,659 £141,659 £141,659 £141,659 £138,760 £157,763 £177,894 £203,776 Dom Dom £286,598 £69,189 Ext dom Ext dom Ext dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £210,381 £210,381 Ext dom Ext dom Unvaccinated Amantadine Zanamivir Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Dom Ext dom Sensitivity analysis – healthy adults Scenario Seasonal prophylaxis Base case (stochastic model) 1. Price reduction zanamivir 1. Price 2. Base-case deterministic model Ext dom 3. Oseltamivir as suspension 4. Multiple prescriptions 5. Vaccine efficacy = 50% 5. Vaccine 6. Vaccine efficacy = 25% 6. Vaccine 7. 100% protection over influenza season Ext dom 8. No antiviral treatment 9. Best-case efficacy for NIs 10. No adverse events 11. No withdrawals 12. 10% resistance for oseltamivir Ext dom 13. 20% resistance for oseltamivir Ext dom 14. 30% resistance for oseltamivir Ext dom 15. 40% resistance for oseltamivir Ext dom 16. 50% resistance for oseltamivir Ext dom 17. Attack rates halved 18. Attack rates doubled

106 71 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued £55,124 £71,507 £46,578 £663,441 £411,095 £410,307 £385,758 £410,832 £414,940 £379,639 £347,440 £103,706 £103,573 £103,558 £103,558 £103,558 £103,558 £103,558 Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Dom Dom Dom Dom Dom Dom Dom Dom Dom £2,957,296 Vaccinated Amantadine Zanamivir Oseltamivir Dom Dom Dom Dom Dom Dom Dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £34,181 £34,099 £34,113 £34,113 £17,161 £34,113 £34,113 £34,113 £34,113 £34,113 £230,072 £141,921 £141,133 £133,013 £141,659 £143,075 £110,466 £119,801 Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Dom Ext dom Dom Dom Dom Dom Dom Dom Dom Dom Dom £1,032,921 Unvaccinated Amantadine Zanamivir Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Scenario 19. Higher influenza threshold 20. GP consultation rates halved 21. GP consultation rates doubled Ext dom 22. VAS to EQ-5D mapping function22. VAS Ext dom 23. QALY loss for at-risk halved 23. QALY 24. Complication disutilities halved Ext dom 25. 10% uncomplicated hospitalised Ext dom 26. Undiscounted Post-exposure prophylaxis Post-exposure Base case (stochastic model) 1. Price reduction zanamivir 1. Price 2. Base-case deterministic model Ext dom 3. Oseltamivir as suspension 4. Multiple prescriptions 5. Vaccine efficacy = 50% 5. Vaccine 6. Vaccine efficacy = 25% 6. Vaccine 7. 100% protection over influenza season Ext dom 8. No antiviral treatment 9. Best-case efficacy for NIs 107

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Assessment of cost-effectiveness £103,558 £101,422 £115,429 Ext dom Ext dom Ext dom Ext dom £210,397 £50,139 £103,558 £103,821 £103,033 £97,238 £103,558 £104,594 £72,366 £87,579 Dom Dom £253,847 £127,024 £127,024 £127,024 £127,024 Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Vaccinated Amantadine Zanamivir Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £34,113 £33,365 £38,268 Ext dom Ext dom Ext dom Ext dom £71,507 £15,416 £34,113 £34,376 £33,588 £32,031 £34,113 £34,454 £2920 £28,849 Dom Dom £86,714 £42,326 £42,326 £42,326 £42,326 Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Unvaccinated Amantadine Zanamivir Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Sensitivity analysis – healthy adults (continued) Scenario 10. No adverse events 11. No withdrawals 12. 10% resistance for oseltamivir Ext dom 13. 20% resistance for oseltamivir Ext dom 14. 30% resistance for oseltamivir Ext dom 15. 40% resistance for oseltamivir Ext dom 16. 50% resistance for oseltamivir Ext dom 17. Attack rates halved 18. Attack rates doubled 19. Higher influenza threshold 20. GP consultation rates halved 21. GP consultation rates doubled Ext dom 22. VAS to EQ-5D mapping function22. VAS Ext dom 23. QALY loss for at-risk halved 23. QALY 24. Complication disutilities halved Ext dom 25. 10% uncomplicated hospitalised Dom 26. Undiscounted Dom, dominated; EQ-5D, EuroQol-5D; Ext dom, extendedly dominated; GP, general practitioner; NI, neuraminidase inhibitor; QALY, quality-adjusted life-year; VAS, visual analogue life-year; VAS, quality-adjusted general practitioner; NI, neuraminidase inhibitor; QALY, Dom, dominated; EQ-5D, EuroQol-5D; Ext dom, extendedly GP, scale.

108 71 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued Dom Dom Dom £395,839 £199,287 £175,421 £179,061 £164,748 £177,346 Dom £81,979 £124,452 £179,061 £151,177 £179,061 £313,592 £186,651 £216,773 £216,773 £216,773 £216,773 Ext dom Ext dom Ext dom Ext dom Ext dom £150,850 Ext dom Ext dom Ext dom Dom Ext dom £157,216 Ext dom Dom Dom Dom Dom Dom Dom Ext dom Dom Dom Ext dom Ext dom Ext dom Dom Dom Dom Dom Dom Amantadine Zanamivir Oseltamivir Vaccinated Dom Dom Dom £136,614 £67,821 £59,468 £60,742 £55,732 £60,133 Dom £60,742 £60,742 £60,742 £50,982 £60,742 £108,379 £63,552 £73,941 £73,941 £73,941 £73,941 Ext dom Ext dom Ext dom Ext dom Ext dom £50,868 Ext dom Ext dom Ext dom Dom Ext dom £53,159 Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Unvaccinated Amantadine Zanamivir Oseltamivir Sensitivity analysis – at-risk adults 16. 50% resistance for oseltamivir Ext dom 15. 40% resistance for oseltamivir Ext dom 14. 30% resistance for oseltamivir Ext dom 13. 20% resistance for oseltamivir Ext dom 12. 10% resistance for oseltamivir Ext dom 11. No withdrawals 10. No adverse events 9. Best-case efficacy for NIs 8. No antiviral treatment 7. 100% protection over influenza season Ext dom 6. Vaccine efficacy = 25% 6. Vaccine 5. Vaccine efficacy = 50% 5. Vaccine 4. Multiple prescriptions 3. Oseltamivir as suspension 2. Base-case deterministic model Ext dom 1. Price reduction zanamivir 1. Price Seasonal prophylaxis Base case (stochastic model) Scenario

TABLE 72 TABLE 109

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Assessment of cost-effectiveness £43,542 £43,994 £18,947 £29,905 £22,704 £43,994 £43,994 £44,163 £43,970 £88,046 £151,197 £166,024 £180,476 £214,817 £189,314 £180,578 £178,314 £290,100 £361,091 Dom Dom Dom Dom Dom Dom Dom Dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Dom Dom Dom Dom Dom Dom Dom Dom Ext dom Dom Amantadine Zanamivir Oseltamivir Vaccinated £6017 £13,301 £13,468 £13,468 £13,468 £13,468 £13,468 £13,539 £13,459 £51,290 £47,704 £61,222 £72,871 £64,220 £61,130 £60,550 £99,605 £28,887 £124,452 Dom Dom Dom Dom Dom Dom Dom Dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Amantadine Zanamivir Oseltamivir Unvaccinated Sensitivity analysis – at-risk adults (continued) 8. No antiviral treatment 7. 100% protection over influenza season Ext dom 6. Vaccine efficacy = 25% 6. Vaccine 5. Vaccine efficacy = 50% 5. Vaccine 4. Multiple prescriptions 3. Oseltamivir as suspension 2. Base-case deterministic model Ext dom 1. Price reduction zanamivir 1. Price Post-exposure prophylaxis Post-exposure Base case (stochastic model) 26. Undiscounted 25. 10% uncomplicated hospitalised Ext dom 24. Complication disutilities halved Ext dom 23. QALY loss for at-risk halved 23. QALY 22. VAS to EQ-5D mapping function22. VAS Ext dom 21. GP consultation rates doubled Ext dom 20. GP consultation rates halved 19. Higher influenza threshold 18. Attack rates doubled 17. Attack rates halved Scenario

110 72 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 £37,148 £30,956 £44,342 £52,779 £46,513 £44,223 £43,881 £43,994 £20,513 £90,957 Ext dom Ext dom Ext dom Ext dom £49,212 £43,055 £43,994 Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom £54,309 £54,309 £54,309 £54,309 £110,056 Dom Dom £1,298,402 £43,994 Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Amantadine Zanamivir Oseltamivir Vaccinated £11,372 £430 £13,575 £16,158 £14,239 £13,406 £13,499 £13,468 £5250 £29,905 Ext dom Ext dom Ext dom Ext dom £15,295 £13,140 £13,468 £13,468 Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom £17,078 £17,078 £17,078 £17,078 £36,590 Dom Dom £452,511 Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Unvaccinated Amantadine Zanamivir Oseltamivir Dom, dominated; EQ-5D, EuroQol-5D; ext dom, extendedly dominated; GP, general practitioner; NI, neuraminidase inhibitor; QALY, quality-adjusted life-year; VAS, visual analogue life-year; VAS, quality-adjusted general practitioner; NI, neuraminidase inhibitor; QALY, Dom, dominated; EQ-5D, EuroQol-5D; ext dom, extendedly GP, scale. 26. Undiscounted 25. 10% uncomplicated hospitalised Dom 24. Complication disutilities halved Ext dom 23. QALY loss for at-risk halved 23. QALY 22. VAS to EQ-5D mapping function22. VAS Ext dom 21. GP consultation rates doubled Ext dom 20. GP consultation rates halved 19. Higher influenza threshold 18. Attack rates doubled 17. Attack rates halved 16. 50% resistance for oseltamivir Ext dom 15. 40% resistance for oseltamivir Ext dom 14. 30% resistance for oseltamivir Ext dom 13. 20% resistance for oseltamivir Ext dom 12. 10% resistance for oseltamivir Ext dom 11. No withdrawals 10. No adverse events 9. Best-case efficacy for NIs Scenario 111

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Assessment of cost-effectiveness £121,728 £120,292 £116,346 £98,192 £116,346 £97,384 £64,201 £116,346 £115,020 £116,346 £116,346 £113,976 £129,515 £145,975 £167,138 Dom Dom £234,859 £57,090 Ext dom Ext dom Ext dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £176,176 £176,176 Ext dom Ext dom Vaccinated Amantadine Zanamivir Oseltamivir Dom Dom Dom Dom Dom Ext dom Ext dom Ext dom Dom Dom Ext dom Ext dom Dom Dom Dom Dom Dom Dom Ext dom £49,742 £49,590 £47,609 £39,984 £47,609 £47,609 £47,609 £47,609 £47,055 £47,609 £47,609 £46,613 £53,140 £60,053 £68,941 Dom Dom £97,384 £22,721 Ext dom Ext dom Ext dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £72,737 £72,737 Ext dom Ext dom Unvaccinated Amantadine Zanamivir Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Sensitivity analysis – healthy elderly Scenario Seasonal prophylaxis Base case (stochastic model) 1. Price reduction zanamivir 1. Price 2. Base-case deterministic model Ext dom 3. Oseltamivir as suspension 4. Multiple prescriptions 5. Vaccine efficacy = 50% 5. Vaccine 6. Vaccine efficacy = 25% 6. Vaccine 7. 100% protection over influenza season Ext dom 8. No antiviral treatment 9. Best-case efficacy for NIs 10. No adverse events 11. No withdrawals 12. 10% resistance for oseltamivir Ext dom 13. 20% resistance for oseltamivir Ext dom 14. 30% resistance for oseltamivir Ext dom 15. 40% resistance for oseltamivir Ext dom 16. 50% resistance for oseltamivir Ext dom 17. Attack rates halved 18. Attack rates doubled

112 73 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued £28,473 £28,608 £28,597 £28,597 £14,651 £23,675 £15,061 £28,597 £28,257 £28,597 £28,597 £188,639 £115,805 £117,447 £121,537 £116,346 £116,950 £103,957 £108,402 Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Dom Dom Dom Dom Dom Dom Dom Dom Dom £850,316 Dom Vaccinated Amantadine Zanamivir Oseltamivir Dom Dom Dom Dom Dom Dom Dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £4897 £10,716 £10,734 £10,754 £10,754 £10,754 £10,754 £10,754 £10,615 £10,754 £10,754 £77,972 £47,456 £47,919 £49,733 £47,609 £47,856 £35,219 £44,358 Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Dom Ext dom Dom Dom Dom Dom Dom Dom Dom Dom Dom £355,876 Dom Unvaccinated Amantadine Zanamivir Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Scenario 19. Higher influenza threshold 20. GP consultation rates halved 21. GP consultation rates doubled Ext dom 22. VAS to EQ-5D mapping function22. VAS Ext dom 23. QALY loss for at-risk halved 23. QALY 24. Complication disutilities halved Ext dom 25. 10% uncomplicated hospitalised Ext dom 26. Undiscounted Post-exposure prophylaxis Post-exposure Base case (stochastic model) reduction zanamivir 1. Price 2. Base-case deterministic model3. Oseltamivir as suspension 4. Multiple prescriptions Ext dom efficacy = 50% 5. Vaccine efficacy = 25% 6. Vaccine 7. 100% protection over influenza season Ext dom 8. No antiviral treatment 9. Best-case efficacy for NIs 10. No adverse events 113

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Assessment of cost-effectiveness £27,982 £32,015 Ext dom Ext dom Ext dom Ext dom £59,361 £13,215 £28,597 £28,552 £28,689 £29,873 £28,597 £28,746 £16,207 £26,645 Dom £71,872 £35,354 £35,354 £35,354 £35,354 Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Vaccinated Amantadine Zanamivir Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Dom Ext dom £10,496 £12,190 Ext dom Ext dom Ext dom Ext dom £23,675 £4294 £10,754 £10,810 £10,641 £11,234 £10,754 £10,810 Dom £10,020 Dom £28,930 £13,592 £13,592 £13,592 £13,592 Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Unvaccinated Amantadine Zanamivir Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Sensitivity analysis – healthy elderly (continued) Scenario 11. No withdrawals 12. 10% resistance for oseltamivir Ext dom 13. 20% resistance for oseltamivir Ext dom 14. 30% resistance for oseltamivir Ext dom 15. 40% resistance for oseltamivir Ext dom 16. 50% resistance for oseltamivir Ext dom 17. Attack rates halved 18. Attack rates doubled 19. Higher influenza threshold 20. GP consultation rates halved 21. GP consultation rates doubled Ext dom 22. VAS to EQ-5D mapping function22. VAS Ext dom 23. QALY loss for at-risk halved 23. QALY 24. Complication disutilities halved Ext dom 25. 10% uncomplicated hospitalised Dom 26. Undiscounted Dom, dominated; EQ-5D, EuroQol-5D; Ext dom, extendedly dominated; GP, general practitioner; NI, neuraminidase inhibitor; QALY, quality-adjusted life-year; VAS, visual analogue life-year; VAS, quality-adjusted general practitioner; NI, neuraminidase inhibitor; QALY, Dom, dominated; EQ-5D, EuroQol-5D; Ext dom, extendedly GP, scale.

114 73 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued £93,763 £93,581 £89,781 £75,699 £89,781 £75,072 £49,331 £89,781 £88,639 £89,781 £89,781 £87,942 £99,996 £112,764 £129,181 Dom Dom Ext dom Ext dom Ext dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £136,192 £136,192 Vaccinated Amantadine Zanamivir Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £38,098 £37,968 £36,460 £30,545 £36,460 £36,460 £36,460 £36,460 £35,983 £36,460 £36,460 £35,688 £40,750 £46,113 £53,008 Dom Dom Ext dom Ext dom Ext dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £55,953 £55,953 Unvaccinated Amantadine Zanamivir Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Sensitivity analysis – at-risk elderly Scenario Seasonal prophylaxis Base case (stochastic model) 1. Price reduction zanamivir 1. Price 2. Base-case deterministic model Ext dom 3. Oseltamivir as suspension 4. Multiple prescriptions 5. Vaccine efficacy = 50% 5. Vaccine 6. Vaccine efficacy = 25% 6. Vaccine 7. 100% protection over influenza season Ext dom 8. No antiviral treatment 9. Best-case efficacy for NIs 10. No adverse events 11. No withdrawals 12. 10% resistance for oseltamivir Ext dom 13. 20% resistance for oseltamivir Ext dom 14. 30% resistance for oseltamivir Ext dom 15. 40% resistance for oseltamivir Ext dom 16. 50% resistance for oseltamivir Ext dom

TABLE 74 TABLE 115

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Assessment of cost-effectiveness £43,815 £89,304 £90,754 £92,858 £90,288 £80,480 £83,016 £21,608 £21,749 £21,712 £21,712 £10,894 £17,894 £11,212 £21,712 £21,419 £181,714 £145,860 £141,511 Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Vaccinated Amantadine Zanamivir Oseltamivir Dom Ext dom Dom Ext dom Ext dom Ext dom Dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom £7866 £7892 £7871 £7871 £3327 £7871 £7871 £7871 £7750 £75,072 £17,154 £60,013 £36,317 £36,751 £37,709 £57,467 £36,666 £27,159 £33,713 Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Dom Ext dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Unvaccinated Amantadine Zanamivir Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Sensitivity analysis – at-risk elderly (continued) Scenario 17. Attack rates halved 18. Attack rates doubled 19. Higher influenza threshold 20. GP consultation rates halved 21. GP consultation rates doubled Ext dom 22. VAS to EQ-5D mapping function22. VAS Ext dom 23. QALY loss for at-risk halved 23. QALY 24. Complication disutilities halved Ext dom 25. 10% uncomplicated hospitalised Ext dom 26. Undiscounted Post-exposure prophylaxis Post-exposure Base case (stochastic model) 1. Price reduction zanamivir 1. Price 2. Base-case deterministic model Ext dom 3. Oseltamivir as suspension 4. Multiple prescriptions 5. Vaccine efficacy = 50% 5. Vaccine 6. Vaccine efficacy = 25% 6. Vaccine 7. 100% protection over influenza season Ext dom 8. No antiviral treatment

116 74 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 £21,712 £21,712 £21,235 £24,364 Ext dom Ext dom Ext dom Ext dom £45,576 £9780 £21,712 £21,662 £21,814 £22,456 £34,222 £21,835 £12,411 £20,076 £659,137 Dom Dom £55,281 £26,954 £26,954 £26,954 £26,954 Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Vaccinated Amantadine Zanamivir Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Dom Ext dom £7871 £7871 £7671 £8985 Ext dom Ext dom Ext dom Ext dom £17,894 £2860 £7871 £7908 £7796 £8141 £12,406 £7915 Dom £7278 £275,589 Dom Dom £21,970 £10,072 £10,072 £10,072 £10,072 Dom Dom Dom Dom Dom Dom Dom Dom Dom Dom Unvaccinated Amantadine Zanamivir Oseltamivir Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Ext dom Scenario 9. Best-case efficacy for NIs 10. No adverse events 11. No withdrawals 12. 10% resistance for oseltamivir Ext dom 13. 20% resistance for oseltamivir Ext dom 14. 30% resistance for oseltamivir Ext dom 15. 40% resistance for oseltamivir Ext dom 16. 50% resistance for oseltamivir Ext dom 17. Attack rates halved 18. Attack rates doubled 19. Higher influenza threshold 20. GP consultation rates halved 21. GP consultation rates doubled Ext dom 22. VAS to EQ-5D mapping function22. VAS Ext dom 23. QALY loss for at-risk halved 23. QALY 24. Complication disutilities halved Ext dom 25. 10% uncomplicated hospitalised Dom 26. Undiscounted Dom, dominated; EQ-5D, EuroQol-5D; Ext dom, extendedly dominated; GP, general practitioner; NI, neuraminidase inhibitor; QALY, quality-adjusted life-year; VAS, visual analogue life-year; VAS, quality-adjusted general practitioner; NI, neuraminidase inhibitor; QALY, Dom, dominated; EQ-5D, EuroQol-5D; Ext dom, extendedly GP, scale. 117

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Assessment of cost-effectiveness 0.00 0.01 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.01 0.00 0.00 0.00 0.08 0.00 0.00 0.00 0.00 0.00 0.00 0.03 0.94 0.00 0.03 0.00 0.02 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.03 0.00 0.00 1.00 0.89 1.00 1.00 1.00 1.00 1.00 1.00 0.97 0.02 1.00 0.97 Probability optimal at £30,000/QALY Probability 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.70 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.03 0.00 0.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 0.27 1.00 1.00 Probability optimal at £20,000/QALY Probability prophylaxisNo Amantadine Oseltamivir Zanamivirprophylaxis No Amantadine Oseltamivir Zanamivir Uncertainty analysis results: probability of being optimal at willingness-to-pay thresholds (base-case scenario) Vaccinated At-risk elderly Unvaccinated Vaccinated Healthy elderly Unvaccinated Vaccinated At-risk adults Unvaccinated Vaccinated Healthy adults Unvaccinated Vaccinated At-risk children Unvaccinated Vaccinated Seasonal prophylaxis Healthy children Unvaccinated Population

118 75 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 0.07 0.23 0.03 0.18 0.00 0.16 0.00 0.00 0.31 0.73 0.00 0.45 0.78 0.77 0.50 0.82 0.04 0.84 0.00 0.19 0.29 0.27 0.00 0.40 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.15 0.00 0.47 0.00 0.96 0.00 1.00 0.81 0.39 0.00 1.00 0.15 Probability optimal at £30,000/QALY Probability 0.01 0.17 0.00 0.13 0.00 0.10 0.00 0.00 0.08 0.67 0.00 0.15 0.35 0.83 0.09 0.87 0.00 0.89 0.00 0.00 0.11 0.33 0.00 0.22 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.64 0.00 0.91 0.00 1.00 0.02 1.00 1.00 0.81 0.00 1.00 0.63 No prophylaxisNo Amantadine Oseltamivir Zanamivirprophylaxis No Amantadine Oseltamivir Zanamivir Probability optimal at £20,000/QALY Probability QALY, quality-adjusted life-year. quality-adjusted QALY, Vaccinated At-risk elderly Unvaccinated Vaccinated Healthy elderly Unvaccinated Vaccinated At-risk adults Unvaccinated Vaccinated Healthy adults Unvaccinated Vaccinated At-risk children Unvaccinated Vaccinated Post-exposure prophylaxis Post-exposure Healthy children Unvaccinated Population 119

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Assessment of cost-effectiveness 0.00 0.00 0.05 0.00 0.00 0.00 0.01 0.00 0.03 0.00 0.16 0.00 0.03 0.00 0.91 0.03 0.00 0.00 0.00 0.00 0.00 0.00 0.05 0.00 0.00 0.00 0.02 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.02 0.00 0.97 1.00 0.01 0.97 1.00 1.00 0.99 1.00 0.97 1.00 0.77 1.00 Probability optimal at £30,000/QALY Probability 0.00 0.00 0.03 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.70 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.03 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Probability optimal at £20,000/QALY Probability No prophylaxis Amantadine Oseltamivir Zanamivir No prophylaxis Amantadine Oseltamivir Zanamivir Uncertainty analysis results: probability of being optimal at willingness-to-pay thresholds (incorporating proposed reduction in price of zanamivir) Population Seasonal prophylaxis Healthy children UnvaccinatedVaccinatedAt-risk children 1.00 Unvaccinated 1.00 Vaccinated Healthy adults 0.25 Unvaccinated 1.00 VaccinatedAt-risk adults 1.00 Unvaccinated 1.00 Vaccinated Healthy elderly 1.00 Unvaccinated 1.00 Vaccinated At-risk elderly 1.00 Unvaccinated 1.00 Vaccinated 0.99 1.00

120 76 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 0.79 0.01 0.85 0.65 0.06 0.00 0.41 0.01 0.38 0.20 0.40 0.34 0.15 0.00 0.15 0.12 0.18 0.00 0.59 0.04 0.62 0.38 0.60 0.54 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.06 0.99 0.00 0.24 0.76 1.00 0.00 0.95 0.00 0.42 0.00 0.11 Probability optimal at £30,000/QALY Probability 0.47 0.00 0.85 0.26 0.00 0.00 0.40 0.00 0.38 0.03 0.40 0.15 0.09 0.00 0.15 0.04 0.00 0.00 0.59 0.00 0.62 0.07 0.60 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Probability optimal at £20,000/QALY Probability No prophylaxis Amantadine Oseltamivir Zanamivir No prophylaxis Amantadine Oseltamivir Zanamivir

Population prophylaxis Post-exposure Healthy children Unvaccinated Vaccinated At-risk children 0.44 Unvaccinated 1.00 Vaccinated Healthy adults 0.00 Unvaccinated 0.70 Vaccinated At-risk adults 1.00 Unvaccinated 1.00 Vaccinated Healthy elderly 0.00 Unvaccinated 1.00 Vaccinated At-risk elderly 0.00 Unvaccinated 0.90 Vaccinated 0.00 life-year. quality-adjusted QALY, 0.60 121

TABLE 77 Number of individuals in each model subgroup

Population group No. of individuals Community dwelling Residential care home

Healthy children Unvaccinated 9,940,304 9,940,304 0 Vaccinated 0 0 0

At-risk children Unvaccinated 784,832 784,832 0 Vaccinated 570,664 570,664 0

Healthy adults Unvaccinated 25,366,725 25,366,725 0 Vaccinated 0 0 0

At-risk adults Unvaccinated 4,895,778 4,895,778 0 Vaccinated 3,559,797 3,559,797 0

Healthy elderly Unvaccinated 1,033,777 968,344 65,433 Vaccinated 3,960,313 3,709,646 250,667

At-risk elderly Unvaccinated 748,597 701,215 47,382 Vaccinated 2,867,813 2,686,295 181,518

ONS. The estimated budget impact for seasonal that if a household is infected, all contact cases will prophylaxis options is presented in Table 78. be eligible for prophylaxis if they present within 48 hours of contact with the index case. The model For the post-exposure prophylaxis budget impact estimates the additional cost of each policy in the model, the population of interest relates to light of the existing NICE guidance (the ‘current individuals who have come into contact with an policy cost’ column details the expected cost per index ILI case. The number of potentially eligible patient of prophylaxis according to current NICE contact cases is crudely estimated by multiplying guidance). The budget impact for the residential the number of individuals in each model subgroup care home population was based on an assumed by an estimated overall household ILI attack ILI attack rate of 41%.132 The estimated budget rate (the estimated household influenza attack impact for post-exposure prophylaxis options is rate multiplied by the probability that ILI is presented in Tables 79 and 80. influenza).20 The budget impact model assumes

122 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 £0 £0 £0 £0 £0 £0 Additional budget impact over eligible population Amantadine Zanamivir Oseltamivir Current cost Expected cost per patient NP Amantadine Zanamivir Oseltamivir Current policy – NP £35.64 £71.34 £133.74 £141.62 £35.64 – NP £43.23 £78.64 £140.36 £115.05 £43.23 No. of individuals Seasonal prophylaxis budget impact estimates At-risk adults UnvaccinatedVaccinated 4,846,375Healthy elderly NPUnvaccinated 3,523,875Vaccinated NP 1,033,813 £13.57At-risk elderly NPUnvaccinated £52.74 3,960,451 £40.39Vaccinated NP £75.94 £10.43 748,623 no prophylaxis NP, £108.33 NP £49.93 2,867,913 £38.59 £137.67 NP £115.63 £74.16 £13.45 £106.16 £145.53 £52.63 £40.75 £13.57 £136.02 £76.25 £112.80 £189,831,470 £40.39 £108.39 £143.54 £459,262,856 £125,278,544 £10.43 £137.84 £494,635,028 £114.54 £342,831,299 £40,836,559 £38.59 £145.15 £370,497,449 £140,896,254 £98,974,490 £13.45 £385,872,027 £40.75 £105,837,889 £29,333,408 £415,636,663 £101,827,060 £71,075,149 £278,453,842 £75,678,598 £299,415,220 Vaccinated At-risk children UnvaccinatedVaccinatedHealthy adults 808,567Unvaccinated NP 587,921 25,110,750 NP NP £29.89 £66.92 £51.71 £6.63 £86.84 £46.49 £121.56 £147.86 £103.70 £93.57 £122.06 £111.09 £29.89 £51.71 £13,970,266 £6.63 £9,632,657 £26,347,333 £1,000,937,591 £2,437,345,426 £20,090,863 £48,599,333 £2,622,899,442 £39,033,738 Vaccinated Population Population group Healthy children Unvaccinated 10,240,912 NP £17.72 £56.23 £112.15 £85.51 £17.72 £183,952,396 £343,735,708 £655,247,656

TABLE 78 TABLE 123

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Assessment of cost-effectiveness £0 £0 £0 £0 £0 £0 £0 £0 £0 £0 £0 £0 £0 £0 Additional budget impact over eligible population Amantadine Zanamivir Oseltamivir Current cost NP Amantadine Zanamivir Oseltamivir Expected cost per patient Current policy – NP £37.36 £67.80 £85.67 £77.46 £37.36 – NP £44.09 £73.84 £91.00 £83.30 £44.09 163,273118,719 Ose/NP Ose/NP £32.56 £53.57 £57.55 £82.44978,625711,574 £69.76 Ose £98.67 Ose195,544 £63.97749,114 £19.34 £91.35 Ose £44.32 £47.99 Ose £47.10141,601 £72.13 £74.21542,462 £17.75 –£254,503 Ose £43.82 £61.49 –£256,859 Ose £45.76 £91.27 –£1,873,897 £73.59 £22.88 –£1,966,380 £53.18 £47.50 £60.50 £83.04 £50.05 £90.52 £24.61 £76.92 £52.17 £50.35 £63.68 £82.27 –£927,521 £93.37 –£978,796 £21.63 £55.33 £48.16 £1,265,252 £85.11 –£141,505 £911,673 –£733,300 £26.54 £51.75 £183,604 –£84,394 £696,777 –£500,882 £133,358 £505,397 No. of individuals Post-exposure prophylaxis budget impact estimates (including community-dwelling elderly) prophylaxis budget impact estimates (including community-dwelling Post-exposure At-risk children Unvaccinated Vaccinated Healthy adults UnvaccinatedVaccinated At-risk adults 5,070,595Unvaccinated Vaccinated NPHealthy elderly Unvaccinated £9.17Vaccinated At-risk elderly £38.48Unvaccinated Vaccinated no prophylaxis; Ose, oseltamivir. NP, £55.19 £46.94 £9.17 £23,136,834 £36,323,410 £29,814,690 Population group Population Healthy children UnvaccinatedVaccinated 2,067,940 NP £18.96 £46.40 £61.18 £54.35 £18.96 £31,971,071 £16,526,348 £35,963,481

124 79 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 Zanamivir Oseltamivir Additional budget impact over eligible population Amantadine Current cost Expected cost per patient NP Amantadine Zanamivir Oseltamivir Current policy 74,422 Ose £47.50 £76.92 £93.37 £85.11 £51.75 –£68,717.81 £3,097,413 £0.00 102,774 Ose £43.82 £73.59 £90.52 £82.27 £48.16 –£100,603.99 £4,352,991 £0.00 No. of individuals Post-exposure prophylaxis budget impact estimates: residential care elderly Post-exposure Population group Population Healthy elderly Unvaccinated 26,827 Ose £17.75 £45.76 £60.50 £52.17 £21.63 –£19,413.59 £25,189 £0.00 Vaccinated At-risk elderly Unvaccinated 19,427 Ose £22.88 £50.05 £63.68 £55.33 £26.54 –£11,578.37 £721,445 £0.00 Vaccinated Vaccinated NP, no prophylaxis; Ose, oseltamivir. NP, able 80

T 125

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Chapter 5 Assessment of factors relevant to the NHS and other parties

Use of amantadine for Additional support Parkinson’s disease and in using antivirals herpes zoster virus In the clinical effectiveness review, a number of issues were identified relating to the external It should be borne in mind that, as amantadine validity of a minority of the oseltamivir and is also licensed for the treatment of Parkinson’s zanamivir trials; these are discussed in Chapter disease and herpes zoster, individuals receiving the 6. It was noted that in some studies, subjects who drug for these conditions may be protected against had lower levels of cognitive function and/or influenza A. manual dexterity were excluded from participation. Therefore, it is possible that the reported levels of adherence and acceptability of the use of Herd immunity the Diskhaler device for delivery of zanamivir, and the ability of subjects to take oral antivirals The concept of herd immunity postulates independently, may not accurately reflect the that the higher the proportion of individuals scenario in the general population, and that in a population who are protected from an older individuals or those with lower cognitive infection, the less likely it is that an outbreak functioning and/or manual dexterity may require of the same infection may become established additional support from health- and social care in that community. With respect to influenza, it professionals or carers in administration of could be proposed that, where the number of antivirals. individuals who are able to transmit the virus is reduced as a result of vaccination and/or influenza prophylaxis, unprotected individuals are less Prescribing patterns for likely to become exposed to infection and are thus influenza prophylaxis indirectly protected. Although this concept has not been modelled in this assessment, it should It was typically stipulated in the study inclusion be considered that influenza prophylaxis in at- criteria in the clinical trials of the use of oseltamivir risk groups may result in herd immunity effects and zanamivir in post-exposure prophylaxis in the population with which they are in contact. that the administration of antivirals should be Additional studies that examine the degree of viral commenced within 48 hours of exposure to the shedding among subjects receiving prophylaxis ILI index case for oseltamivir and within 36 versus placebo may provide further information hours for zanamivir. In clinical practice, this with regard to this effect. requirement may be problematic, as it relies on both the identification of index cases and the An additional issue relating to immunity initiation of prophylaxis in contact cases within against influenza was raised by study authors, the recommended cut-off period. In addition, who proposed that, while antivirals may be initiation of post-exposure prophylaxis relies on effective in preventing the development of the patient having access to GP services within the SLCI, asymptomatic individuals may in fact have specified time period. The requirement for testing subclinical influenza infection, which may have of creatinine clearance for dose adjustment for the potential to confer immunity to the circulating amantadine and oseltamivir also has the potential strain on the exposed individual. to affect the speed with which prophylaxis may be implemented.

127

A GP can usually prescribe medication only for primary health-care professionals. It should be individuals who present for consultation. The noted that the economic analysis presented here requirement for early identification of index cases makes very few assumptions about the way in and contact cases in post-exposure prophylaxis which prophylaxis would be implemented or the may lead to variations in prescribing practices, infrastructure required to manage this. In certain e.g. giving multiple prescriptions of prophylaxis to patient groups, this may be a lesser issue (e.g. household contacts. the use of post-exposure prophylaxis to manage opportunistically outbreaks in residential care The future use of rapid diagnostic tests for homes) while for other settings the infrastructure influenza in clinical practice could be anticipated may be of greater concern (e.g. introducing routine to facilitate the rapid identification of influenza- prophylaxis in schools). positive index cases and the circulation of influenza in the local community and, as such, has the potential to increase the clinical effectiveness of Involvement of pharmacist antivirals in prophylaxis. in use of powder for oral suspension Impact on primary care As noted in Chapter 1, the summary of product characteristics for oseltamivir recommends that Raised awareness of the availability of antiviral powder for oral suspension should be reconstituted prophylaxis among the general population may by a pharmacist before being dispensed to the lead to increased workloads for GPs and other patient.

128 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Chapter 6 Discussion

Statement of does not affect this finding. The incremental cost- principal findings effectiveness of oseltamivir versus no prophylaxis is expected to be greater than £44,000 per QALY Clinical effectiveness review gained. Assuming a willingness-to-pay threshold Twenty-six published references and one of £30,000 per QALY gained, the probability that unpublished report relating to a total of 23 no prophylaxis produces the greatest level of net RCTs were included in the review of clinical benefit is expected to be around 0.97. effectiveness. The quality of the studies identified was variable and gaps in the evidence base limited In at-risk children the assessment of the clinical effectiveness of the Amantadine and zanamivir as seasonal prophylaxis interventions across population subgroups and are expected to be dominated or extendedly settings. The evidence for amantadine prophylaxis dominated in the at-risk children subgroup. Again, across subgroups was very limited. However, the proposed reduction in the price of zanamivir evidence of the effectiveness of amantadine in does not affect this finding. The incremental cost- preventing SLCI in outbreak control among effectiveness of oseltamivir versus no prophylaxis is adolescent subjects was identified. Oseltamivir expected to be around £17,000 per QALY gained was shown to be effective in preventing SLCI in for at-risk children who have not been vaccinated. a number of subgroups, particularly in seasonal For at-risk children who have previously been prophylaxis in at-risk elderly subjects and in post- vaccinated, the incremental cost-effectiveness exposure prophylaxis in households of mixed of oseltamivir versus no prophylaxis is expected composition. The effectiveness of zanamivir in to be in excess of £50,000 per QALY gained. preventing SLCI was also demonstrated, and was The cost-effectiveness estimates for oseltamivir most convincing in trials of seasonal prophylaxis are based on efficacy data that have been drawn in at-risk adults and adolescents and in healthy from a trial of seasonal prophylaxis in healthy and at-risk elderly subjects and in post-exposure adults. Assuming a willingness-to-pay threshold prophylaxis in mixed households. Interventions of £20,000 per QALY gained, the probability appeared to be tolerated reasonably well by that oseltamivir is optimal in unvaccinated at-risk subjects, with a relatively low proportion of subjects children is approximately 0.70 (this probability is experiencing drug-related adverse events and also 0.70 when the proposed price reduction for drug-related withdrawals. Very limited evidence was zanamivir is included). Assuming a willingness- reported for the effectiveness of the interventions to-pay threshold of £30,000 per QALY gained, in preventing complications, hospitalisations and the probability that oseltamivir is optimal in in minimising length of illness and time to return unvaccinated at-risk children is around 0.94 (p to normal activities. No data could be identified = 0.91 when the proposed price reduction for for HRQoL or mortality outcomes. Additional zanamivir is included). For at-risk children who consideration should be paid to the issues of have previously been vaccinated, the probability antiviral resistance and adverse events associated that no prophylaxis is optimal at £30,000 per with amantadine during the interpretation of the QALY gained is approximately 0.97 or higher. findings of the review. In healthy adults Cost-effectiveness review Amantadine and zanamivir as seasonal prophylaxis Cost-effectiveness of amantadine, are expected to be dominated or extendedly zanamivir and oseltamivir as dominated in the healthy adult subgroup. The seasonal prophylaxis incremental cost-effectiveness of oseltamivir versus In healthy children no prophylaxis is expected to be around £148,000 per QALY gained for healthy adults who have Amantadine and zanamivir as seasonal prophylaxis not been vaccinated and more than £427,000 per are expected to be dominated or extendedly QALY gained for healthy adults who have been dominated in the healthy children subgroup. vaccinated. These estimates are based on a trial The proposed reduction in the price of zanamivir of oseltamivir as seasonal prophylaxis in healthy 129

adults. Assuming a willingness-to-pay threshold of probability is around 0.97 and 1.0 when the £30,000 per QALY gained, the probability that no proposed price reduction for zanamivir is included prophylaxis is optimal is close to 1.0, irrespective of in the analysis for unvaccinated and vaccinated vaccination status. subgroups respectively).

In at-risk adults In at-risk elderly individuals Based on the current list price for zanamivir, In this subgroup, amantadine and zanamivir are the model suggests that both amantadine and expected to be extendedly dominated despite zanamivir are ruled out of the analysis in at-risk the proposed reduction in the price of zanamivir. adults. The incremental cost-effectiveness of The incremental cost-effectiveness of oseltamivir oseltamivir versus no prophylaxis is expected to be versus no prophylaxis in at-risk elderly individuals around £64,000 per QALY gained in unvaccinated who have not been vaccinated is expected to be at-risk adults and around £187,000 per QALY around £38,000 per QALY gained. For previously gained in previously vaccinated at-risk adults. vaccinated at-risk elderly individuals, the These estimates are based on a trial of oseltamivir incremental cost-effectiveness of oseltamivir versus as seasonal prophylaxis in healthy adults. Assuming no prophylaxis is expected to be around £94,000 a willingness-to-pay threshold of £30,000 per per QALY gained. These estimates are based QALY gained, the probability that no prophylaxis on a trial of oseltamivir as seasonal prophylaxis produces the greatest amount of net benefit is close in elderly subjects. Assuming a willingness-to- to 1.0. pay threshold of £30,000 per QALY gained, the probability that no prophylaxis is optimal is around When the proposed price reduction for zanamivir 0.77 or higher. is included in the analysis for at-risk adults, zanamivir is no longer dominated. The incremental The simple sensitivity analysis suggests that the cost-effectiveness of seasonal prophylaxis using cost-effectiveness of seasonal prophylaxis using zanamivir versus no prophylaxis is expected to be amantadine, oseltamivir and zanamivir is sensitive around £53,000 per QALY gained in unvaccinated to assumptions regarding the influenza attack rate, at-risk adults and £157,000 per QALY gained in the level of resistance against oseltamivir, vaccine at-risk adults who have previously been vaccinated. efficacy, the threshold used to describe when The incremental cost-effectiveness of oseltamivir is influenza is circulating in the community, the risk expected to be around £108,000 per QALY gained of hospitalisation in uncomplicated cases and the in unvaccinated at-risk adults and around £314,000 discount rate. per QALY gained in previously vaccinated at-risk adults. Assuming a willingness-to-pay threshold Cost-effectiveness of amantadine, of £30,000 per QALY gained, the probability zanamivir and oseltamivir as that no prophylaxis is optimal is around 0.99 for post-exposure prophylaxis unvaccinated at-risk adults and close to 1.0 for In healthy children previously vaccinated at-risk adults. Amantadine and oseltamivir as post-exposure prophylaxis are expected to be dominated or In healthy elderly individuals extendedly dominated in the healthy children In this subgroup, amantadine and zanamivir subgroup. For unvaccinated healthy children, the are expected to be dominated or extendedly incremental cost-effectiveness of zanamivir post- dominated. The proposed reduction in the price exposure prophylaxis versus no prophylaxis is of zanamivir does not affect this result. The expected to be around £23,000 per QALY gained incremental cost-effectiveness of oseltamivir versus at the current list price, and around £19,000 per no prophylaxis in healthy elderly individuals QALY gained when the proposed price reduction who have not been vaccinated is expected to be for zanamivir is included in the analysis. For around £50,000 per QALY gained. For previously vaccinated healthy children, the incremental cost- vaccinated healthy elderly individuals, the effectiveness of zanamivir is expected to be at least incremental cost-effectiveness of oseltamivir £59,000 per QALY gained; this estimate includes versus no prophylaxis is expected to be greater the proposed price reduction for zanamivir. These than £120,000 per QALY gained. These estimates cost–utility estimates are based on effectiveness are based on a trial of oseltamivir as seasonal data derived from trials of post-exposure prophylaxis in elderly individuals. Assuming prophylaxis in households of mixed composition a willingness-to-pay threshold of £30,000 per (children and adults). Based on the current list QALY gained, the probability that no prophylaxis price for zanamivir, the probability that zanamivir 130 is expected to be optimal is close to 1.0 (this is optimal in unvaccinated healthy children is DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

expected to be 0.15 and 0.45 at willingness-to- that zanamivir is optimal in unvaccinated at- pay thresholds of £20,000 and £30,000 per QALY risk children is expected to be 0.26 and 0.65 at gained respectively. When the proposed price willingness-to-pay thresholds of £20,000 and reduction is included in the analysis, the probability £30,000 per QALY gained respectively. that zanamivir is optimal in unvaccinated healthy children is expected to be 0.47 and 0.79 at For at-risk children under the age of 5 years, the willingness-to-pay thresholds of £20,000 and incremental cost-effectiveness of oseltamivir versus £30,000 per QALY gained respectively. For the no prophylaxis is expected to be around £9000 per vaccinated subgroup, the probability that no QALY gained for unvaccinated at-risk children and prophylaxis is optimal at a threshold of £30,000 around £29,000 per QALY gained for vaccinated per QALY gained is close to 1.0 (p = 0.99 when at-risk children. the proposed price reduction for zanamivir is included). In healthy adults Amantadine and zanamivir prophylaxis are For children under the age of 5 years, oseltamivir is expected to be dominated or extendedly the only licensed antiviral prophylaxis option. The dominated in the healthy adult subgroup. The incremental cost-effectiveness of oseltamivir versus proposed price reduction for zanamivir does not no prophylaxis is expected to be around £24,000 affect this result. For unvaccinated healthy adults, per QALY gained and £74,000 per QALY gained in the incremental cost-effectiveness of oseltamivir unvaccinated and vaccinated groups respectively. post-exposure prophylaxis versus no prophylaxis is expected to be around £34,000 per QALY In at-risk children gained. For previously vaccinated healthy adults, Amantadine and oseltamivir as post-exposure the incremental cost-effectiveness of oseltamivir prophylaxis are expected to be dominated or is expected to be around £104,000 per QALY extendedly dominated in the at-risk children gained. These cost–utility estimates are based subgroup. For unvaccinated at-risk children, the on effectiveness data derived from trials of post- incremental cost-effectiveness of zanamivir post- exposure prophylaxis in households of mixed exposure prophylaxis versus no prophylaxis is composition (children and adults). The probability expected to be around £8000 per QALY gained that oseltamivir is optimal in unvaccinated at the current list price, and around £6000 per otherwise healthy adults is expected to be around QALY gained when the proposed price reduction 0 and 0.19 at willingness-to-pay thresholds for zanamivir is included in the analysis. For of £20,000 and £30,000 per QALY gained vaccinated at-risk children, the incremental respectively. For healthy adults who have previously cost-effectiveness of zanamivir is expected to be been vaccinated, the probability that oseltamivir around £28,000 per QALY gained at the current is optimal is close to 0 at a willingness-to-pay list price, and £23,000 per QALY gained when threshold of £30,000 per QALY gained. the proposed price reduction is included in the analysis. Again, these cost–utility estimates are In at-risk adults based on effectiveness data derived from trials Amantadine and zanamivir prophylaxis are of post-exposure prophylaxis in households expected to be dominated or extendedly of mixed composition (children and adults). dominated in the at-risk adult subgroup. The Based on its current list price, the probability proposed price reduction for zanamivir does not that zanamivir is optimal in unvaccinated at- affect this result. For unvaccinated at-risk adults, risk children is expected to be 0.67 and 0.73 at the incremental cost-effectiveness of oseltamivir willingness-to-pay thresholds of £20,000 and post-exposure prophylaxis versus no prophylaxis £30,000 per QALY gained respectively. When is expected to be around £13,000 per QALY the proposed price reduction is included in the gained. For previously vaccinated at-risk adults, analysis, the probability that zanamivir is optimal the incremental cost-effectiveness of oseltamivir in unvaccinated at-risk children is expected to be is expected to be around £44,000 per QALY 0.85 at willingness-to-pay thresholds of £20,000 gained. These cost–utility estimates are based and £30,000 per QALY gained. Based on the on effectiveness data derived from trials of post- current list price for zanamivir, the probability that exposure prophylaxis in households of mixed zanamivir is optimal in vaccinated at-risk children composition (children and adults). Based on the is expected to be 0.08 and 0.31 at willingness-to- current list price for zanamivir, the probability that pay thresholds of £20,000 and £30,000 per QALY oseltamivir is optimal in unvaccinated at-risk adults gained respectively. When the proposed price is 0.89 and 0.84 at willingness-to-pay thresholds of reduction is included in the analysis, the probability £20,000 and £30,000 per QALY gained respectively 131

(p = 0.59 when the proposed price reduction for of £20,000 and £30,000 per QALY gained (this zanamivir is included in the analysis). For at-risk probability is around 0.60 when the proposed price adults who have previously been vaccinated, the reduction for zanamivir is included in the analysis). probability that no prophylaxis is optimal is around For vaccinated at-risk elderly individuals, the 0.96 at a willingness-to-pay threshold of £30,000 probability that oseltamivir is optimal is 0.35 and per QALY gained (p = 0.95 when the proposed 0.78 at willingness-to-pay thresholds of £20,000 price reduction for zanamivir is included). per QALY gained and £30,000 per QALY gained respectively (p = 0.25 and 0.54 when the proposed In healthy elderly individuals price reduction for zanamivir is included in the Amantadine and zanamivir prophylaxis are analysis). expected to be dominated or extendedly dominated in the healthy elderly subgroup. The The simple sensitivity analysis suggests that the proposed price reduction for zanamivir does not cost-effectiveness of post-exposure prophylaxis affect this result. For unvaccinated healthy elderly using amantadine, oseltamivir and zanamivir is individuals, the incremental cost-effectiveness of sensitive to assumptions regarding the influenza oseltamivir post-exposure prophylaxis versus no attack rate, the level of resistance against prophylaxis is expected to be around £11,000 oseltamivir, assumptions regarding the comparative per QALY gained. For previously vaccinated efficacy of oseltamivir and zanamivir, the efficacy healthy elderly individuals, the incremental cost- of influenza vaccination, multiple prescribing effectiveness of oseltamivir is expected to be of prophylaxis to contact cases, the risk of around £28,000 per QALY gained. These cost– hospitalisation in uncomplicated cases and the utility estimates are based on effectiveness data discount rate. derived from trials of post-exposure prophylaxis in households of mixed composition (children and adults). Based on the current list price for Strengths and limitations zanamivir, the probability that oseltamivir is of the assessment optimal in unvaccinated healthy elderly individuals is 0.87 and 0.82 at willingness-to-pay thresholds of The methods used for reviewing the evidence for £20,000 and £30,000 per QALY gained respectively the clinical effectiveness of amantadine, oseltamivir (p = 0.62 when the proposed price reduction and zanamivir in seasonal and post-exposure for zanamivir is included in the analysis). For prophylaxis against influenza were comprehensive healthy elderly individuals who have previously and systematic and we are confident that we been vaccinated, the probability that oseltamivir identified all RCTs suitable for inclusion in the is optimal is 0.09 and 0.50 at willingness-to-pay assessment. However, a limitation of the review was thresholds of £20,000 per QALY gained and the necessity to exclude non-English studies, owing £30,000 per QALY gained respectively (p = 0.07 to time constraints. Where abstracts in English and 0.38 when the proposed price reduction for could be obtained for potentially relevant trials, zanamivir is included in the analysis). the available data were discussed. An additional limitation was that a small number of full papers In at-risk elderly individuals could not be retrieved by information specialists. Amantadine and zanamivir as post-exposure However, as discussed earlier, it was considered prophylaxis are expected to be dominated or unlikely that these articles were suitable for extendedly dominated in the at-risk elderly inclusion in the review. subgroup. For unvaccinated at-risk elderly individuals, the incremental cost-effectiveness The health economic model presented in Chapter of oseltamivir post-exposure prophylaxis versus 4 was developed following a detailed critical review no prophylaxis is expected to be around £8000 of previous economic evaluations of influenza per QALY gained. For vaccinated at-risk elderly prophylaxis and clinical input. The review individuals, the incremental cost-effectiveness of highlighted a number of concerns with previous oseltamivir is expected to be around £22,000 per health economic evaluations of amantadine, QALY gained. Again, these cost–utility estimates oseltamivir and zanamivir prophylaxis (see Chapter are based on effectiveness data derived from 4, Systematic review of existing cost-effectiveness trials of post-exposure prophylaxis in households data); the model presented here addresses each of mixed composition (children and adults). of these concerns. Despite this, the evidence base The probability that oseltamivir is optimal in is subject to considerable uncertainty, and the unvaccinated at-risk elderly individuals is around evidence identified for the model is far from ideal, 132 0.83 and 0.77 at willingness-to-pay thresholds particularly in terms of the expected benefits of DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

prophylaxis. The main limitation of the health healthy and at-risk children, at-risk adults and economic model presented within this assessment healthy elderly subjects, and the representation is the use of a static rather than dynamic modelling of a range of risk and age subgroups in post- approach. As such, the model captures only the exposure prophylaxis studies would be of value. benefits accrued by patients receiving prophylaxis, Although the report by LaForce et al.75 presented and does not include other potential indirect considerable evidence since the last HTA review10 benefits accrued through decreased transmission concerning the protective efficacy of zanamivir in of influenza through the use of prophylaxis. seasonal prophylaxis for at-risk adolescents and However, the use of a more sophisticated modelling adults, further research is required on zanamivir approach would require additional assumptions in seasonal prophylaxis in healthy and at-risk and would not serve to reconcile the problems children and healthy elderly subjects, and a more associated with an already limited evidence base comprehensive representation of age and risk (see below). subgroups in studies of post-exposure prophylaxis in households is needed. Studies of influenza antiviral prophylaxis in which the effect of the Uncertainties confounding variable of vaccination is explored further are recommended. Research to assess Although a considerable amount of evidence the impact of seasonal prophylaxis in certain was identified relating to the use of amantadine, groups, such as children, on the transmission and oseltamivir and zanamivir in seasonal and post- circulation of influenza in the community would exposure prophylaxis against influenza, the also be of value. assessment of the clinical effectiveness of these interventions was limited by the variation in the A number of head-to-head trials of antiviral quality of trials in terms of internal validity and interventions used in prophylaxis against clarity of reporting and by the heterogeneity influenza were identified and excluded in between studies. The capacity of a number of the clinical effectiveness review. Research was trials to demonstrate efficacy against SLCI was identified in which the efficacies of amantadine hindered by low attack rates during the seasons and rimantadine in prophylaxis against influenza under study. The quality of the study design and were compared,133,134 while the evidence base for reporting of the amantadine prophylaxis trials was amantadine and rimantadine prophylaxis was particularly poor and few data could be abstracted reviewed in a recent Cochrane publication.33 to inform the clinical effectiveness review. Further Additional data identified and excluded in this trials would be required to enable a meaningful assessment examined the prophylactic efficacies evaluation of the effectiveness of this intervention. of ribavirin versus amantadine134 and zanamivir Stronger evidence was identified for the efficacy versus rimantadine.78 However, no relevant head- of both oseltamivir and zanamivir in preventing to-head RCTs in which amantadine, oseltamivir SLCI, with some limited data being available on and/or zanamivir were directly compared could be the impact of the interventions on complications identified. Such trials would be of significant value and hospitalisations, and on reducing length and in determining the relative clinical effectiveness severity of clinical disease across age groups, risk of these interventions in prophylaxis against status groups and settings. However, significant influenza. The undertaking of a large-scale RCT of gaps in knowledge still exist, which require the efficacy of these interventions in seasonal and further research. Further studies among those post-exposure prophylaxis with the incorporation population groups considered to be at higher risk of quality of life and resistance measurements of influenza-associated complications are necessary would significantly expand the evidence base, to strengthen the evidence base for efficacy in although it is acknowledged that such a trial would the most clinically relevant subgroups. There is require considerable resources. a particular requirement for further evidence relating to the clinical effectiveness of antivirals in The weaknesses in the clinical evidence base post-exposure prophylaxis among elderly subjects, are directly relevant to the interpretation of the particularly in long-term care settings, as subjects health economic model results. There is a marked over 65 years of age were not well represented paucity of robust evidence concerning the relative in the post-exposure prophylaxis trials. Further efficacy of alternative antiviral prophylactic drugs research to investigate the use of zanamivir by in specific subgroups. The non-exchangeability of patients with low cognitive function is warranted. studies of individual antivirals and the absence of Randomised controlled trials to investigate the head-to-head trials suggests that the use of more use of oseltamivir in seasonal prophylaxis in advanced Bayesian meta-analytic techniques (e.g. 133

mixed treatment comparisons) would add little the period of prophylaxis, with obvious limitations to the findings. As such, the economic analysis is for evaluation of any longer-term outcomes, such pivoted on assumptions of equivalent efficacy of as the potential impact of subclinical infection antivirals across numerous subgroups based on few on subjects. Variation was observed between the trials (this is particularly the case for amantadine). post-exposure prophylaxis trials undertaken in households in terms of whether index cases were A number of attributes of the study designs treated with antivirals, which would be expected of identified trials have implications for the to have an impact on the transmission of virus to interpretation of study findings. One issue relates contacts. to the variation in timing of prophylaxis within trials. Variation was evident in the timing of the An additional area of inconsistency between the onset of prophylaxis in experimental challenge different studies was the definition of clinical or studies, with subjects being dosed 1 day62,67 to symptomatic influenza, which was used to define 4 days63 before viral challenge. In the post- SLCI. Around half the included studies defined exposure prophylaxis studies based in households, symptomatic influenza as a raised temperature prophylaxis in contact cases with oseltamivir plus one or two additional symptoms, while other began within 48 hours of the onset of symptoms studies defined it as the presence of at least two of a in the index case;48,49 however, in the zanamivir list of symptoms which included raised temperature trials prophylaxis was initiated within 36 hours as one of the options. Also, of the 12 studies giving of the onset of symptoms in the index case in two a specific value for a raised temperature, eight used studies46,47 and where contacts had been exposed ≥ 37.8°C, while three used ≥ 37.2°C and one used to an index case with ILI of no longer than 4 days’ ≥ 37.3 °C. The study by Ambrozaitis et al.76 defined duration.72 Considerable variation was also present SLCI as the presence of a new influenza-like sign in the timing of the initiation of prophylaxis or symptom, but also reported separately cases of in trials of amantadine59–61 and zanamivir76,78 ‘febrile SLCI’, which was defined as a new symptom in outbreak control, where medications were plus a temperature of ≥ 37.8°C (and gave fewer administered upon levels of influenza activity cases than SLCI alone). Therefore, the number reaching a level specific to that study. These of cases of SLCI identified, and the protective variations in the onset of prophylaxis following efficacies reported by the different studies may vary exposure to influenza have the potential to impact depending on the definition of SLCI used. on estimates of efficacy. Most studies of seasonal prophylaxis were initiated when influenza virus The external validity of the RCTs must also be activity was detected locally or when virus was considered. A study by Diggory et al.136 previously identified in the community and there was an demonstrated that elderly individuals experienced increase in the observed cases of ILI. However, difficulties in loading and priming the Diskhaler, only two studies58,70 described the rationale for the by means of which zanamivir is administered by length of prophylaxis administered, typically as a oral inhalation, and suggested that such practical result of cessation of local activity. Therefore, the difficulties posed a barrier to use among older proportion of the influenza season across which patients. Conversely, the adherence data presented subjects received prophylaxis varied from study to within the identified zanamivir trials would suggest study. This variation in the period of prophylaxis that the use of the Diskhaler was acceptable to is especially pertinent, as the risk of developing elderly study participants.76,78 However, subjects SLCI following antiviral prophylaxis is considered who were unable to understand study personnel to be ongoing, with an apparent drop-off in were excluded from trial participation by efficacy on cessation of prophylaxis. Additional Ambrozaitis et al.76 and Gravenstein et al.,78 while consideration should be afforded to the timing a requirement of participation in the trials by of the measurement of the primary outcome of Monto et al.47 and LaForce et al.75 was that subjects SLCI in relation to the prophylactic period. In should be able to use the Diskhaler adequately. It most cases, SLCI was reported across the whole is therefore important to consider that individuals prophylactic period. Some studies undertook with low cognitive function or poor manual additional analyses of data from days 2–4 of dexterity would not be represented in some of prophylaxis onwards, in order to exclude subjects the study populations, and that such groups may who may have been infected with influenza virus experience difficulties in administering zanamivir prior to receipt of prophylaxis, but in whom clinical independently in clinical practice. Similar external illness did not manifest until the early stages of the validity issues apply to the trials by Peters et al.64 prophylaxis period. Only a small number of trials and Welliver et al.49 in which individuals scoring 134 undertook follow-up measurement of SLCI beyond below 7 on a mental status questionnaire were DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

excluded from participation. Such patients may Variation in the levels of resistance to antivirals require support in taking oral antiviral prophylaxis. among influenza isolates was taken into account in the cost-effectiveness analysis. Although the It is important to highlight the emerging clinical base case assumes oseltamivir resistance to be 0 evidence surrounding serious adverse events (as current levels of resistance to oseltamivir were caused by NIs, in order to reflect the effects of considered sufficiently low to warrant exclusion these interventions on patients in clinical practice. from the base case), multiple sensitivity analyses Although a higher incidence of severe adverse were undertaken in order to assess the impact of events in oseltamivir and zanamivir was not variation in levels of resistance among influenza apparent in the RCTs identified in this review, strains to the interventions under study. It the occurrence of serious neuropsychiatric events should be noted that in the 2 weeks preceding among a minority of patients treated with NIs has completion of this assessment report, the HPA been described;20,137 these circumstances should issued a press release stating that approximately be monitored and taken into account during 5% (8/162) of H1N1 influenza tested isolates were the interpretation of this evidence. Indeed, the resistant to oseltamivir. However, further research assumptions made in the economic analysis reflect and monitoring are required to fully assess the the current uncertainties regarding the incidence, impact of this resistance. The sensitivity analysis duration and quality of life impact of adverse undertaken using the economic model suggests events caused by individual prophylactic drugs. that low levels of resistance do not have a marked impact on the cost-effectiveness of oseltamivir. The emergence of variants of influenza that However, increasing levels of resistance to are resistant to amantadine, oseltamivir and/ oseltamivir do have the capacity to dramatically or zanamivir has significant potential to reduce influence the conclusions of the economic analysis. the efficacy of these interventions in clinical It is therefore of key importance that the results of practice. Although a number of identified trials the economic analysis are interpreted in the light tested viral isolates for resistance to oseltamivir of current levels of influenza activity and resistance. and zanamivir in vitro and found no evidence of reduced sensitivity, as noted in Chapter 1 and A further problem, noted in Chapter 4, is the Chapter 3, the emergence of strains of influenza complete absence of preference-based estimates of resistant to amantadine, in particular, and also the impact of influenza and influenza prophylaxis oseltamivir has been demonstrated and it is on HRQoL. In addition, systematic searches were therefore important that, during interpretation unable to identify robust estimates of the impact of the clinical effectiveness evidence, such issues of influenza complications on quality of life. relating to antiviral resistance should be taken Consequently, the benefit side of the economic into account. Susceptibility should be continued analysis is based entirely on an intermediate to be monitored and testing of isolates should outcome measure (SLCI) and indirect estimates of continue to be undertaken in future clinical trials. its impact on health outcomes.

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DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Chapter 7 Conclusions

he availability of clinical effectiveness is expected to be greater than £44,000 per QALY Tdata used to inform the cost-effectiveness gained. modelling was limited for a number of population subgroups. This should be considered during the In at-risk children interpretation of the review findings. Amantadine and zanamivir as seasonal prophylaxis are expected to be dominated or extendedly dominated in the at-risk children subgroup. Again, Conclusions on the the proposed reduction in the price of zanamivir clinical effectiveness of does not affect this finding. The incremental cost- influenza prophylaxis effectiveness of oseltamivir versus no prophylaxis is expected to be around £17,000 per QALY gained Few data relating to the use of amantadine in for at-risk children who have not been vaccinated. prophylaxis could be identified and were taken For at-risk children who have previously been from older trials of poorer quality. Oseltamivir vaccinated, the incremental cost-effectiveness of and zanamivir were demonstrated to be effective oseltamivir versus no prophylaxis is expected to be in preventing SLCI in a number of subgroups. in excess of £50,000 per QALY gained. Interventions appeared to be well tolerated by subjects, with a relatively low incidence of few In healthy adults drug-related adverse events and drug-related Amantadine and zanamivir as seasonal prophylaxis withdrawals. Very limited evidence could be are expected to be dominated or extendedly identified for the effectiveness of the interventions dominated in the healthy adult subgroup. The in preventing complications and hospitalisations incremental cost-effectiveness of oseltamivir versus and in minimising length of illness and time to no prophylaxis is expected to be around £148,000 return to normal activities. No data were identified per QALY gained for healthy adults who have not relating to health-related quality of life or mortality been vaccinated and greater than £427,000 per outcomes. The increasing emergence of antiviral QALY gained for healthy adults who have been resistance among influenza isolates (particularly vaccinated. in the case of amantadine but also for oseltamivir) and the high frequency of adverse events associated In at-risk adults with amantadine pose significant challenges to Based on the current list price for zanamivir, the use of the interventions in clinical practice the model suggests that both amantadine and and, whilst not directly reflected within the trials zanamivir are ruled out of the analysis in at-risk identified in the review, such issues must be adults. The incremental cost-effectiveness of considered during interpretation of the findings oseltamivir versus no prophylaxis is expected to be from the clinical effectiveness review. around £64,000 per QALY gained in unvaccinated at-risk adults and around £187,000 per QALY gained in previously vaccinated at-risk adults. Conclusions on the When the proposed price reduction for zanamivir cost-effectiveness of is included in the analysis for at-risk adults, influenza prophylaxis zanamivir is no longer dominated. The incremental cost-effectiveness of seasonal prophylaxis using Seasonal prophylaxis zanamivir versus no prophylaxis is expected to be In healthy children around £53,000 per QALY gained in unvaccinated at-risk adults and £157,000 per QALY gained in Amantadine and zanamivir as seasonal prophylaxis at-risk adults who have previously been vaccinated. are expected to be dominated or extendedly The incremental cost-effectiveness of oseltamivir is dominated in the healthy children subgroup. expected to be around £108,000 per QALY gained The proposed reduction in the price of zanamivir in unvaccinated at-risk adults and around £314,000 does not affect this finding. The incremental cost- per QALY gained in previously vaccinated at-risk effectiveness of oseltamivir versus no prophylaxis adults. 137

In healthy elderly individuals extendedly dominated in the at-risk children In this subgroup, amantadine and zanamivir subgroup. For unvaccinated at-risk children, the are expected to be dominated or extendedly incremental cost-effectiveness of zanamivir post- dominated. The proposed reduction in the price exposure prophylaxis versus no prophylaxis is of zanamivir does not affect this result. The expected to be around £8000 per QALY gained incremental cost-effectiveness of oseltamivir versus at the current list price, and around £6000 per no prophylaxis in healthy elderly individuals QALY gained when the proposed price reduction who have not been vaccinated is expected to be for zanamivir is included in the analysis. For around £50,000 per QALY gained. For previously vaccinated at-risk children, the incremental cost- vaccinated healthy elderly individuals, the effectiveness of zanamivir is expected to be around incremental cost-effectiveness of oseltamivir versus £28,000 per QALY gained at the current list price, no prophylaxis is expected to be greater than and £23,000 per QALY gained when the proposed £120,000 per QALY gained. price reduction is included in the analysis.

In at-risk elderly individuals For at-risk children under the age of 5 years, the In this subgroup, amantadine and zanamivir are incremental cost-effectiveness of oseltamivir versus expected to be extendedly dominated despite no prophylaxis is expected to be around £9000 per the proposed reduction in the price of zanamivir. QALY gained for unvaccinated at-risk children and The incremental cost-effectiveness of oseltamivir around £29,000 per QALY gained for vaccinated versus no prophylaxis in at-risk elderly individuals at-risk children. who have not been vaccinated is expected to be around £38,000 per QALY gained. For previously In healthy adults vaccinated at-risk elderly individuals, the Amantadine and zanamivir prophylaxis are incremental cost-effectiveness of oseltamivir versus expected to be dominated or extendedly no prophylaxis is expected to be around £94,000 dominated in the healthy adult subgroup. The per QALY gained. proposed price reduction for zanamivir does not affect this result. For unvaccinated healthy adults, Post-exposure prophylaxis the incremental cost-effectiveness of oseltamivir In healthy children post-exposure prophylaxis versus no prophylaxis is expected to be around £34,000 per QALY Amantadine and oseltamivir as post-exposure gained. For previously vaccinated healthy adults, prophylaxis are expected to be dominated or the incremental cost-effectiveness of oseltamivir is extendedly dominated in the healthy children expected to be around £104,000 per QALY gained. subgroup. For unvaccinated healthy children, the incremental cost-effectiveness of zanamivir post- In at-risk adults exposure prophylaxis versus no prophylaxis is Amantadine and zanamivir prophylaxis are expected to be around £23,000 per QALY gained expected to be dominated or extendedly at the current list price, and around £19,000 per dominated in the at-risk adult subgroup. The QALY gained when the proposed price reduction proposed price reduction for zanamivir does not for zanamivir is included in the analysis. For affect this result. For unvaccinated at-risk adults, vaccinated healthy children, the incremental cost- the incremental cost-effectiveness of oseltamivir effectiveness of zanamivir is expected to be at least post-exposure prophylaxis versus no prophylaxis £59,000 per QALY gained; this estimate includes is expected to be around £13,000 per QALY the proposed price reduction for zanamivir. gained. For previously vaccinated at-risk adults, the incremental cost-effectiveness of oseltamivir is For children under the age of 5 years, oseltamivir is expected to be around £44,000 per QALY gained. the only licensed antiviral prophylaxis option. The incremental cost-effectiveness of oseltamivir versus In healthy elderly individuals no prophylaxis is expected to be around £24,000 Amantadine and zanamivir prophylaxis are per QALY gained and £74,000 per QALY gained in expected to be dominated or extendedly unvaccinated and vaccinated groups respectively. dominated in the healthy elderly subgroup. The proposed price reduction for zanamivir does not In at-risk children affect this result. For unvaccinated healthy elderly Amantadine and oseltamivir as post-exposure individuals, the incremental cost-effectiveness of prophylaxis are expected to be dominated or oseltamivir post-exposure prophylaxis versus no

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prophylaxis is expected to be around £11,000 current levels of influenza activity and resistance. per QALY gained. For previously vaccinated The evidence base relating to the clinical healthy elderly individuals, the incremental cost- effectiveness and cost-effectiveness of amantadine, effectiveness of oseltamivir is expected to be oseltamivir and zanamivir in seasonal and post- around £28,000 per QALY gained. exposure influenza prophylaxis would be reinforced by further research in the following areas: In at-risk elderly individuals Amantadine and zanamivir as post-exposure • Additional RCTs in subgroups for which data prophylaxis are expected to be dominated or are currently lacking (as described in Chapter extendedly dominated in the at-risk elderly 6 and including assessments of oseltamivir in subgroup. For unvaccinated at-risk elderly seasonal prophylaxis in children, at-risk adults individuals, the incremental cost-effectiveness and healthy elderly subjects; zanamivir in of oseltamivir post-exposure prophylaxis versus seasonal prophylaxis in children and healthy no prophylaxis is expected to be around £8000 elderly subjects; and post-exposure prophylaxis per QALY gained. For vaccinated at-risk elderly trials of the interventions in elderly subjects individuals, the incremental cost-effectiveness of and individuals with low cognitive function oseltamivir is expected to be around £22,000 per and/or manual dexterity) QALY gained. • RCTs in which the follow-up period extends beyond the duration of prophylaxis • head-to-head RCTs in which the clinical Recommendations effectiveness of amantadine, oseltamivir and/ for research or zanamivir in different subgroups is directly compared It should be noted that increasing levels of • quality of life studies to inform future economic resistance to antiviral prophylaxis have the capacity decision modelling to dramatically influence the conclusions of the • further research concerning the incidence economic analysis. The results of the economic and management of complications caused by analysis should be interpreted in the light of influenza.

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Acknowledgements

e would like to thank Piers Mook, Joanna Ellis the report. Jim Chilcott and Eva Kaltenthaler are Wand Maria Zambon at the Health Protection guarantors. Agency for providing advice and data for the model. We would also like to thank Alex Elliot, About ScHARR Andrew Ross and Douglas Fleming (Director) at the Royal College of General Practitioners for The School of Health and Related Research providing expert input and data for the modelling (ScHARR) is one of the four Schools that comprise process. We would like to acknowledge Allan the Faculty of Medicine at the University of Wailoo, David Turner, John Brazier and Jim Sheffield. ScHARR brings together a wide range of Chilcott for providing further methodological medical- and health-related disciplines including advice within the model development process. public health, general practice, mental health, Myfanwy Lloyd-Jones provided methodological epidemiology, health economics, management suggestions for the systematic review of clinical sciences, medical statistics, operational research effectiveness. We would like to thank Hazel Pilgrim and information science. It includes the Sheffield for her comments and validation of the model. unit of the Trent Research and Development Finally, we would like to thank Dr Rod Taylor Support Unit (RDSU), which is funded by NIHR to (Peninsula Technology Assessment Group), Dr facilitate high-quality health services research and Martin Wiselka (University Hospitals of Leicester capacity development. NHS Trust) and Dr Wei Shen Lim (Nottingham City Hospital) for commenting on this report. The ScHARR Technology Assessment Group (ScHARR-TAG) synthesises research on the Contribution of authors effectiveness and cost-effectiveness of healthcare interventions for the NHS R&D Health Paul Tappenden (Senior Cost-effectiveness Technology Assessment (HTA) Programme on Modeller/Research Fellow) was the Assessment behalf of a range of policy makers, including Group lead, undertook the cost-effectiveness the National Institute for Health and Clinical review and developed the cost-effectiveness model. Excellence (NICE). ScHARR-TAG is part of Rachel Jackson (Research Associate) and Katy a wider collaboration of six units from other Cooper (Research Associate) undertook the clinical regions. The other units are: Southampton effectiveness review. Emma Simpson (Research Health Technology Assessment Centre (SHTAC), Fellow) was involved in the preparation of the University of Southampton; Aberdeen Health scope and protocol and advised on the clinical Technology Assessment Group (Aberdeen HTA effectiveness review. Angie Rees (Information Group), University of Aberdeen; Liverpool Reviews Officer) performed the literature searches. Robert & Implementation Group (LRiG), University of Read (Honorary Consultant Physician in Infectious Liverpool; Peninsular Technology Assessment Diseases) and Karl Nicholson (Consultant Group (PenTAG), University of Exeter; NHS Physician and Professor of Infectious Diseases) Centre for Reviews and Dissemination, University provided clinical input to both the systematic of York; and West Midlands Health Technology review and health economic modelling throughout Assessment Collaboration (WMHTAC), University the assessment. Andrea Shippam helped in the of Birmingham. retrieval of papers and in preparing and formatting

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References

1. Wiselka M. Influenza: diagnosis, management and 13. Nicholson KG, Wood JM, Zambon M. Influenza. prophylaxis. BMJ 1994;308:1341–5. Lancet 2003;362:1733–45.

2. Nicholson KG. Human influenza. In Nicholson KG, 14. British Medical Association and Royal Webster RG, Hay AJ, editors. Textbook of influenza. Pharmaceutical Society of Great Britain. British Oxford: Blackwell Science; 1998, pp. 219–64. national formulary. No. 54, 2007.

3. Tillett HE, Smith JWG, Gooch CD. Excess deaths 15. Department of Health Immunisation programme attributable to influenza in England and Wales: for poultry workers. Guidance on the implementation of age at death and certified cause. Int J Epidemiol a seasonal flu vaccination programme for poultry workers. 1983;12:344–52. 2007.

4. Nicholson KG. Impact of influenza and respiratory 16. National Institute for Clinical Excellence. Guidance syncytial virus on mortality in England and Wales on the use of oseltamivir and amantadine for the from January 1975 to December 1990. Epidemiol prophylaxis of influenza. Technology Appraisal Infect 1996;116:51–63. Guidance 67. 2003.

5. Fleming DM. The contribution of influenza to 17. NHS and National Institute for Clinical Excellence. combined acute respiratory infections, hospital Guidance on the use of zanamivir, oseltamivir and admissions and deaths in winter. Commun Dis Publ amantadine for the treatment of influenza. Technology Health 2000;3:32–8. Appraisal 58. 2003.

6. Ruigrok RWH. Structure of influenza A, B and C 18. Joint Formulary Committee. British national viruses. In Nicholson KG, Webster RG, Hay AJ, formulary. No. 53, 2007. editors. Textbook of influenza. Oxford: Blackwell Science; 1998, pp. 29–42. 19. Department of Health. The influenza immunisation programme 2007/2008. 2007. 7. Jefferson T, Demicheli V. Socioeconomics of influenza. In Nicholson KG, Webster RG, Hay AJ, 20. Roche. Tamiflu (oseltamivir) influenza prophylaxis: editors. Textbook of influenza. Oxford: Blackwell achieving clinical excellence in influenza prophylaxis. Science; 1998, pp. 541–7. Roche submission to the National Institute for Health and Clinical Excellence. 2007. pp. 1–197. 8. Health Protection Agency (HPA). www.hpa.org.uk/ infections/topics_az/influenza/seasonal/default.htm. 21. Monto AS, McKimm-Breschkin JL, Macken C, 2007. Hampson AW, Hay A, Klimov A, et al. Detection of influenza viruses resistant to neuraminidase 9. Douglas RG. Prophylaxis and treatment of inhibitors in global surveillance during the first influenza. New Engl J Med 1990;322:443–50. 3 years of their use. Antimicrob Agents Chemother 2006;50:2395–402. 10. Turner D, Wailoo A, Nicholson K, Cooper N, Sutton, A, Abrams K. Systematic review and 22. Department of Health. National Service Framework economic decision modelling for the prevention for Older People. 2001. and treatment of influenza A and B. Health Technol Assess 2003;7:1–170. 23. Department of Health. National Service Framework for Coronary Heart Disease. 2000. 11. Health Protection Agency (HPA) Centre for Infections (CfI). HPA national influenza season 24. Alliance Pharmaceuticals. Lysovir 100 mg capsules. summary 2006/2007. 2007. Summary of product characteristics. 2005.

12. Meier CR, Napalkov PN, Wegmuller Y, Jefferson T, 25. Roche. Tamiflu 12 mg/ml powder for oral Jick H. Population-based study on incidence, risk suspension. Summary of product characteristics. 2007. factors, clinical complications and drug utilisation associated with influenza in the United Kingdom. 26. Roche. Tamiflu 30 mg hard capsules. Summary of Eur J Clin Microbiol Infect Dis 2000;19:834–42. product characteristics. 2007. 143

27. Roche. Tamiflu 45 mg hard capsules. Summary of 40. Smorodintsev AA, Romanov YA, Rumovski VI, product characteristics. 2007. Zlydniko DM. Effectiveness of hydrochloric amantadine (midantane) in prevention of artificially 28. Roche. Tamiflu 75 mg hard capsules. Summary of induced influenza infection. Vopr Virusol 1972;152– Product Characteristics. 2007. 6.

29. GlaxoSmithKline. Relenza 5 mg/dose inhalation 41. Kashiwagi S, Kudoh S, Watanabe A, Yoshimura powder. Summary of product characteristics. 2006. I. [Efficacy and safety of the selective oral neuraminidase inhibitor oseltamivir for prophylaxis 30. Aoki F. Amantadine and rimantadine. In KG against influenza – placebo-controlled double-blind Nicholson, RG Webster, AJ Hay, editors. Textbook multicenter phase III trial]. Kansenshogaku zasshi of influenza. Oxford: Blackwell Science; 1998, pp. (Journal of the Japanese Association for Infectious 457–476. Diseases) 2000;74:1062–76.

31. Hayden FG. Antiviral resistance in influenza viruses 42. Shinjoh M, Sato S, Sugaya N, Mitamura K, – implications for management and pandemic Takeuchi Y, Kosaki K, et al. Effect of post-exposure response. New Engl J Med 2006;354:785–8. prophylaxis with oseltamivir for those in contacts with influenza patients in pediatric wards. 32. Schilling M, Gravenstein S, Drinka P, Cox N, Krause Kansenshogaku Zasshi (Journal of the Japanese P, Povinelli L, et al. Emergence and transmission Association for Infectious Diseases) 2004;78:262–9. of amantadine-resistant influenza A in a nursing home. J Am Geriatr Soc 2004;52:2069–73. 43. Diaz-Pedroche C, Lizasoain M, Lopez-Medrano F, Escalante F, Lumbreras C, Folgueira D, et al. 33. Jefferson T, Demicheli V, Di Pietrantonj C, Rivetti [Nosocomial outbreak of influenza in high-risk D. Amantadine and rimantadine for influenza A in hematological patients. Efficacy of control measures adults. [Update of Cochrane Database System and the use of zanamivir]. [Spanish]. Enferm Infecc Review 2004;(3):CD001169; PMID: 15266442]. Microbiol Clin 2006;24:10–13. Cochrane Database of Systematic Reviews 2006. 44. GlaxoSmithKline Pharmaceuticals. Drugs for 34. Penn C. Inhibitors of influenza virus neuraminidase. the prophylaxis of influenza – review of zanamivir. In KG Nicholson, RG Webster, AJ Hay, editors. Submission to the National Institute for Health and Textbook of influenza. Oxford: Blackwell Science; Clinical Excellence. 2007 1998, pp. 477–487. 45. Halloran M, Hayden FG., Yang Y, Longini IM, 35. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie Monto AS. Antiviral effects on influenza viral D, Stroup DF and for the QUOROM Group. transmission and pathogenicity: observations Improving the quality of reports of meta-analyses from household-based trials. Am J Epidemiol of randomised controlled trials: the QUOROM 2007;165:212–21. statement. Lancet 1999;354:1896–1900. 46. Hayden FG, Gubareva LV, Monto AS, Klein TC, 36. NHS Centre for Reviews and Dissemination. Report Elliott MJ, Hammond JM, et al. Inhaled zanamivir 4: undertaking systematic reviews on effectiveness; CRDs for the prevention of influenza in families. New Engl guidance for those carrying out or commissioning reviews. J Med 2000;343:1282–9. 2001. 47. Monto AS, Pichichero ME, Blanckenberg SJ, 37. Hess P. Amantadine and rimantadine in Ruuskanen O, Cooper C, Fleming DM, et al. the prophylaxis of influenza A. Med Hygiene Zanamivir prophylaxis: an effective strategy for 1982;40:3496. the prevention of influenza types A and B within households. J Infect Dis 2002;186:1582–8. 38. Plesnik V, Heinz F, Bindas B, Cechova D, Eliasova J, Galetkova A, et al. Controlled study of influenza 48. Hayden FG, Belshe R, Villanueva C, Lanno R, prophylaxis by VUFB amantadin. Cesk Epidemiol Hughes C, Small I, et al. Management of influenza Mikrobiol Imunol 1977;26:216–26. in households: a prospective, randomized comparison of oseltamivir treatment with or 39. Quilligan Jr JJ, Hirayama M, Baernstein Jr HD. without postexposure prophylaxis. J Infect Dis [The prevention of A2-influenza in children by 2004;189:440–9. chemoprophylaxis with amantadine hydrochloride]. [German]. Schweizerische Medizinische 49. Welliver R, Monto AS, Carewicz O, Schatteman Wochenschrift, 17 December 1966. J Suisse Med E, Hassman M, Hedrick J, et al. Effectiveness of 1966;96:1689–92. oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA 144 2001;285:748–54. DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

50. Jefferson TO, Demicheli V, Deeks JJ, Rivetti D. influenza in Leningrad in 1969. Bull World Health Amantadine and rimantadine for preventing and Organ 1970;42:865–72. treating influenza A in adults. Cochrane Database of Systematic Reviews 2000;2. 62. Smorodintsev AA, Zlydnikov DM, Kiseleva AM, Romanov JA, Kazantsev AP, Rumovsky VI. 51. Finklea JF, Hennessy AV, Davenport FM. A field Evaluation of amantadine in artificially induced A2 trial of amantadine prophylaxis in naturally- and B influenza. JAMA 1970;213:1448–54. occurring acute respiratory illness. Am J Epidemiol 1967;85:403–12. 63. Sears SD, Clements ML. Protective efficacy of low- dose amantadine in adults challenged with wild- 52. Quilligan JJ, Hirayama M, Baernstein HD. The type influenza A virus. Antimicrob Agents Chemother suppression of A2 influenza in children by the 1987;31:1470–3. chemoprophylactic use of amantadine. J Pediatr 1966;69:572–5. 64. Peters PH, Gravenstein S, Norwood P, De Bock V, Van Couter A, Gibbens M, et al. Long-term use of 53. Leung P, McIntosh K, Chai H. Amantadine oseltamivir for the prophylaxis of influenza in a prophylaxis against influenza A/USSR in children vaccinated frail older population. J Am Geriatr Soc with chronic asthma. J Allergy Clin Immunol 2001;49:1025–31. 1979;63:140. 65. De Bock V, Peters P, Von Planta T-A, Gibbens M, 54. Wright PF, Khaw KT, Oxman MN, Shwachman H. Ward P. Oral oseltamivir for prevention of influenza Evaluation of the safety of amantadine-HC1 and the in the frail elderly. Clin Microbiol Infect 2000;6:140. role of respiratory viral infections in children with cystic fibrosis. J Infect Dis 1976;134:144–9. 66. Hayden FG, Atmar RL, Schilling M, Johnson C, Poretz D, Paar D, et al. Use of the selective oral 55. Pettersson RF, Hellström PE, Penttinen K, Pyhälä R, neuraminidase inhibitor oseltamivir to prevent Tokola O, Vartio T, et al. Evaluation of amantadine influenza. New Engl J Med 1999;341:1336–43. in the prophylaxis of influenza A (H1N1) virus infection: a controlled field trial among 67. Hayden FG, Jennings L, Robson R, Schiff G, young adults and high-risk patients. J Infect Dis Jackson H, Rana B, et al. Oral oseltamivir in human 1980;142:377–83. experimental influenza B infection. Antiviral Ther 2000;5:205–13. 56. Leeming JT. Amantidine hydrochloride and the elderly. BMJ 1969;1:313–14. 68. Jefferson TO, Demicheli V, Di Pietrantonj C, Jones M, Rivetti D. Neuraminidase inhibitors for preventing 57. Reuman PD, Bernstein DI, Keefer MC, Young EC, and treating influenza in healthy adults. Cochrane Sherwood JR., Schiff GM. Efficacy and safety of low Database of Systematic Reviews 2006. dosage amantadine hydrochloride as prophylaxis for influenza A. Antiviral Res 1989;11:27–40. 69. Schilling M, Povinelli L, Krause P, Gravenstein M, Ambrozaitis A, Jones H, et al. Efficacy of zanamivir 58. Aoki FY, Stiver HG, Sitar DS, Hammond GW, for chemoprophylaxis of nursing home influenza Milley EV, Vermeersch C, et al. Potential of influenza outbreaks. Vaccine 1998;16:1771–4. vaccine and amantadine to prevent influenza A illness in Canadian forces personnel 1980–1983. Mil 70. Monto AS, Robinson DP, Louise M, James H, Med 1986;151:459–65. Hinson M, Elliott MJ, et al. Zanamivir in the prevention of influenza among healthy adults: a 59. Payler DK, Purdham PA. Influenza A prophylaxis randomized controlled trial. JAMA 1999;282:31–5. with amantadine in a boarding school. Lancet 1984;1:502–4. 71. Monto AS, Robinson D, Griffin AD, Edmundson S. The effects of zanamivir on productivity in the 60. Smorodintsev A, Karpuchin G, Zlydnikov D. The prevention of influenza among healthy adults. prospect of amantadine for prevention of influenza J Antimicrob Chemother 1999;44. A in humans (effectiveness of amantadine during influenza A2/Hong Kong epidemics in January– 72. Kaiser L, Henry D, Flack NP, Keene O, Hayden FG. February 1969 in Leningrad). Ann N Y Acad Sci Short-term treatment with zanamivir to prevent 1970;173:44–73. influenza: results of a placebo-controlled study. Clin Infect Dis 2000;30:587–9. 61. Smorodintsev AA, Karapuhi GI, Zlydniko DM, Malyseva AM, Svecova EG, Burov SA, et 73. Hayden F, Belshe R, Villanueva C, Lanno R, Small al. Prophylactic effectiveness of amantadine I, Hughes C, et al. Oral oseltamivir prevents the hydrochloride in an epidemic of Hong-Kong spread of influenza between children in households. 145

Abstracts of the Interscience Conference on 83. Hatakeyama S, Sugaya N, Ito M, Yamazaki M, Antimicrobial Agents and Chemotherapy 2002;42. Ichikawa M, Kimura K, Kiso M, et al. Emergence of influenza B viruses with reduced sensitivity to 74. Belshe R, Hayden F, Carewicz O, Lanno R, Martin neuraminidase inhibitors. JAMA 2007;297:1435–42. C, Hughes C, et al. Effectiveness of oral oseltamivir in preventing spread of influenza-like illness in 84. Escuret V, Frobert E, Bouscambert-Duchamp M, households with proven influenza. Abstracts of the Sabatier M, Grog I, Valette M, et al. Detection of Interscience Conference on Antimicrobial Agents human influenza A (H1N1) and B strains with and Chemotherapy 2001;41. reduced sensitivity to neuraminidase inhibitors. J Clin Virol 2007;41:25–8. 75. LaForce C, Man CY, Henderson FW, McElhaney JE, Hampel Jr FC, Bettis R, et al. Efficacy and safety of 85. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, inhaled zanamivir in the prevention of influenza in Kawakami C, Kimura K, et al. Resistant influenza community-dwelling, high-risk adult and adolescent A viruses in children treated with oseltamivir: subjects: a 28-day, multicenter, randomized, descriptive study. Lancet 2004;364:759–65. double-blind, placebo-controlled trial. Clin Ther 2007;29:1579–90. 86. European Centre for Disease Prevention and Control. Emergence of seasonal influenza viruses type 76. Ambrozaitis, A., Gravenstein, S., Van Essen, G. A/H1N1 with oseltamivir resistance in some European A., Rubinstein, E., Balciuniene, L., Stikleryte, A., Countries at the start of the 2007–8 influenza season. Crawford, C., Elliott, M., and Shult, P. Inhaled 2008. zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long- 87. Health Protection Agency. Oseltamivir resistance in term care population. J of the American Medical European influenza viruses – update. 2008. Directors Association 2005;6 367–374. 88. Cooper NJ, Sutton AJ, Abrams KR, Wailoo 77. Ambrozaitis, A, Van Essen G, Rubinstein E, A, Turner DA, Nicholson KG. Effectiveness Balciuniene L, Stikleryte A, Gravenstein S, et al. of neuraminidase inhibitors in treatment and Inhaled zanamivir versus placebo for the prevention prevention of influenza A and B: systematic review of influenza outbreaks in an unvaccinated long- and meta-analyses of randomised controlled trials. term care population (NAIA3004). J Am Geriatr Soc BMJ 2003;326:1235–9. 2001;49:S130–1. 89. Drummond MF, Sculpher MJ, Torrance GW, 78. Gravenstein S, Drinka P, Osterweil D, Schilling M, O’Brien BJ, Stoddart GL. Methods for the economic Krause P, Elliott M, et al. Inhaled zanamivir versus evaluation of health care programmes. 3rd edn. New rimantadine for the control of influenza in a highly York: Oxford University Press; 2007. vaccinated long-term care population. J Am Med Dir Assoc 2005;6:359–66. 90. Eddy DM. Technology assessment: the role of mathematical modeling. In Institute of Medicine, 79. Jefferson T, Deeks JJ, Demicheli V, Rivetti D, Rudin editor. Assessing medical technology. Washington, DC: M Amantadine and rimantadine for preventing and National Academy Press; 1985, pp. 144–153. treating influenza A in adults. [Update in Cochrane Database Syst Rev. 2006;(2):CD001169; PMID: 91. Sander B, Hayden FG, Gyldmark M, Garrison 16625539][update of Cochrane Database Syst Rev. Jr LP. Post-exposure influenza prophylaxis with 2002;(3):CD001169; PMID: 12137620]. Cochrane oseltamivir: cost effectiveness and cost utility in Database of Systematic Reviews 2004. families in the UK. Pharmacoeconomics 2006;24:373– 86. 80. European Medicines Agency Scientific discussion. Tamiflu-H-402-II-20. 2006. 92. Risebrough NA, Bowles SK, Simor AE, McGeer A, Oh PI. Economic evaluation of oseltamivir 81. Matheson NJ, Harnden AR, Perera R, Sheikh A, phosphate for postexposure prophylaxis of Symmonds-Abrahams M. Neuraminidase inhibitors for influenza in long-term care facilities. J Am Geriatr preventing and treating influenza in children. [Update Soc 2005;53:444–51. of Cochrane Database Syst Rev. 2003;(3):CD002744; PMID: 12917931]. Cochrane Database of Systematic 93. Scuffham P, West P. Economic evaluation of Reviews 2007. strategies for the control and management of influenza in Europe. Vaccine 2002; 20:2562–78. 82. Aoki FY, Boivin G, Roberts N. Influenza virus susceptibility and resistance to oseltamivir. Antiviral 94. Demicheli V, Jefferson T, Rivetti D, Deeks J. Ther 2007;12:603–16. Prevention and early treatment of influenza in healthy adults. Vaccine 2000;18:957–1030. 146 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

95. Patriarca PA, Arden NH, Koplan JP, Goodman volume 1. Cambridge, MA: Harvard School of RA. Prevention and control of type A influenza Public Health;1996. infections in nursing homes: benefits and costs of four approaches using vaccination and amantadine. 110. Fleming DM. The contribution of influenza to Ann Intern Med 1987;107:732–40. combined acute respiratory infections, hospital admissions and deaths in winter. Comm Dis Publ 96. National Institute for Health and Clinical Health 2000;3:32–8. Excellence. Guide to the methods of technology appraisal. 2004. 111. Netten A, Curtis L. Unit costs of health and social care. Canterbury: Personal Social Services Research Unit 97. Monto AS, Gunn RA, Bandyk MG, King CL. (PSSRU); 2000. Prevention of Russian influenza by amantadine. JAMA 1979;241:1003–7. 112. CHKS Ltd. Hospitalisation data for England and Wales 1995–1999. 2000. 98. Cox NJ, Subbarao K. Global epidemiology of influenza: past and present. Annu Rev Med 113. Department of Health. Prescription cost analysis. 2000;51:407–21. 2000.

99. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, 114. Department of Health. Drug Tariff National Health Hayden F. Oseltamivir prevents complications from Service, England and Wales. 1999. influenza-related lower respiratory tract infections. ACOG Clin Rev 2003;8:12. 115. Patriarca PA, Weber JA, Parker RA, Orenstein WA, Hall WN, Kendal AP, et al. Risk factors for outbreaks 100. Stouthard M, Essink-Bot M, Bonsel G, et al. of influenza in nursing homes. Am J Epidemiol Disability weights for diseases in the Netherlands. 1986;124(1):114–119. Rotterdam, Netherlands: Department of Public Health, Erasmus University Rotterdam; 1997. 116. National Institute for Clinical Excellence. Guidance on the use of zanamivir, oseltamivir and amantadine 101. Department of Health and Human Services. for the treatment of influenza. Technology appraisal National ambulatory medical care survey (NACMS). guidance no. 58. 2003. National Centre for Health Statistics; 1997. 117. Smith S, Demicheli V, Pietrantonj C, Harnden 102. Curtis L, Netten A. Unit costs of health and social care. AR, Jefferson T, Matheson NJ, et al. Vaccines for Canterbury: Personal Social Services Research Unit preventing influenza in healthy children (review). The (PSSRU); 2006. Cochrane Library: 2007.

103. MIMS. The prescribing reference for general practice. 118. Jefferson TO, Rivetti D, Pietrantonj C, Rivetti A, September 2007. Demicheli V. Vaccines for preventing influenza in healthy adults (review). The Cochrane Library; 2007. 104. van Noort SP. Gripenet: an internet-based system to monitor influenza-like illness uniformly across 119. Rivetti D, Jefferson TO, Thomas R, Rudin M, Europe. Euro Surveill 2007; 12 Rivetti A, Pietrantonj C, et al. Vaccines for preventing influenza in the elderly (review). The Cochrane 105. MVH Group. The measurement and valuation of health. Library; 2007. First report on the main survey. 1994. 120. Gross PA, Hermogenes AW, Sacks HS, Lau J, 106. Ontario Ministry of Health and Long Term Care. Levandowski RA. The efficacy of influenza vaccine Ontario Ministry of Health Schedule of Benefits and Fees. in elderly persons: a meta-analysis and review of the 2007. literature. Ann Intern Med 1995;123:518–27.

107. Ontario Case Cost Initiative. Average costs per case 121. Nichol KL, Margolis KL, Lind A, Murdoch M, mix group (CMG) 2000–2001. 2001. McFadden R, Hauge M, et al. Side effects associated with influenza vaccination in healthy working 108. Wailoo A, Abrams K., Turner D, Sutton AJ, Cooper adults. A randomized, placebo-controlled trial. Ann NJ, Nicholson KG. Review of influenza post-exposure Intern Med 1996;156:1546–50. prophylaxis. DSU report to the National Institute for Clinical Excellence. 2003. 122. Pitman R, Melegaro A, Gelb D, Siddiqui M, Gay N, Edmunds W. Assessing the burden of influenza and 109. Murray CJ, Lopez AD. The global burden of disease: a other respiratory infections in England and Wales. J comprehensive assessment of mortality and disabilities from Infect 2007;54:530–8. diseases, injuries and risk factors in 1990 and projected to 2020. Global burden of disease and injury series, 147

123. Ross AM, Kai J, Salter R, Ross J, Fleming DM. 132. Gupta RK, Zhao H, Cooke M, Harling R, Regan M, Presentation with influenza-like illness in general Bailey L, et al. Public health responses to influenza practice: implications for use of neuraminidase in care homes: a questionnaire-based study of local inhibitors. Commun Dis Publ Health 2000;3:256–60. health protection units. J Publ Health 2007;29:88– 90. 124. Briggs AH, Ades AE, Price MJ. Probabilistic sensitivity analysis for decision trees with multiple 133. Quarles JM, Couch RB, Cate TR, Goswick CB. branches: use of the Dirichlet distribution Comparison of amantadine and rimantadine for in a Bayesian framework. Med Decis Making prevention of type A (Russian) influenza. Antiviral 2003;23:341–50. Res 1981;1:149–55.

125. Department of Health. NHS Reference Costs 2005– 134. Dolin R, Reichman RC, Madore HP, Maynard R, 2006. 2007. Linton PN, Webber-Jones J. A controlled trial of amantadine and rimantadine in the prophylaxis 126. Oliveira EC, Marik PE, Colice G. Influenza of influenza A infection. New Engl J Med pneumonia: a descriptive study. Chest 1982;307:580–4. 2001;119:1723. 135. Cohen A, Togo Y, Khakoo R, Waldman R, 127. Griffin ADP. Cost-effectiveness analysis of inhaled Sigel M. Comparative clinical and laboratory zanamivir in the treatment of influenza A and B in evaluation of the prophylactic capacity of high-risk patients. Pharmacoeconomics 2001;19:293– ribavirin, amantadine hydrochloride and placebo 301. in induced human influenza type A. J Infect Dis 1976;133(Suppl):A114–20. 128. Rothberg MBH. Management of influenza symptoms in healthy adults: cost-effectiveness of 136. Diggory P, Fernandez C, Humphrey A, Jones rapid testing and antiviral therapy. J Gen Intern Med V, Murphy M. Comparison of elderly people’s 2003;18:808–15. technique in using two dry powder inhalers to deliver zanamivir: randomised controlled trial. BMJ 129. Stratton KR, Durch JS, Lawrence RS. Vaccines 2001;322:577–9. for the 21st century: a tool for decisionmaking. Washington, DC: National Academy Press; 2007. 137. Pocock N. US FDA staff recommend additional neuropsychiatric warnings for oseltamivir and zanamivir. 130. Office for National Statistics. Mortality statistics: NHS National Electronic Library for Medicines; cause. Review of the Registrar General on deaths 2007 by cause, sex and age in England and Wales, 2005. 2006;DH2 no.32

131. Kind P, Hardman G, Macran S. UK population norms for EQ-5D. Centre for Health Economics Discussion Paper Series; 1999.

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Appendix 1 Literature search strategies

MEDLINE search strategy 40. controlled clinical trial.pt. to identify clinical trials 41. randomized controlled trials/ 42. random allocation/ 1. Oseltamivir/526 43. double blind method/ 2. (gs 4071 or gs 4104 or gs4104 or gs4071 or 44. single blind method/ tamiflu).mp. 45. or/39–44 3. Amantadine/ 46. clinical trial.pt. 4. amantadine.mp. 47. exp clinical trials/ 5. aman.mp. 48. (clin$adj25 trial$).tw. 6. amanta.mp. 49. ((singl$or doubl$or trebl$or tripl$) adj25 7. amantadin.mp. (blind$or mask$)).tw. 8. amantadina.mp. 50. placebos/ 9. amixx.mp. 51. placebo$.tw. 10. cerebramed.mp. 52. random$.tw. 11. endantadine.mp. 53. research design/ 12. gen-amantadine.mp. 54. or/46–53 13. infecto-flu.mp. 55. “comparative study”/ 14. infex.mp. 56. exp evaluation studies/ 15. mantadix.mp. 57. follow-up studies/ 16. midrantan.mp. 58. prospective studies/ 17. pms-amantadine.mp. 59. (control$or prospectiv$or volunteer$).tw. 18. symadine.mp. 60. (control$or prospectiv$or volunteer$).tw. 19. symmetrel.mp. 61. or/55–60 20. viregyt.mp. 62. 45 or 54 or 61 21. wiregyt.mp. 63. “animal”/ 22. tregor.mp. 64. “human”/ 23. oseltami.mp. 65. 63 not 64 24. Zanamivir/ 66. 62 not 65 25. zanamivir.mp. 67. 66 and 38 26. 2,3-didehydro-2,4-dideoxy-4-guanidino-n- 68. Influenza, Human/ acetyl-d-neuraminic acid.mp. 69. 68 and 67 27. 2,3-didehydro-2,4-dideoxy-4-guanidinyl-n- acetylneuraminic acid.mp. MEDLINE search strategy 28. 4-guanidino-2,4-dideoxy-2,3-didehydro-n- to identify utility estimates acetylneuraminic acid.mp. for influenza and related 29. 4-guanidino-2-deoxy-2,3-didehydro-n- complications acetylneuraminic acid.mp. 30. 4-guanidino-neu5ac2en.mp. 1. Influenza/ 31. 5-acetylamino-2,6-anhydro-4-guanidino- 2. (influenza or flu).tw. 3,4,5-trideoxy-d-galacto-non-enoic acid. 3. 1 or 2 mp. - 4. “Quality of Life”/ 32. (gg 167 or gg167).mp. 5. (quality of life or qol).ti,ab. 33. relenza.mp. 6. (quality adjusted life year or qaly).ti,ab. 34. or/1–33 7. utilit$.ti,ab. 35. prophyla$.ti,ab. 8. Health Status Indicators/ 36. prevent$.ti,ab. 9. disability adjusted life.tw. 37. 35 or 36 10. daly$.tw. 38. 37 and 34 11. (sf36 or sf 36 or short form 36 or shortform 39. randomized controlled trial.pt. 36 or sf thirtysix or sf thirty six or shortform thirtysix or shortform thirty six 149

or short form thirtysix or short form thirty 23. rosser.tw. six).tw. 24. quality of wellbeing.tw. 12. (sf6 or sf 6 or short form 6 or shortform 6 25. qwb.tw. or sf six or sfsix or shortform six or short 26. willingness to pay.tw. form six).tw. 27. standard gamble$.tw. 13. (sf12 or sf 12 or short form 12 or shortform 28. time trade off.tw. 12 or sf twelve or sftwelve or shortform 29. time tradeoff.tw. twelve or short form twelve).tw. 30. tto.tw. 14. (sf16 or sf 16 or short form 16 or shortform 31. exp models, economic/ 16 or sf sixteen or sfsixteen or shortform 32. economic model$.tw. sixteen or short form sixteen).tw. 33. markov$.tw. 15. (sf20 or sf 20 or short form 20 or shortform 34. monte carlo.tw. 20 or sf twenty or sftwenty or shortform 35. (decision$adj2 (tree$or analy$or model$)). twenty or short form twenty).tw. tw. 16. (euroqol or euro qol or eq5d or eq 5d).tw. 36. letter.pt. 17. (hql or hqol or h qol or hrqol or hr qol).tw. 37. editorial.pt. 18. (hye or hyes).tw. 38. comment.pt. 19. health$year$equivalent$.tw. 39. or/36–38 20. health utilit$.tw. 40. or/4–35 21. (hui or hui1 or hui2 or hui3).tw. 41. (40 and 3) not 39 22. disutili$.tw.

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Appendix 2 Quality assessment

Quality assessment criteria for experimental studies These quality assessment criteria were based on those proposed by the NHS Centre for Reviews and Dissemination.35

Yes/No/Unclear/ Not applicable Was the method used to assign participants to the treatment groups really random? What method of assignment was used? Was the allocation of treatment concealed? What method was used to conceal treatment allocation? Was the number of participants who were randomised stated? Were the eligibility criteria for study entry specified? Were details of baseline comparability presented? Was baseline comparability achieved? Were the participants who received the intervention blinded to the treatment allocation? Were the individuals who administered the intervention blinded to the treatment allocation? Were the outcome assessors blinded to the treatment allocations? Was the success of the blinding procedure assessed? Were any co-interventions identified that may influence the outcomes for each group? Was an intention-to-treat analysis included? Were at least 80% of the participants originally included in the randomised process followed up in the final analysis?

151

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Appendix 3 Study quality characteristics for amantadine prophylaxis trials

153

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 3 62 Smorodintsev et al. , 1970 U U U N U N U 63 Sears and Clements, 1987 U U Y N U Y U 60,61 Smorodintsev et al. , 1970 U Y Y N U N For adverse effect and morbidity assessment: Y 59 Payler and Payler Purdham, 1984 U U Y N U Y U 55 Pettersson et Pettersson al. , 1980 Y U Y Y N N U For self- recorded symptoms and adverse effects: Y 58 Aoki et al. , 1986 Y U Y N U Y For measurement of amantadine concentrations in plasma and urine: Y For incidence of illness and adverse events: self-recorded: Y For serum HAI assessment: U For nurses classifying illness: U a (2) 57 U Reuman et al. , Reuman 1989 U Y N U Y U a (1) 57 Reuman et al. , Reuman 1989 Y U Y N U Y U For self- notification of illness: Y Quality criterion the method used to Was assign participants to the treatment groups really random? Was the allocation of Was treatment concealed? Was the number of Was participants who were randomised stated? Were details of baseline Were comparability presented? Was baseline Was comparability achieved? Were the eligibility Were criteria for study entry specified? 154 the outcome Were assessors blinded to allocation? DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 62 Smorodintsev et al. , 1970 U Described as double blind but no further details U Described as double blind but no further details NA Y 63 Sears and Clements, 1987 U Described as double blind but no further details U Described as double blind but no further details Y Y 60,61 Smorodintsev et al. , 1970 Y Y N N 59 Payler and Payler Purdham, 1984 N N Y N 55 Pettersson et Pettersson al. , 1980 U Described as double blind but no further details Y Y Mixed For efficacy analysis: N For adverse event analysis: Y 58 Aoki et al. , 1986 U Described as single blind but no further details Y Y N a (2) 57 U Described as double blind but no further details Reuman et al. , Reuman 1989 U Described as double blind but no further details Y Y a (1) 57 Reuman et al. , Reuman 1989 U Described as double blind but no further details Y Y Y (1) Seasonal influenza study; (2) experimentally induced study. Quality criterion the individuals Were who administered the intervention blinded to allocation? Were the participants Were receiving intervention blinded to allocation? Were the reasons for Were withdrawal stated? Was intention-to-treat Was analysis included? HAI, haemagglutination inhibition assay; NA, not applicable. a Y, N and U are used to denote positive, negative unclear decisions with respect each quality criterion. Y, 155

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Appendix 4 Study quality characteristics for oseltamivir prophylaxis trials

157

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 4 67 2000 al. , et Y N U Described as double blind but no further details U Described as double blind but no further details U U U N Y U U Hayden 48,73,74 Y Y N Open-label N Open-label U For self-recording of data: Y Y Y Y Y U U Hayden et al. , 2004 49 2001 et al. , et N Y U Described as double blind but no further details U Described as double blind but no further details U For self-recording of data: Y Y Y Y Y U U Welliver Welliver 66 N Y Y Double-blind labelling Y Double-blind labelling U For self-recording of data: Y Y Y Y Y Y Y Hayden et al. , 1999 64 U N Y U Described as double blind but no further details For self-recording of data: Y Y Y Y Peters et al. , 2001 Peters Y Y, N and U are used to denote positive, negative unclear decisions with respect each quality criterion. Y, Was intention-to-treat analysis included? Was Were the reasons for withdrawal stated? Were Were the participants receiving intervention Were blinded to allocation? Were the individuals who administered Were intervention blinded to allocation? Were the outcome assessors blinded to allocation?to blinded assessors outcome the Were U Were the eligibility criteria for study entry Were specified? Was baseline comparability achieved? Was Were details of baseline comparability presented?Were Y Was the number of participants who were Was randomised stated? Was the allocation of treatment concealed?Was Y 158 the method used to assign participants Was treatment groups really random? DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Appendix 5 Study quality characteristics for zanamivir prophylaxis trials

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© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 5 44 N N GSK study 167/101 U U; described as double blind but no further details U; described as double blind but no further details U N U N Y U 78 44 44 44 Y Y Gravenstein et al. , 2005 Y Y Y Y(albeit relatively weakly for age, sex, vaccination status, chronic cardiac condition and diabetes variables) Y Y Y Y Y 76,77 Y Y Y Ambrozaitis et al. , 2005 Y Y Y Y Y U Y Y 72 Y Y U Kaiser et al. , Kaiser 2000 U Y Y Y Y U U; described as double blind but no further details U; described as double blind but no further details 46 Y Y U U; for self- recording of data: Y Y Y Y Y Hayden et al. , 2000 U U; described as double blind but no further details U; described as double blind but no further details 47 44 44 44 Y Y Y U Monto et al. , 2002 N Y U; for self- recording of data: Y Y Y Y Y 75 44 44 Y Y Y Y Y Y LaForce et al. , 2007 U; for self- recording of data: Y Y Y Y Y 72,73 Y Y Y Y Y Y Monto et al. , 1999 U; for self- recording of data: Y Y Y Y Y Y, N and U are used to denote positive, negative unclear decisions with respect each quality criterion. Y, Was intention-to-treat analysis Was included? Were the individuals who Were administered the intervention blinded to allocation? the participants Were receiving intervention blinded to allocation? the reasons for Were withdrawal stated? Was the allocation of Was treatment concealed? Was the method used to Was assign participants to the treatment groups really random? Quality criterion Were the outcome assessors Were blinded to allocation? Were the eligibility criteria for Were study entry specified? Was baseline comparability Was achieved? Were details of baseline Were comparability presented? 160 the number of Was participants who were randomised stated? DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Appendix 6 Studies excluded after close scrutiny with rationale

Study Reason for exclusion Aoki et al., 1985 Not in line with licensed indications Bowles et al., 1999 Not a randomised controlled trial Bowles et al., 2002 Not a randomised controlled trial Bryson et al., 1980 Not in line with licensed indications Bush et al., 2004 Not a randomised controlled trial Calfee et al., 1999a Not in line with licensed indications Calfee et al., 1999b Not in line with licensed indications Callmander et al., 1968 Not in line with licensed indications Cass et al., 2000 Not in line with licensed indications Cohen et al., 1976 Not in line with licensed indications Davies et al., 1988 Not a randomised controlled trial Dawkins et al., 1968 Analogue of amantadine hydrochloride. Not in line with licensed indications Degelau et al., 1990 Not a randomised controlled trial Diaz-Pedroche et al., 2006 Not available to read in English Dolin et al., 1982 Not in line with licensed indications Drinka et al., 1998 Comparison of short and long-term amantadine prophylaxis protocols Finklea et al., 1967 Not in line with licensed indications – dosage not established in children Galbraith et al., 1969a Data for subgroup in line with licensed indications not presented Galbraith et al., 1969b Data for subgroup in line with licensed indications not presented Galbraith et al., 1971 Data for subgroup in line with licensed indications not presented Hayden et al., 1981 Not in line with licensed indications Hayden et al., 1996 Not in line with licensed indications Hayden et al., 1999b Not in line with licensed indications Hayden, 2001 Abstract only. Insufficient data Hess, 1982 Not available to read in English Hirji et al., 2001 Not a randomised controlled trial Hirji et al., 2002 Not a randomised controlled trial Jackson et al., 1963 Not in line with licensed indications Kantor et al., 1980 Not in line with licensed indications Kashiwagi et al., 2000 Not available to read in English Lee et al., 2000 Not a randomised controlled trial Leeming et al., 1969 Not in line with licensed indications Leung et al., 1979 Not in line with licensed indications Libow et al., 1996 Not a randomised controlled trial Mate et al., 1970 Not in line with licensed indications continued

161

Study Reason for exclusion McLeod & Lau, 2001 Not a randomised controlled trial Millet et al., 1982 Not in line with licensed indications Monto et al., 1979 Not in line with licensed indications Monto et al., 2004 Not a randomised controlled trial Muldoon et al., 1976 Not in line with licensed indications Nafta et al., 1970 Not in line with licensed indications O’Donoghue et al., 1973 Not in line with licensed indications Oker-Blom et al., 1970 Not in line with licensed indications Peckinpaugh et al., 1970 Not in line with licensed indications Peters et al., 1989 Not a randomised controlled trial Plesnik et al., 1977 Not available to read in English Quarles et al., 1981 Not in line with licensed indications Quilligan et al., 1966a Not in line with licensed indications – dosage not established in children Quilligan et al., 1966 Not available to read in English Schapira et al., 1971 Not in line with licensed indications Schilling et al., 1998 Not in line with licensed indications Shinjoh et al., 2004 Not available to read in English Smorodintsev et al., 1972 Not available to read in English Somani et al., 1991 Not a randomised controlled trial Stanley et al., 1965 Not in line with licensed indications Togo et al., 1968 Not in line with licensed indications Tyrrell et al., 1965 Not in line with licensed indications Vogel, 2002 Not a randomised controlled trial Walker et al., 1997 Not in line with licensed indications Wendel et al., 1966 Not in line with licensed indications Wright et al., 1974 Not in line with licensed indications Wright et al., 1976 Not in line with licensed indications – dosage not established in children

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Appendix 7 List of all model parameters

The following abbreviations are used in this appendix:

A&E, accident and emergency; CNS, central nervous system; GP, general practitioner; ICU, intensive care unit; ILI, influenza-like illness; ITU, intensive therapy unit; LOS, length of stay; NA, not applicable; QALY, quality-adjusted life-year; RR, relative risk; SE, standard error.

Distribution parameter key

Distribution type Parameter 1 Parameter 2 Normal Mean SE Beta Alpha Alpha + beta Gamma Alpha Beta Lognormal Ln mean SE ln mean Dirichlet (multinomial) Alpha Beta

163

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – 1.23 0.14 0.83 0.45 0.34 12 86.11 859 281 199 100 200 237.89 800.78 1469 1256 1125 Parameter 2 Parameter 9 0.72 1 1 0.53 1 0.70 2 1.72 –1.02 –0.92 –1.43 83 –1.13 32.65 73.40 10 13.56 10.41 256 622 740 Parameter 1 Parameter 0.17 0.50 0.75 0.86 0.30 0.72 0.36 0.40 0.24 0.32 0.37 1 1 0.53 1 0.70 0.02 0.05 0.06 0.02 0.01 40 Mean Distribution Beta Beta Beta NA Gamma Lognormal Lognormal Lognormal Lognormal Beta Beta NA NA NA Beta Beta Beta Beta Beta Seasonal prophylaxis: healthy children No. description Parameter Baseline event probabilities (disease) 1 Baseline attack rate for influenza 2 ILI is influenza within epidemic period Probability 3 influenza A strain is dominant Probability 4 influenza is A in dominant seasons Probability Beta 5 influenza is A in B dominant years Probability Beta 6 influenza is A Probability 7 Duration of influenza epidemic (days) Effectiveness parameters (prevention) 8 RR for influenza – vaccine 9 RR for influenza – amantadine prophylaxis 10 RR for influenza – oseltamivir prophylaxis 11 RR for influenza – zanamivir prophylaxis 12 of amantadine resistance Probability 13 influenza case occurs within epidemic Probability 14 influenza case avoidable – amantadine Probability 15 influenza case avoidable – amantadine (vaccination) Probability NA 16 influenza case avoidable – oseltamivir Probability 17 of influenza cases avoidable – zanamivir Percentage Adverse events/withdrawals (prophylaxis) 18 adverse event – vaccination Probability 19 adverse event – amantadine prophylaxis Probability 20 withdrawal – amantadine prophylaxis Probability 21 withdrawal – oseltamivir prophylaxis Probability 22 withdrawal – zanamivir prophylaxis Probability

164 List of model parameters – seasonal prophylaxis 81 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – – – 0 0.16 86.11 20 73 800.78 2423 2423 2423 2423 2423 2423 1697 2962 2311 17,910 Parameter 2 Parameter 17,201 5 0 1 0 1.72 0 1 3 1 38 –0.36 10.41 18 18 29 £9.60 685 £14.40 £49.08 £73.65 2417 1698 4997 2183 Parameter 1 Parameter 0.25 0.52 0 1 0 0.02 0.01 0.14 0.65 0.70 0.70 0 0.01 0 0.28 0.01 0.02 0.28 0.74 0 £9.60 £14.40 £49.08 £73.65 Mean Distribution Beta Beta NA NA Beta Beta Beta Lognormal Lognormal Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Beta Beta Beta Beta NA NA NA NA 48 hours NA No. description Parameter ILI event probabilities (treatment) 23 patient with ILI presents Probability 24 patient presents within 48 hours of ILI onset Probability 25 | presents < patient given antiviral Treatment Probability 26 patient receives oseltamivir | prescribed antiviral Probability 27 patient receives zanamivir | prescribed antiviral Probability 28 adverse events – oseltamivir treatment Probability 29 adverse events – zanamivir treatment Probability 30 complication – no treatment Probability 31 Odds ratio complication – oseltamivir treatment 32 Odds ratio complication – zanamivir treatment 3334 complication is respiratory Probability 35 complication is cardiac Probability 36 complication is CNS Probability 37 complication is renal Probability complication is otitis media Probability 3839 complication is other Probability 40 respiratory complication is pneumonia Probability 41 patient receives antibiotics | no complication Probability 42 patient receives antibiotics | complication Probability of influenza death | complication Probability Cost/resource parameters 43 Cost of amantadine prophylaxis course (without vaccine) 44 Cost of amantadine prophylaxis course (with vaccine) 45 Cost of oseltamivir prophylaxis course 46 Cost of zanamivir prophylaxis course 165

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – – – – – – – – – – – – – – – 5.16 4 73 73 46 270.11 270.11 453 Parameter 2 Parameter 8.35 0.97 4 8.35 0.97 4 5 1 21 42 28 £5.63 £6.80 £1.69 22 £16.36 £24.55 £42 £25 £25 £69 £95.56 £29.52 £29.52 £25 £25 £261.17 Parameter 1 Parameter 0.03 0.97 0.05 0.03 0.97 0.05 0.11 0.05 2.30 21 42 28 £5.63 £6.80 £1.69 £16.36 £24.55 £42 £25 £25 £69 £95.56 £29.52 £29.52 £25 £25 £261.17 Mean Distribution NA NA NA NA NA NA NA NA NA NA NA Beta NA Beta NA NA NA NA NA NA Gamma Beta Beta Gamma Seasonal prophylaxis: healthy children (continued) No. description Parameter 47 Cost of oseltamivir treatment course 48 Cost of zanamivir treatment course 49 Days per course – amantadine prophylaxis 50 Days per course – amantadine prophylaxis (prior vaccination) 51 Days per course – oseltamivir prophylaxis 52 Days per course – zanamivir prophylaxis 53 Acquisition cost for vaccination 54 Administration cost for vaccination 55 Cost of attendance at GP surgery consultation 56 Cost of attendance at GP home visit 57 Cost of attendance at A&E 58 A&E attendance | patient presents (no complication) Probability Beta 59 GP attendance | patient presents (no complication) Probability NA 60 home GP visit | presentation (no complication) Probability Beta 61 A&E attendance | patient presents (complication) Probability 62 GP attendance | patient presents (complication) Probability 63 home GP visit | presentation (complication) Probability 64 Cost of uncomplicated influenza presentation 65 Cost of complicated influenza presentation 66 Cost of antibiotics course 67 Cost of anti-emetics course (metaclopramide 7-day course) 68 Cost of managing adverse events – vaccination 69 Cost of managing adverse events – amantadine prophylaxis 70 Cost of inpatient episode 71 hospitalisation no treatment | complication Probability 72 ICU care | complication Probability 73 (days) Inpatient LOS

166 81 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – 2.41 0 0.41 0.14 0.14 0.14 0.41 0.14 1.14 1.14 1.14 1.14 0.96 1.14 0.01 0.01 0.01 0.01 £31.95 1000 100,000 100,000 100,000 Parameter 2 Parameter 0.01 0.01 0.01 6.92 6.92 6.92 6.92 9.73 6.92 0.94 0.93 0.91 0.85 11.60 –1.90 –0.99 –0.99 –0.99 25 –1.90 –0.99 200 4146 4247 4247 £1345.39 £2430.18 Parameter 1 Parameter 0.04 0.04 0.04 0.01 0.01 0.01 0.20 0.01 0.15 0.37 0.37 0.37 0.15 0.37 0.02 0.02 0.02 0.02 0.03 0.02 0.94 0.93 0.91 0.85 28 Mean £1345.39 £2430.18 Distribution Normal Gamma NA Beta Beta Beta NA NA NA Beta Gamma Lognormal Lognormal Lognormal Lognormal Lognormal Lognormal Gamma Gamma Gamma Gamma Gamma Gamma Normal Normal Normal Normal No. description Parameter 7475 Cost of ITU day (days) ITU LOS 76 Expected cost of hospitalisation HRQoL parameters 77 for influenza case – no treatment 21-day QALYs 78 for influenza case – oseltamivir treatment 21-day QALYs 79 for influenza case – zanamivir treatment 21-day QALYs 80 loss for influenza case – no treatment QALY 81 loss for influenza case – oseltamivir treatment QALY 82 loss for influenza case – zanamivir treatment QALY 83 Utility decrement – adverse events 84 Duration adverse events 85 Utility decrement respiratory complication 86 Utility decrement cardiac complication 87 Utility decrement CNS complication 88 Utility decrement renal complication 89 Utility decrement otitis media complication 90 Utility decrement other complication 91 Duration respiratory complication (years) 92 Duration cardiac complication (years) 93 Duration CNS complication (years) 94 Duration renal complication (years) 95 Duration otitis media complication (years) 96 Duration other complication (years) 97 Utility general population 0–24 98 Utility general population 25–34 99 Utility general population 35–44 100 Utility general population 45–54 167

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 0.02 – – – Parameter 2 Parameter 0.01 0.01 0.73 0.51 3.50% 0.80 0.78 24.74 Parameter 1 Parameter 0.73 0.51 3.50% 0.80 0.78 24.74 Mean Normal NA NA NA Distribution Normal Normal 75 Seasonal prophylaxis: healthy children (continued) 104 population female Percentage 105 loss for premature death QALY 106 Discount rate for QALYs No. description Parameter 101 Utility general population 55–64 102 Utility general population 65–74 103 Utility general population >

168 81 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – 1.23 0.14 0.83 0.45 0.34 12 859 281 199 100 200 237.89 1469 1256 1125 Parameter 2 Parameter 9 0.72 1 1 0.53 1 0.70 2 –1.02 –0.92 –1.43 –1.13 83 32.65 73.40 10 13.56 256 622 740 Parameter 1 Parameter 0.17 0.50 0.75 0.86 0.30 0.36 0.40 0.24 0.32 0.37 0.72 1 1 0.53 1 0.70 0.02 0.05 0.06 40 Mean Distribution Beta Beta Beta Beta Beta Lognormal Lognormal Lognormal Lognormal Beta NA Gamma Beta NA NA NA NA Beta Beta Beta Seasonal prophylaxis: at-risk children seasons years (vaccination) No. description Parameter Baseline event probabilities (disease) 12 Baseline attack rate for influenza 3 ILI is influenza within epidemic period Probability 4 influenza A strain is dominant Probability influenza is A in dominant Probability 5 influenza is A in B dominant Probability Effectiveness parameters (prevention) 89 RR for influenza – vaccine 10 RR for influenza – amantadine prophylaxis 11 RR for influenza – oseltamivir prophylaxis 12 RR for influenza – zanamivir prophylaxis of amantadine resistance Probability 67 influenza is A Probability Duration of influenza epidemic (days) 1314 influenza case occurs within epidemic Probability 15 influenza case avoidable – amantadine Probability influenza case avoidable – amantadine Probability 1617 influenza case avoidable – oseltamivir Probability of influenza cases avoidable – zanamivir Percentage Adverse events/withdrawals (prophylaxis) 1819 adverse event – vaccination Probability adverse event – amantadine prophylaxis Probability 20 withdrawal – amantadine prophylaxis Probability

TABLE 82 TABLE 169

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – – 0 0.38 86.11 20 73 86.11 650 800.78 800.78 681 681 681 681 681 681 520 2962 3695 Parameter 2 Parameter 17,910 1 1.72 5 1 1 0 1.72 0 1 1 1 3 9 –0.71 £9.60 10.41 38 10.41 £14.40 £49.08 675 521 154 Parameter 1 Parameter 4997 2183 0 0.02 0.01 0.25 0.52 1 1 0 0.02 0.01 0.18 0.65 0.28 0.74 0.49 0.77 0 0 0 0.23 0 0.02 £9.60 £14.40 £49.08 Mean Distribution Beta NA Beta Beta Beta NA Beta Beta Beta Lognormal Lognormal Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Beta 48 Seasonal prophylaxis: at-risk children (continued) hours No. description Parameter 42 of influenza death | complication Probability Cost/resource parameters 4344 Cost of amantadine prophylaxis course (without vaccine) Cost of amantadine prophylaxis course (with vaccine) NA NA 45 Cost of oseltamivir prophylaxis course 2122 withdrawal – oseltamivir prophylaxis Probability withdrawal – zanamivir prophylaxis Probability ILI event probabilities (treatment) 23 patient with ILI presents Probability 24 patient presents within 48 hours of ILI onset Probability Beta 25 patient given antiviral treatment | presents < Probability 2627 patient receives oseltamivir | prescribed antiviral Probability 28 patient receives zanamivir | prescribed antiviral Probability NA 29 adverse events – oseltamivir treatment Probability NA adverse events – zanamivir treatment Probability 3031 complication – no treatment Probability Odds ratio complication – oseltamivir treatment 3233 Odds ratio complication – zanamivir treatment 34 complication is respiratory Probability 35 complication is cardiac Probability 36 complication is CNS Probability 37 complication is renal Probability 38 complication is otitis media Probability 39 complication is other Probability 40 respiratory complication is pneumonia Probability 41 patient receives antibiotics | no complication Probability patient receives antibiotics | complication Probability Beta Beta

170 82 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – – – – – – – – – – – – – – – – 5.16 73 73 95 270.11 270.11 Parameter 2 Parameter 8.35 0.97 4 8.35 0.97 4 21 42 28 £5.63 £6.80 £1.69 15 £73.65 £16.36 £24.55 £42 £25 £25 £69 £95.56 £29.52 £29.52 £25 £25 £261.17 Parameter 1 Parameter 0.03 0.97 0.05 0.03 0.97 0.05 0.16 21 42 28 £5.63 £6.80 £1.69 £73.65 £16.36 £24.55 £42 £25 £25 £69 £95.56 £29.52 £29.52 £25 £25 £261.17 Mean Distribution NA NA NA NA NA NA NA NA NA NA NA Beta NA Beta NA NA NA NA Gamma complication) complication) complication) No. description Parameter 4647 Cost of zanamivir prophylaxis course 48 Cost of oseltamivir treatment course 49 Cost of zanamivir treatment course 50 Days per course – amantadine prophylaxis 51 Days per course – amantadine prophylaxis (prior vaccination)52 NA Days per course – oseltamivir prophylaxis 53 Days per course – zanamivir prophylaxis 54 Acquisition cost for vaccination 55 Administration cost for vaccination 56 Cost of attendance at GP surgery consultation 57 Cost of attendance at GP home visit 58 Cost of attendance at A&E A&E attendance | patient presents (no Probability 59 GP attendance | patient presents (no Probability 60 home GP visit | presentation (no Probability 61 A&E attendance | patient presents (complication) Probability Beta 62 GP attendance | patient presents (complication) Probability NA 6364 home GP visit | presentation (complication) Probability 65 Cost of uncomplicated influenza presentation Beta 66 Cost of complicated influenza presentation 67 Cost of antibiotics course 68 Cost of anti-emetics course (metaclopramide 7-day course) Cost of managing adverse events – vaccination 69 NA 70 Cost of managing adverse events – amantadine prophylaxis71 Cost of inpatient episode NA hospitalisation no treatment | complication Probability Beta 171

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – 4 2.41 0 0.41 0.14 0.14 0.14 0.41 0.14 1.11 1.11 1.11 1.11 0.96 1.11 0.01 453 £31.95 1000 Parameter 2 Parameter 100,000 100,000 100,000 1 0.02 0.02 0.02 7.24 7.24 7.24 7.24 9.73 7.24 0.94 –1.90 –0.99 –0.99 –0.99 –1.90 –0.99 22 11.60 25 200 2820 2977 2977 £1345.39 £2430.18 Parameter 1 Parameter 0.05 2.30 0.03 0.03 0.03 0.02 0.02 0.02 0.20 0.01 0.15 0.37 0.37 0.37 0.15 0.37 0.02 0.02 0.02 0.02 0.03 0.02 0.94 28 £1345.39 £2430.18 Mean Distribution Beta Gamma Normal NA Gamma Beta NA NA Beta Gamma Lognormal Lognormal Lognormal Lognormal Lognormal Lognormal Gamma Gamma Gamma Gamma Gamma Gamma Normal Seasonal prophylaxis: at-risk children (continued) No. description Parameter 72 ICU care | complication Probability 73 (days) Inpatient LOS 74 Cost of ITU day 76 Expected cost of hospitalisation 75 (days) ITU LOS HRQoL parameters 77 for influenza case – no treatment 21-day QALYs 7879 for influenza case – oseltamivir treatment 21-day QALYs 80 for influenza case – zanamivir treatment 21-day QALYs 81 Beta loss for influenza case – no treatment QALY 82 loss for influenza case – oseltamivir treatment QALY Beta 83 loss for influenza case – zanamivir treatment QALY 84 Utility decrement – adverse events 85 NA Duration adverse events 86 Utility decrement respiratory complication 87 Utility decrement cardiac complication 88 Utility decrement CNS complication 89 Utility decrement renal complication 90 Utility decrement otitis media complication 91 Utility decrement other complication 92 Duration respiratory complication (years) 93 Duration cardiac complication (years) 94 Duration CNS complication (years) 95 Duration renal complication (years) 96 Duration otitis media complication (years) 97 Duration other complication (years) Utility general population 0–24

172 82 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 – – – 0.01 0.01 0.01 0.01 0.01 0.02 Parameter 2 Parameter 0.93 0.91 0.85 0.80 0.78 0.73 0.51 3.50% 24.74 Parameter 1 Parameter 0.73 0.93 0.91 0.85 0.80 0.78 0.51 3.50% 24.74 Mean Distribution Normal Normal Normal Normal Normal Normal NA NA NA 75 No. description Parameter 9899 Utility general population 25–34 100 Utility general population 35–44 Utility general population 45–54 101 Utility general population 55–64 102 Utility general population 65–74 103 Utility general population > 104 population female Percentage 105 loss for premature death QALY 106 Discount rate for QALYs 173

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – 0.34 0.45 0.83 0.17 1.23 86.11 12 800.78 237.89 200 100 199 281 859 1125 1256 1670 Parameter 2 Parameter 1.72 2 0.70 1 0.53 1 1 0.72 9 10.41 13.56 10 –1.13 –1.43 –0.92 –1.05 73.40 32.65 83 740 622 104 Parameter 1 Parameter 0.01 0.02 0.06 0.05 0.02 0.70 1 0.53 1 1 0.37 0.32 0.24 0.40 0.35 0.72 0.30 0.86 0.75 0.50 0.06 40 Mean Beta Beta Beta Beta Beta NA NA NA Beta Beta Lognormal Lognormal Lognormal Lognormal Gamma NA Beta Beta Beta Distribution Seasonal prophylaxis: healthy adults 22 withdrawal – zanamivir prophylaxis Probability 21 withdrawal – oseltamivir prophylaxis Probability 20 withdrawal – amantadine prophylaxis Probability 19 adverse event – amantadine prophylaxis Probability Adverse events/withdrawals (prophylaxis) 18 adverse event – vaccination Probability 17 of influenza cases avoidable – zanamivir Percentage 16 influenza case avoidable – oseltamivir Probability 15 influenza case avoidable – amantadine (vaccination) Probability NA 14 influenza case avoidable – amantadine Probability 13 influenza case occurs within epidemic Probability 12 of amantadine resistance Probability 11 RR for influenza – zanamivir prophylaxis 10 RR for influenza – oseltamivir prophylaxis 9 RR for influenza – amantadine prophylaxis Effectiveness parameters (prevention) 8 RR for influenza – vaccine 7 Duration of influenza epidemic (days) 6 influenza is A Probability 5 influenza is A in B dominant years Probability Beta 4 influenza is A in dominant seasons Probability Beta 3 influenza A strain is dominant Probability 2 ILI is influenza within epidemic period Probability Baseline event probabilities (disease) 1 Baseline attack rate for influenza No. description Parameter

174 83 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – – – – 0 0.16 20 86.11 668 800.78 6437 5636 8579 6515 6515 6515 6515 6515 6515 47,169 85,248 Parameter 2 Parameter 5 0 0.89 0.11 1.72 –1 –0.36 £9.60 33 10 10.41 12 £16.36 £73.65 £81.80 £14.40 237 253 501 102 104 6983 6509 5637 19811 Parameter 1 Parameter 0.42 0.81 0.01 0.04 0.04 0.08 0 0.89 0.11 0.02 0.02 0.25 0.16 0 0.01 0.08 0.40 0.70 0.87 0 £9.60 £16.36 £73.65 £81.80 £14.40 Mean NA NA NA NA NA Beta Beta Beta Beta Dirichlet Dirichlet Dirichlet Beta Dirichlet Beta Beta Beta Beta Lognormal Lognormal Dirichlet Dirichlet Distribution 48 hours NA 47 Cost of oseltamivir treatment course 46 Cost of zanamivir prophylaxis course 4445 Cost of amantadine prophylaxis course (with vaccine) Cost of oseltamivir prophylaxis course Cost/resource parameters 43 Cost of amantadine prophylaxis course (without vaccine) 4041 patient receives antibiotics | no complication Probability 42 patient receives antibiotics | complication Probability of influenza death | complication Probability 39 respiratory complication is pneumonia Probability 38 complication is other Probability 37 complication is otitis media Probability 36 complication is renal Probability 2627 patient receives oseltamivir | prescribed antiviral Probability 28 patient receives zanamivir | prescribed antiviral Probability adverse events – oseltamivir treatment Probability NA NA 35 complication is CNS Probability ILI event probabilities (treatment) 2324 patient with ILI presents Probability 25 patient presents within 48 hours of ILI onset Probability patient given antiviral treatment | presents < Probability 2930 adverse events – zanamivir treatment Probability 31 complication – no treatment Probability 32 Odds ratio complication – oseltamivir treatment 33 Odds ratio complication – zanamivir treatment 34 complication is respiratory Probability complication is cardiac Probability No. description Parameter 175

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – – – – – – – – – – – – – – 5.16 1 46 270.11 270.11 674 674 £31.95 453 Parameter 2 Parameter 8.35 0.97 8.35 0.97 5 21 42 28 £5.63 56 56 £6.80 £1.69 22 16 £24.55 £42 £25 £25 £69 £95.56 £30.73 £30.73 £25 £25 £261.17 £1345.39 Parameter 1 Parameter 0.97 0.97 0.03 0.08 0.03 0.08 0.11 0.05 21 42 28 £5.63 £6.80 £1.69 11.90 £24.55 £42 £25 £25 £69 £95.56 £30.73 £30.73 £25 £25 £261.17 £1345.39 Mean NA NA NA NA NA NA NA NA NA NA NA NA Beta Normal NA Gamma Beta Gamma Distribution Seasonal prophylaxis: healthy adults (continued) 4849 Cost of zanamivir treatment course 50 Days per course – amantadine prophylaxis Days per course – amantadine prophylaxis (prior vaccination) NA 51 Days per course – oseltamivir prophylaxis 52 Days per course – zanamivir prophylaxis 53 Acquisition cost for vaccination 59 GP attendance | patient presents (no complication) Probability 62 NA GP attendance | patient presents (complication) Probability NA 5455 Administration cost for vaccination 56 Cost of attendance at GP surgery consultation 57 Cost of attendance at GP home visit 58 Cost of attendance at A&E A&E attendance | patient presents (no complication) Probability 60 Beta 61 home GP visit | presentation (no complication) Probability A&E attendance | patient presents (complication) Probability 63 Beta 64 home GP visit | presentation (complication) Probability Beta 65 Cost of uncomplicated influenza presentation 66 Cost of complicated influenza presentation Beta Cost of antibiotics course 67 Cost of anti-emetics course (metaclopramide 7-day course) NA 71 hospitalisation no treatment | complication Probability 74 Cost of ITU day 6869 Cost of managing adverse events – vaccination 70 Cost of managing adverse events – amantadine prophylaxis Cost of inpatient episode 7273 NA ICU care | complication Probability (days) Inpatient LOS No. description Parameter

176 83 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – 0.41 0.14 0.14 0.14 0.41 0.14 0.98 0.98 0.98 0.98 0.96 0.98 0.01 0.01 0.01 0 2.41 1000 100,000 100,000 100,000 Parameter 2 Parameter 9.46 9.46 9.46 9.46 9.73 9.46 0.94 0.93 0.91 0.01 0.01 0.01 –1.90 –0.99 –0.99 –0.99 –1.90 –0.99 25 11.60 200 4146 4247 4247 £4937.39 Parameter 1 Parameter 0.37 0.37 0.37 0.15 0.37 0.03 0.03 0.03 0.03 0.03 0.03 0.94 0.93 0.91 0.15 0.01 0.04 0.04 0.04 0.01 0.01 0.01 0.20 28 £4937.39 Mean Lognormal Lognormal Lognormal Lognormal Lognormal Gamma Gamma Gamma Gamma Gamma Gamma Normal Normal Normal Lognormal NA Gamma Gamma Beta Beta Beta NA NA NA Beta Distribution 8687 Utility decrement cardiac complication 88 Utility decrement CNS complication 89 Utility decrement renal complication 90 Utility decrement otitis media complication 91 Utility decrement other complication 92 Duration respiratory complication (years) 93 Duration cardiac complication (years) 94 Duration CNS complication (years) 95 Duration renal complication (years) 96 Duration otitis media complication (years) 97 Duration other complication (years) 98 Utility general population 0–24 99 Utility general population 25–34 Utility general population 35–44 85 Utility decrement respiratory complication 76 Expected cost of hospitalisation 84 Duration adverse events 75 (days) ITU LOS HRQoL parameters 7778 for influenza case – no treatment 21-day QALYs 79 for influenza case – oseltamivir treatment 21-day QALYs 80 for influenza case – zanamivir treatment 21-day QALYs 81 loss for influenza case – no treatment QALY 82 loss for influenza case – oseltamivir treatment QALY 83 loss for influenza case – zanamivir treatment QALY Utility decrement – adverse events No. description Parameter 177

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – 0.02 0.01 0.01 0.01 Parameter 2 Parameter 3.50% 0.51 0.73 0.78 0.80 0.85 13.37 Parameter 1 Parameter 3.50% 0.51 0.73 0.78 0.80 0.85 13.37 Mean NA NA NA Normal Normal Normal Normal Distribution 75 Seasonal prophylaxis: healthy adults (continued) 106 Discount rate for QALYs 105 loss for premature death QALY 104 population female Percentage 103 Utility general population > 102 Utility general population 65–74 101 Utility general population 55–64 100 Utility general population 45–54 No. description Parameter

178 83 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – 1.23 0.17 0.83 0.45 0.54 2.55 86.11 12 859 281 199 100 200 800.78 1125 1256 1670 Parameter 2 Parameter 0.72 1 1 0.53 1 0.70 2 0.37 1.72 9 –1.05 –0.92 –1.43 –1.75 83 32.65 73.40 10 10.41 740 622 Parameter 1 Parameter 104 0.30 0.72 0.35 0.40 0.24 0.17 0.37 1 1 0.53 1 0.70 0.02 0.05 0.15 0.02 0.01 0.75 0.86 0.50 0.06 40 Mean NA Gamma Lognormal Lognormal Lognormal Lognormal Beta Beta NA NA NA Beta Beta Beta Beta Beta Beta Distribution Beta Beta Seasonal prophylaxis: at-risk adults 5 influenza is A in B dominant years Probability Beta 6 influenza is A Probability 7Effectiveness parameters (prevention) Duration of influenza epidemic (days) 89 RR for influenza – vaccine 10 RR for influenza – amantadine prophylaxis 11 RR for influenza – oseltamivir prophylaxis 12 RR for influenza – zanamivir prophylaxis of amantadine resistance Probability 1314 influenza case occurs within epidemic Probability influenza case avoidable – amantadine Probability 15 influenza case avoidable – amantadine (vaccination) Probability NA 16 influenza case avoidable – oseltamivir Probability 17 of influenza cases avoidable – zanamivir Percentage Adverse events/withdrawals (prophylaxis) 18 adverse event – vaccination Probability 19 adverse event – amantadine prophylaxis Probability 2021 withdrawal – amantadine prophylaxis Probability withdrawal – oseltamivir prophylaxis Probability 22 withdrawal – zanamivir prophylaxis Probability 3 influenza A strain is dominant Probability 4 influenza is A in dominant seasons Probability Beta No. description Parameter 2 ILI is influenza within epidemic period Probability Baseline event probabilities (disease) 1 Baseline attack rate for influenza

TABLE 84 TABLE 179

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – – – 0 0.38 86.11 20 800.78 668 2172 2172 2172 2172 2172 2172 1941 8579 2142 17,597 47,169 Parameter 2 Parameter 1 0.89 0.11 1.72 6 5 –1 –0.71 10.41 30 16 67 62 16 £9.60 104 111 £14.40 £81.80 £73.65 2166 1942 6983 Parameter 1 Parameter 19811 0.12 0.40 1 0.89 0.11 0.02 0.01 0.49 0.89 0.01 0.01 0 0.25 0.16 0.05 0.03 0.03 0.42 0.81 0.01 £9.60 £14.40 £81.80 £73.65 Mean Distribution Beta Lognormal NA NA Beta Beta Lognormal Dirichlet Dirichlet Dirichlet Dirichlet Beta Beta Dirichlet Dirichlet Beta Beta Beta Beta NA NA NA NA 48 hours NA Seasonal prophylaxis: at-risk adults (continued) No. description Parameter 3031 complication – no treatment Probability Odds ratio complication – oseltamivir treatment 2526 patient given antiviral treatment | presents < Probability 27 patient receives oseltamivir | prescribed antiviral Probability 28 patient receives zanamivir | prescribed antiviral Probability 29 adverse events – oseltamivir treatment Probability adverse events – zanamivir treatment Probability 3233 Odds ratio complication – zanamivir treatment 34 complication is respiratory Probability 35 complication is cardiac Probability 36 complication is CNS Probability complication is renal Probability ILI event probabilities (treatment) 2324 patient with ILI presents Probability patient presents within 48 hours of ILI onset Probability 37 complication is otitis media Probability 3839 complication is other Probability 40 respiratory complication is pneumonia Probability 41 patient receives antibiotics | no complication Probability 42 patient receives antibiotics | complication Probability Cost/resource parameters of influenza death | complication Probability 43 Cost of amantadine prophylaxis course (without vaccine) 44 Cost of amantadine prophylaxis course (with vaccine) 45 Cost of oseltamivir prophylaxis course 46 Cost of zanamivir prophylaxis course

180 84 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – – – – – – – – – – – – – – – 5.16 1 95 674 270.11 674 453 270.11 Parameter 2 Parameter 0.97 8.35 0.97 8.35 21 56 £6.80 42 £1.69 28 56 15 22 16 £5.63 £16.36 £24.55 £42 £30.73 £30.73 £25 £25 £25 £25 £69 £95.56 £261.17 Parameter 1 Parameter 0.97 0.08 0.03 0.97 0.08 0.16 0.05 0.03 21 £6.80 42 £1.69 28 11.90 £5.63 £16.36 £24.55 £42 £30.73 £30.73 £25 £25 £25 £25 £69 £95.56 Mean £261.17 Distribution NA NA NA NA NA NA NA NA Beta NA NA NA NA Gamma Gamma NA Beta Beta NA NA NA NA No. description Parameter 4748 Cost of oseltamivir treatment course 49 Cost of zanamivir treatment course 50 Days per course – amantadine prophylaxis Days per course – amantadine prophylaxis (prior vaccination) NA 6465 Cost of uncomplicated influenza presentation 66 Cost of complicated influenza presentation Cost of antibiotics course 51 Days per course – oseltamivir prophylaxis 6263 GP attendance | patient presents (complication) Probability home GP visit | presentation (complication) Probability 67 Cost of anti-emetics course (metaclopramide 7-day course) 52 Days per course – zanamivir prophylaxis 61 A&E attendance | patient presents (complication) Probability Beta 6869 Cost of managing adverse events – vaccination 70 Cost of managing adverse events – amantadine prophylaxis Cost of inpatient episode 73 (days) Inpatient LOS 53 Acquisition cost for vaccination 5960 GP attendance | patient presents (no complication) Probability home GP visit | presentation (no complication) Probability NA Beta 7172 hospitalisation no treatment | complication Probability ICU care | complication Probability 5455 Administration cost for vaccination 56 Cost of attendance at GP surgery consultation 57 Cost of attendance at GP home visit 58 Cost of attendance at A&E A&E attendance | patient presents (no complication) Probability Beta 181

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – 0 0.41 0.14 0.14 0.14 0.41 0.14 0.85 0.85 0.85 0.85 0.96 0.85 0.01 0.01 0.01 0.01 2.41 £31.95 1000 100,000 100,000 100,000 Parameter 2 Parameter 0.02 0.02 0.02 9.73 0.94 0.93 0.91 0.85 –1.90 –0.99 –0.99 –0.99 –1.90 –0.99 25 12.60 12.60 12.60 12.60 12.60 11.60 200 2820 2977 2977 £4937.39 Parameter 1 Parameter £1345.39 0.03 0.03 0.03 0.02 0.02 0.02 0.20 0.01 0.15 0.37 0.37 0.37 0.15 0.37 0.03 0.03 0.03 0.03 0.03 0.03 0.94 0.93 0.91 0.85 28 £4937.39 £1345.39 Mean Beta Beta Beta NA NA NA Beta Gamma Lognormal Lognormal Lognormal Lognormal Lognormal Lognormal Gamma Gamma Gamma Gamma Gamma Gamma Normal Normal Normal Normal Distribution Gamma NA Normal Seasonal prophylaxis: at-risk adults (continued) HRQoL parameters 77 for influenza case – no treatment 21-day QALYs 78 for influenza case – oseltamivir treatment 21-day QALYs 79 for influenza case – zanamivir treatment 21-day QALYs 80 loss for influenza case – no treatment QALY 81 loss for influenza case – oseltamivir treatment QALY 82 loss for influenza case – zanamivir treatment QALY 8384 Utility decrement – adverse events 85 Duration adverse events 86 Utility decrement respiratory complication 87 Utility decrement cardiac complication 88 Utility decrement CNS complication 89 Utility decrement renal complication 90 Utility decrement otitis media complication 91 Utility decrement other complication 92 Duration respiratory complication (years) 93 Duration cardiac complication (years) 94 Duration CNS complication (years) 95 Duration renal complication (years) 96 Duration otitis media complication (years) 97 Duration other complication (years) 98 Utility general population 0–24 99 Utility general population 25–34 100 Utility general population 35–44 Utility general population 45–54 No. description Parameter 7576 (days) ITU LOS Expected cost of hospitalisation 74 Cost of ITU day

182 84 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 – – – 0.01 0.01 0.02 Parameter 2 Parameter 0.80 0.78 0.73 0.51 3.50% 13.37 Parameter 1 Parameter 0.80 0.78 0.73 0.51 3.50% 13.37 Mean Distribution Normal Normal Normal NA NA NA 75 No. description Parameter 101102 Utility general population 55–64 103 Utility general population 65–74 104 Utility general population > population female Percentage 105 loss for premature death QALY 106 Discount rate for QALYs 183

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – 1.23 0.23 0.83 1.04 1.09 2.55 12 86.11 859 281 199 100 200 800.78 1256 1098 1125 Parameter 2 Parameter 9 0.72 1 1 0.53 1 0.70 2 0.37 1.72 –0.87 –0.92 –2.50 –1.61 83 57 32.65 73.40 10 10.41 622 740 Parameter 1 Parameter 0.75 0.86 0.50 0.30 0.05 0.72 0.42 0.40 0.08 0.20 0.37 1 1 0.53 1 0.70 0.02 0.05 0.15 0.02 0.01 40 Mean Beta Beta Beta Beta Distribution Beta NA Gamma Lognormal Lognormal Lognormal Lognormal Beta NA Beta NA NA Beta Beta Beta Beta Beta Seasonal prophylaxis: healthy elderly seasons years 34 influenza A strain is dominant Probability influenza is A in dominant Probability 2 ILI is influenza within epidemic period Probability 5 influenza is A in B dominant Probability No. description Parameter Baseline event probabilities (disease) 1 Baseline attack rate for influenza 6 influenza is A Probability 7Effectiveness parameters (prevention) Duration of influenza epidemic (days) 89 RR for influenza – vaccine 10 RR for influenza – amantadine prophylaxis 11 RR for influenza – oseltamivir prophylaxis 12 RR for influenza – zanamivir prophylaxis of amantadine resistance Probability 14 influenza case avoidable – amantadine Probability 13 influenza case occurs within epidemic Probability 15 influenza case avoidable – amantadine (vaccination) Probability NA 16 influenza case avoidable – oseltamivir Probability 17 of influenza cases avoidable – zanamivir Percentage Adverse events/withdrawals (prophylaxis) 18 adverse event – vaccination Probability 19 adverse event – amantadine prophylaxis Probability 2021 withdrawal – amantadine prophylaxis Probability 22 withdrawal – oseltamivir prophylaxis Probability withdrawal – zanamivir prophylaxis Probability

184 85 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – – – – 0 0.16 20 86.11 164 800.78 948 948 948 948 948 948 819 981 1916 10,145 15,620 Parameter 2 Parameter 5 1 0.89 0.11 1.72 6 –1 –0.36 18.5 10.41 10 22 22 68 £9.60 942 820 106 110 £14.40 £81.80 £73.65 £16.36 Parameter 1 Parameter 8544 1527 0.25 0.11 1 0.89 0.11 0.02 0.01 0.09 0.40 0.70 0.86 0.01 0.02 0.01 0.02 0.07 0.13 0.11 0.55 0.80 £9.60 £14.40 £81.80 £73.65 £16.36 Mean Distribution Beta NA Beta Beta Beta Lognormal Lognormal Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Beta Beta Beta NA NA NA NA 48 hours No. description Parameter ILI event probabilities (treatment) 2324 patient with ILI presents Probability patient presents within 48 hours of ILI onset Probability Beta 25 patient given antiviral treatment | presents < Probability 26 patient receives oseltamivir | prescribed antiviral Probability NA 27 patient receives zanamivir | prescribed antiviral Probability NA 2829 adverse events – oseltamivir treatment Probability adverse events – zanamivir treatment Probability 3031 complication – no treatment Probability 32 Odds ratio complication – oseltamivir treatment 33 Odds ratio complication – zanamivir treatment 34 complication is respiratory Probability complication is cardiac Probability 35 complication is CNS Probability 36 complication is renal Probability 37 complication is otitis media Probability 38 complication is other Probability 39 respiratory complication is pneumonia Probability 42 of influenza death | complication Probability 4041 patient receives antibiotics | no complication Probability patient receives antibiotics | complication Probability Cost/resource parameters Beta 43 Cost of amantadine prophylaxis course (without vaccine) NA 44 Cost of amantadine prophylaxis course (with vaccine) 4546 Cost of oseltamivir prophylaxis course 47 Cost of zanamivir prophylaxis course Cost of oseltamivir treatment course 185

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – – – – – – – – – – – – – – 5.16 1 95 270.11 165 270.11 165 453 Parameter 2 Parameter 8.35 0.97 8.35 0.97 21 42 28 £5.63 62 62 £6.80 £1.69 15 22 25 £24.55 £42 £25 £25 £69 £95.56 £43.20 £43.20 £25 £25 £261.17 Parameter 1 Parameter 0.03 0.97 0.38 0.03 0.97 0.38 0.16 0.05 21 42 28 £5.63 £6.80 £1.69 15 £24.55 £42 £25 £25 £69 £95.56 £43.20 £43.20 £25 £25 £261.17 Mean Distribution NA NA NA NA NA NA NA NA NA Beta NA NA NA NA Gamma Beta Gamma Seasonal prophylaxis: healthy elderly (continued) complication) No. description Parameter 48 Cost of zanamivir treatment course 49 Days per course – amantadine prophylaxis 50 Days per course – amantadine prophylaxis (prior vaccination) NA 51 Days per course – oseltamivir prophylaxis 52 Days per course – zanamivir prophylaxis 53 Acquisition cost for vaccination 54 Administration cost for vaccination 55 Cost of attendance at GP surgery consultation 56 Cost of attendance at GP home visit 57 Cost of attendance at A&E 58 A&E attendance | patient presents (no Probability 59 GP attendance | patient presents (no complication) Probability NA 60 home GP visit | presentation (no complication) Probability Beta 61 A&E attendance | patient presents (complication) Probability Beta 62 GP attendance | patient presents (complication) Probability NA 63 home GP visit | presentation (complication) Probability Beta 64 Cost of uncomplicated influenza presentation 65 Cost of complicated influenza presentation 66 Cost of antibiotics course 67 Cost of anti-emetics course (metaclopramide 7-day course) NA 68 Cost of managing adverse events – vaccination 69 Cost of managing adverse events – amantadine prophylaxis NA 70 Cost of inpatient episode 71 hospitalisation no treatment | complication Probability Beta 72 ICU care | complication Probability 73 (days) Inpatient LOS

186 85 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – 0 0.41 0.14 0.14 0.14 0.41 0.14 0.83 0.83 0.83 0.83 0.96 0.83 0.01 0.01 0.01 2.41 £31.95 1000 100,000 100,000 100,000 Parameter 2 Parameter 0.02 0.01 0.01 9.73 0.94 0.93 0.91 –1.90 –0.99 –0.99 –0.99 –1.90 –0.99 25 13.15 13.15 13.15 13.15 13.15 11.60 200 2820 2977 2977 £5747.01 Parameter 1 Parameter £1345.39 28 0.02 0.01 0.01 0.20 0.01 0.15 0.37 0.37 0.37 0.15 0.37 0.03 0.03 0.03 0.03 0.03 0.03 0.94 0.93 0.91 0.03 0.03 0.03 £5747.01 Mean £1345.39 NA NA NA Beta Gamma Lognormal Lognormal Lognormal Lognormal Lognormal Lognormal Gamma Gamma Gamma Gamma Gamma Gamma Normal Normal Normal NA Beta Distribution Normal Gamma 7879 for influenza case – oseltamivir treatment 21-day QALYs 80 for influenza case – zanamivir treatment 21-day QALYs 81 loss for influenza case – no treatment QALY Beta 82 loss for influenza case – oseltamivir treatment QALY 83 Beta loss for influenza case – zanamivir treatment QALY 84 Utility decrement – adverse events 85 Duration adverse events 86 Utility decrement respiratory complication 87 Utility decrement cardiac complication 88 Utility decrement CNS complication 89 Utility decrement renal complication 90 Utility decrement otitis media complication 91 Utility decrement other complication 92 Duration respiratory complication (years) 93 Duration cardiac complication (years) 94 Duration CNS complication (years) 95 Duration renal complication (years) 96 Duration otitis media complication (years) 97 Duration other complication (years) 98 Utility general population 0–24 99 Utility general population 25–34 Utility general population 35–44 76HRQoL parameters Expected cost of hospitalisation 77 for influenza case – no treatment 21-day QALYs No. description Parameter 7475 Cost of ITU day (days) ITU LOS 187

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 Parameter 2 Parameter 0.01 0.01 0.01 0.02 – – – Parameter 1 Parameter 0.85 0.80 0.78 0.73 0.51 2.95 3.50% Mean 0.85 0.80 0.78 0.73 0.51 2.95 3.50% Distribution Normal Normal Normal Normal NA NA NA 75 Seasonal prophylaxis: healthy elderly (continued) No. description Parameter 100101 Utility general population 45–54 102 Utility general population 55–64 103 Utility general population 65–74 104 Utility general population > 105 population female Percentage 106 loss for premature death QALY Discount rate for QALYs

188 85 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – 1.23 0.23 0.83 1.04 1.09 2.55 12 86.11 199 100 200 800.78 859 281 1125 1098 1256 Parameter 2 Parameter 9 0.72 1 1 0.53 1 0.70 2 0.37 1.72 –0.87 –0.92 –2.50 –1.61 32.65 73.40 10 10.41 57 83 622 740 Parameter 1 Parameter 0.42 0.40 0.08 0.20 0.37 1 1 1 0.70 0.02 0.05 0.15 0.02 0.01 0.86 0.53 0.05 0.50 0.75 0.72 0.30 40 Mean Distribution Gamma Lognormal Lognormal Lognormal Lognormal Beta Beta NA NA NA Beta Beta Beta Beta Beta Beta Beta Beta NA Seasonal prophylaxis: at-risk elderly No. description Parameter 4 influenza is A in dominant seasons Probability 7 Beta Effectiveness parameters (prevention) Duration of influenza epidemic (days) 89 RR for influenza – vaccine 10 RR for influenza – amantadine prophylaxis 11 RR for influenza – oseltamivir prophylaxis 12 RR for influenza – zanamivir prophylaxis 13 of amantadine resistance Probability 14 influenza case occurs within epidemic Probability 15 influenza case avoidable – amantadine Probability 16 influenza case avoidable – amantadine (vaccination) Probability 17 influenza case avoidable – oseltamivir Probability of influenza cases avoidable – zanamivir Adverse events/withdrawals (prophylaxis) Percentage NA 1819 adverse event – vaccination Probability 20 adverse event – amantadine prophylaxis Probability 21 withdrawal – amantadine prophylaxis Probability 22 withdrawal – oseltamivir prophylaxis Probability withdrawal – zanamivir prophylaxis Probability Baseline event probabilities (disease) 12 Baseline attack rate for influenza 3 ILI is influenza within epidemic period Probability influenza A strain is dominant Probability 56 influenza is A in B dominant years Probability influenza is A Probability Beta

TABLE 86 TABLE 189

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – – – 0 0.38 20 86.11 164 914 800.78 914 914 914 914 914 754 936 7407 1916 Parameter 2 Parameter 15,620 5 1 0.89 0.11 1.72 –1 –0.71 18.5 10.41 60 24 13 12 50 97 £9.60 755 908 114 £14.40 £81.80 £73.65 8544 1527 Parameter 1 Parameter 0.25 0.11 1 0.89 0.11 0.02 0.01 0.40 0.49 0.83 0.07 0.12 0.03 0.01 0.01 0.05 0.13 0.55 0.12 0.80 £9.60 £14.40 £81.80 £73.65 Mean Distribution Beta Beta NA Beta Beta Lognormal Lognormal Dirichlet Dirichlet Beta Dirichlet Dirichlet Dirichlet Dirichlet Beta Beta Beta NA NA Beta NA NA 48 hours NA Seasonal prophylaxis: at-risk elderly (continued) No. description Parameter ILI event probabilities (treatment) 2324 patient with ILI presents Probability patient presents within 48 hours of ILI onset Probability 25 patient given antiviral treatment | presents < Probability 26 patient receives oseltamivir | prescribed antiviral Probability NA 27 patient receives zanamivir | prescribed antiviral Probability 2829 adverse events – oseltamivir treatment Probability adverse events – zanamivir treatment Probability 3132 Odds ratio complication – oseltamivir treatment 33 Odds ratio complication – zanamivir treatment 34 complication is respiratory Probability complication is cardiac Probability 30 complication – no treatment Probability 35 complication is CNS Probability 36 complication is renal Probability 37 complication is otitis media Probability 38 complication is other Probability 39 respiratory complication is pneumonia Probability 40 patient receives antibiotics | no complication Probability 42Cost/resource parameters of influenza death | complication Probability 4344 Cost of amantadine prophylaxis course (without vaccine) Cost of amantadine prophylaxis course (with vaccine) 41 patient receives antibiotics | complication Probability 4546 Cost of oseltamivir prophylaxis course Cost of zanamivir prophylaxis course

190 86 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – – – – – – – – – – – – – – – 5.16 1 95 270.11 165 270.11 165 453 Parameter 2 Parameter 8.35 0.97 8.35 0.97 21 42 28 £5.63 62 62 £6.80 £1.69 22 15 25 £16.36 £24.55 £42 £25 £25 £69 £95.56 £43.20 £43.20 £25 £25 £261.17 Parameter 1 Parameter 0.03 0.97 0.38 0.03 0.97 0.38 0.05 0.16 21 42 28 £5.63 £6.80 £1.69 15 £16.36 £24.55 £42 £25 £25 £69 £95.56 £43.20 £43.20 £25 £25 £261.17 Mean Distribution NA NA NA NA NA NA NA NA NA NA Beta NA NA NA Beta NA NA Gamma Beta Gamma No. description Parameter 4748 Cost of oseltamivir treatment course 49 Cost of zanamivir treatment course 50 Days per course – amantadine prophylaxis Days per course – amantadine prophylaxis (prior vaccination) NA 51 Days per course – oseltamivir prophylaxis 52 Days per course – zanamivir prophylaxis 53 Acquisition cost for vaccination 5455 Administration cost for vaccination 56 Cost of attendance at GP surgery consultation 57 Cost of attendance at GP home visit 58 Cost of attendance at A&E A&E attendance | patient presents (no complication) Probability Beta 59 GP attendance | patient presents (no complication) Probability NA 60 home GP visit | presentation (no complication) Probability Beta 61 A&E attendance | patient presents (complication) Probability Beta 62 GP attendance | patient presents (complication) Probability NA 63 home GP visit | presentation (complication) Probability 6465 Cost of uncomplicated influenza presentation 66 Cost of complicated influenza presentation Cost of antibiotics course 67 Cost of anti-emetics course (metaclopramide 7-day course) NA 72 ICU care | complication Probability 6869 Cost of managing adverse events – vaccination 70 Cost of managing adverse events – amantadine prophylaxis 71 Cost of inpatient episode hospitalisation no treatment | complication Probability 73 (days) Inpatient LOS 191

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – 0 0.41 0.14 0.14 0.14 0.41 0.14 0.83 0.83 0.83 0.83 0.96 0.83 0.01 0.01 0.01 0.01 2.41 £31.95 1000 100,000 100,000 100,000 Parameter 2 Parameter 9.73 0.94 0.93 0.91 0.85 0.01 0.01 0.02 –1.90 –0.99 –0.99 –0.99 –1.90 –0.99 25 13.13 13.13 13.13 13.13 13.13 11.60 200 2820 2977 2977 £1345.39 £5747.01 Parameter 1 Parameter 0.20 0.01 0.15 0.37 0.37 0.37 0.15 0.37 0.03 0.03 0.03 0.03 0.03 0.03 0.94 0.93 0.91 0.85 0.01 0.01 0.03 0.03 0.02 0.03 28 £1345.39 £5747.01 Mean Distribution Beta Gamma Lognormal Lognormal Lognormal Lognormal Lognormal Lognormal Gamma Gamma Gamma Gamma Gamma Gamma Normal Normal Normal Normal NA NA Beta Beta NA Normal Gamma NA Beta Seasonal prophylaxis: at-risk elderly (continued) No. description Parameter 8384 Utility decrement – adverse events 85 Duration adverse events 86 Utility decrement respiratory complication 87 Utility decrement cardiac complication 88 Utility decrement CNS complication 89 Utility decrement renal complication 90 Utility decrement otitis media complication 91 Utility decrement other complication 92 Duration respiratory complication (years) 93 Duration cardiac complication (years) 94 Duration CNS complication (years) 95 Duration renal complication (years) 96 Duration otitis media complication (years) 97 Duration other complication (years) 98 Utility general population 0–24 99 Utility general population 25–34 100 Utility general population 35–44 Utility general population 45–54 82 loss for influenza case – zanamivir treatment QALY 81 loss for influenza case – oseltamivir treatment QALY 7879 for influenza case – oseltamivir treatment 21-day QALYs 80 for influenza case – zanamivir treatment 21-day QALYs loss for influenza case – no treatment QALY 7475 Cost of ITU day 76 (days) ITU LOS HRQoL parameters Expected cost of hospitalisation 77 for influenza case – no treatment 21-day QALYs

192 86 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 – – – 0.01 0.01 0.02 Parameter 2 Parameter 3.50% 2.95 0.80 0.78 0.73 0.51 Parameter 1 Parameter 3.50% 2.95 0.80 0.78 0.73 0.51 Mean Distribution NA NA Normal Normal Normal NA 75 No. description Parameter 106 Discount rate for QALYs 105 loss for premature death QALY 101102 Utility general population 55–64 103 Utility general population 65–74 104 Utility general population > population female Percentage 193

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – 1.23 0.14 0.60 0.41 0.24 12 86.11 111 859 281 199 100 200 237.89 800.78 1256 1125 Parameter 2 Parameter 9 0.72 1 1 1 1 1 2 1.72 21 –1.02 –2.26 83 –1.03 –1.56 32.65 73.40 10 13.56 10.41 622 740 Parameter 1 Parameter 0.19 0.50 0.75 0.86 0.30 0.72 0.36 0.10 0.36 0.21 0.37 1 1 1 1 1 0.02 0.05 0.06 0.02 0.01 40 Mean Distribution Beta Beta Beta NA Gamma Lognormal Lognormal Lognormal Lognormal Beta Beta NA NA NA Beta Beta Beta Beta Beta Post-exposure: healthy children Post-exposure: No. description Parameter Baseline event probabilities (disease) 1 Baseline attack rate for influenza 2 ILI is influenza within epidemic period Probability 3 influenza A strain is dominant Probability 4 influenza is A in dominant seasons Probability Beta 5 influenza is A in B dominant years Probability Beta 6 influenza is A Probability 7 Duration of influenza epidemic (days) Effectiveness parameters (prevention) 8 RR for influenza – vaccine 9 RR for influenza – amantadine prophylaxis 10 RR for influenza – oseltamivir prophylaxis 11 RR for influenza – zanamivir prophylaxis 12 of amantadine resistance Probability 13 influenza case occurs within epidemic Probability 14 influenza case avoidable – amantadine Probability 15 influenza case avoidable – amantadine (vaccination) Probability NA 16 influenza case avoidable – oseltamivir Probability 17 of influenza cases avoidable – zanamivir Percentage Adverse events/withdrawals (prophylaxis) 18 adverse event – vaccination Probability 19 adverse event – amantadine prophylaxis Probability 20 withdrawal – amantadine prophylaxis Probability 21 withdrawal – oseltamivir prophylaxis Probability 22 withdrawal – zanamivir prophylaxis Probability

194 prophylaxis List of model parameters – post-exposure 87 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – – – – 0 0.16 20 73 86.11 800.78 2423 2423 2423 2423 2423 2423 1697 2962 2311 Parameter 2 Parameter 17,201 17,910 5 0 1 0 1.72 0 1 3 1 38 –0.36 10.41 18 18 29 £4.80 £4.80 685 £16.36 £24.55 £16.36 2417 1698 4997 2183 Parameter 1 Parameter 0.25 0.52 0 1 0 0.02 0.01 0.14 0.65 0.70 0.70 0 0.01 0 0.28 0.01 0.02 0.28 0.74 0 £4.80 £4.80 £16.36 £24.55 £16.36 Mean Distribution Beta Beta Beta Beta Beta Lognormal Lognormal Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Beta Beta Beta Beta NA NA NA NA NA 48 hours NA No. description Parameter ILI event probabilities (treatment) 23 patient with ILI presents Probability 24 patient presents within 48 hours of ILI onset Probability 25 patient given antiviral treatment | presents < Probability 26 patient receives oseltamivir | prescribed antiviral Probability NA 27 patient receives zanamivir | prescribed antiviral Probability NA 28 adverse events – oseltamivir treatment Probability 29 adverse events – zanamivir treatment Probability 3031 complication – no treatment Probability Odds ratio complication – oseltamivir treatment 32 Odds ratio complication – zanamivir treatment 33 complication is respiratory Probability 34 complication is cardiac Probability 35 complication is CNS Probability 36 complication is renal Probability 37 complication is otitis media Probability 38 complication is other Probability 39 respiratory complication is pneumonia Probability 4041 patient receives antibiotics | no complication Probability patient receives antibiotics | complication Probability 42 of influenza death | complication Probability Cost/resource parameters 43 Cost of amantadine prophylaxis course (without vaccine) 44 Cost of amantadine prophylaxis course (with vaccine) 45 Cost of oseltamivir prophylaxis course 46 Cost of zanamivir prophylaxis course 47 Cost of oseltamivir treatment course 195

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – – – – – – – – – – – – – – 4 5.16 46 73 73 £31.95 453 270.11 270.11 Parameter 2 Parameter 1 5 4 0.97 8.35 4 0.97 8.35 22 £1.69 £6.80 £5.63 10 10 10 £25 £25 £29.52 £29.52 £95.56 £69 £25 £25 £10 £24.55 £261.17 £1345.39 Parameter 1 Parameter 2.30 0.05 0.11 0.05 0.97 0.03 0.05 0.97 0.03 £1.69 £6.80 £5.63 10 10 10 £25 £25 £29.52 £29.52 £95.56 £69 £25 £25 £10 £24.55 £261.17 £1345.39 Mean Normal Gamma Beta Beta Gamma NA NA NA NA NA NA NA NA NA NA NA NA Distribution NA Post-exposure: healthy children (continued) Post-exposure: 74 Cost of ITU day 73 (days) Inpatient LOS 72 ICU care | complication Probability 71 hospitalisation no treatment | complication Probability 70 Cost of inpatient episode 69 Cost of managing adverse events – amantadine prophylaxis NA 68 Cost of managing adverse events – vaccination 67 Cost of anti-emetics course (metaclopramide 7-day course) NA 66 Cost of antibiotics course 65 Cost of complicated influenza presentation 64 Cost of uncomplicated influenza presentation 63 home GP visit | presentation (complication) Probability Beta 62 GP attendance | patient presents (complication) Probability NA 61 A&E attendance | patient presents (complication) Probability Beta 60 home GP visit | presentation (no complication) Probability Beta 59 GP attendance | patient presents (no complication) Probability NA 58 A&E attendance | patient presents (no complication) Probability Beta 57 Cost of attendance at A&E 56 Cost of attendance at GP home visit 55 Cost of attendance at GP surgery consultation 54 Administration cost for vaccination 53 Acquisition cost for vaccination 52 Days per course – zanamivir prophylaxis 51 Days per course – oseltamivir prophylaxis 50 Days per course – amantadine prophylaxis (prior vaccination) NA 49 Days per course – amantadine prophylaxis No. description Parameter 48 Cost of zanamivir treatment course

196 87 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – 0.01 0.01 0.01 0.01 1.14 0.96 1.14 1.14 1.14 1.14 0.14 0.41 0.14 0.14 0.14 0.41 0 2.41 1000 100,000 100,000 100,000 Parameter 2 Parameter 0.85 0.91 0.93 0.94 6.92 9.73 6.92 6.92 6.92 6.92 0.01 0.01 0.01 –0.99 –1.90 –0.99 –0.99 –0.99 –1.90 25 11.60 200 4247 4247 4146 £2430.18 Parameter 1 Parameter 0.85 0.91 0.93 0.94 0.02 0.03 0.02 0.02 0.02 0.02 0.37 0.15 0.37 0.37 0.37 0.15 0.01 0.20 0.01 0.01 0.01 0.04 0.04 0.04 28 £2430.18 Mean Normal Normal Normal Normal Gamma Gamma Gamma Gamma Gamma Gamma Lognormal Lognormal Lognormal Lognormal Lognormal Lognormal Gamma Beta NA NA NA Beta Beta NA Beta Distribution Gamma 100 Utility general population 45–54 99 Utility general population 35–44 98 Utility general population 25–34 97 Utility general population 0–24 96 Duration other complication (years) 95 Duration otitis media complication (years) 94 Duration renal complication (years) 93 Duration CNS complication (years) 92 Duration cardiac complication (years) 91 Duration respiratory complication (years) 90 Utility decrement other complication 89 Utility decrement otitis media complication 88 Utility decrement renal complication 87 Utility decrement CNS complication 86 Utility decrement cardiac complication 85 Utility decrement respiratory complication 84 Duration adverse events 83 Utility decrement – adverse events 82 loss for influenza case – zanamivir treatment QALY 81 loss for influenza case – oseltamivir treatment QALY 80 loss for influenza case – no treatment QALY 79 for influenza case – zanamivir treatment 21-day QALYs 78 for influenza case – oseltamivir treatment 21-day QALYs 76HRQoL parameters Expected cost of hospitalisation 77 for influenza case – no treatment 21-day QALYs No. description Parameter 75 (days) ITU LOS 197

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – 0.02 0.01 0.01 Parameter 2 Parameter 3.50% 0.51 0.73 0.78 0.80 24.74 Parameter 1 Parameter 3.50% 0.51 0.73 0.78 0.80 24.74 Mean NA NA NA Normal Normal Distribution Normal 75 Post-exposure: healthy children (continued) Post-exposure: 106 Discount rate for QALYs 105 loss for premature death QALY 104 population female Percentage 103 Utility general population > 102 Utility general population 65–74 No. description Parameter 101 Utility general population 55–64

198 87 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – 1.23 0.14 0.60 0.41 0.24 12 86.11 111 859 281 199 100 200 237.89 800.78 1256 1125 Parameter 2 Parameter 9 0.72 1 1 1 1 1 2 1.72 21 –1.02 –2.26 –1.03 83 –1.56 32.65 73.40 10 13.56 10.41 622 740 Parameter 1 Parameter 0.19 0.50 0.75 0.86 0.30 0.72 0.36 0.10 0.36 0.21 0.37 1 1 1 1 1 0.02 0.05 0.06 0.02 0.01 40 Mean Distribution Beta Beta Beta NA Gamma Lognormal Lognormal Lognormal Lognormal Beta Beta NA NA NA Beta Beta Beta Beta Beta Post-exposure: at-risk children Post-exposure: No. description Parameter Baseline event probabilities (disease) 1 Baseline attack rate for influenza 2 ILI is influenza within epidemic period Probability 3 influenza A strain is dominant Probability 4 influenza is A in dominant seasons Probability Beta 5 influenza is A in B dominant years Probability Beta 6 influenza is A Probability 7 Duration of influenza epidemic (days) Effectiveness parameters (prevention) 8 RR for influenza – vaccine 9 RR for influenza – amantadine prophylaxis 10 RR for influenza – oseltamivir prophylaxis 11 RR for influenza – zanamivir prophylaxis 12 of amantadine resistance Probability 13 influenza case occurs within epidemic Probability 14 influenza case avoidable – amantadine Probability 15 influenza case avoidable – amantadine (vaccination) Probability NA 16 influenza case avoidable – oseltamivir Probability 17 of influenza cases avoidable – zanamivir Percentage Adverse events/withdrawals (prophylaxis) 18 adverse event – vaccination Probability 19 adverse event – amantadine prophylaxis Probability 20 withdrawal – amantadine prophylaxis Probability 21 withdrawal – oseltamivir prophylaxis Probability 22 withdrawal – zanamivir prophylaxis Probability

TABLE 88 TABLE 199

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – – – 0 0.38 20 73 86.11 800.78 681 681 681 681 681 681 520 650 3695 2962 Parameter 2 Parameter 17,910 5 1 1 0 1.72 0 1 1 1 3 9 1 38 –0.71 10.41 £4.80 £4.80 675 521 154 £16.36 £24.55 Parameter 1 Parameter 4997 2183 0.25 0.52 1 1 0 0.02 0.01 0.18 0.65 0.49 0.77 0 0 0 0.23 0 0.02 0.28 0.74 0 £4.80 £4.80 £16.36 £24.55 Mean Distribution Beta Beta NA Beta Beta Beta Lognormal Lognormal Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Beta Beta Beta Beta NA NA NA NA 48 hours NA Post-exposure: at-risk children (continued) Post-exposure: No. description Parameter ILI event probabilities (treatment) 23 patient with ILI presents Probability 24 patient presents within 48 hours of ILI onset Probability 25 patient given antiviral treatment | presents < Probability 26 patient receives oseltamivir | prescribed antiviral Probability NA 27 patient receives zanamivir | prescribed antiviral Probability 28 adverse events – oseltamivir treatment Probability 29 adverse events – zanamivir treatment Probability 30 complication – no treatment Probability 31 Odds ratio complication – oseltamivir treatment 32 Odds ratio complication – zanamivir treatment 33 complication is respiratory Probability 34 complication is cardiac Probability 35 complication is CNS Probability 36 complication is renal Probability 37 complication is otitis media Probability 38 complication is other Probability 39 respiratory complication is pneumonia Probability 40 patient receives antibiotics | no complication Probability 41 patient receives antibiotics | complication Probability 42 of influenza death | complication Probability Cost/resource parameters 43 Cost of amantadine prophylaxis course (without vaccine) 44 Cost of amantadine prophylaxis course (with vaccine) 45 Cost of oseltamivir prophylaxis course 46 Cost of zanamivir prophylaxis course

200 88 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – – – – – – – – – – – – – – – 5.16 4 73 73 95 270.11 270.11 453 Parameter 2 Parameter 8.35 0.97 4 8.35 0.97 4 1 10 10 10 £5.63 £6.80 £1.69 15 22 £16.36 £24.55 £10 £25 £25 £69 £95.56 £29.52 £29.52 £25 £25 Parameter 1 Parameter £261.17 0.03 0.97 0.05 0.03 0.97 0.05 0.16 0.05 2.30 10 10 10 £5.63 £6.80 £1.69 £16.36 £24.55 £10 £25 £25 £69 £95.56 £29.52 £29.52 £25 £25 Mean £261.17 Distribution NA NA NA NA NA NA NA NA NA NA Beta NA NA NA NA NA Gamma Beta Beta Gamma No. description Parameter 47 Cost of oseltamivir treatment course 48 Cost of zanamivir treatment course 49 Days per course – amantadine prophylaxis 50 Days per course – amantadine prophylaxis (prior vaccination) NA 51 Days per course – oseltamivir prophylaxis 52 Days per course – zanamivir prophylaxis 53 Acquisition cost for vaccination 54 Administration cost for vaccination 55 Cost of attendance at GP surgery consultation 56 Cost of attendance at GP home visit 57 Cost of attendance at A&E 58 A&E attendance | patient presents (no complication) Probability Beta 59 GP attendance | patient presents (no complication) Probability NA 60 home GP visit | presentation (no complication) Probability Beta 61 A&E attendance | patient presents (complication) Probability Beta 62 GP attendance | patient presents (complication) Probability NA 63 home GP visit | presentation (complication) Probability 64 Cost of uncomplicated influenza presentation 65 Cost of complicated influenza presentation 66 Cost of antibiotics course 67 Cost of anti-emetics course (metaclopramide 7-day course) NA 68 Cost of managing adverse events – vaccination 69 Cost of managing adverse events – amantadine prophylaxis 70 Cost of inpatient episode 71 hospitalisation no treatment | complication Probability 72 ICU care | complication Probability 73 (days) Inpatient LOS 201

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – 2.41 0 0.41 0.14 0.14 0.14 0.41 0.14 1.11 1.11 1.11 1.11 0.96 1.11 0.01 0.01 £31.95 1000 100,000 100,000 100,000 Parameter 2 Parameter 0.02 0.02 0.02 7.24 7.24 7.24 7.24 9.73 7.24 0.94 0.93 –1.90 –0.99 –0.99 –0.99 –1.90 –0.99 11.60 25 200 2977 2977 2820 £1345.39 £2430.18 Parameter 1 Parameter 0.03 0.03 0.02 0.03 0.02 0.02 0.01 0.20 0.15 0.37 0.37 0.37 0.15 0.37 0.02 0.02 0.02 0.02 0.03 0.02 0.94 0.93 28 £1345.39 £2430.18 Mean Distribution Normal Beta Beta NA Gamma NA Beta NA NA Gamma Beta Lognormal Lognormal Lognormal Lognormal Lognormal Lognormal Gamma Gamma Gamma Gamma Gamma Gamma Normal Normal Post-exposure: at-risk children (continued) Post-exposure: No. description Parameter 74 Cost of ITU day 7879 for influenza case – oseltamivir treatment 21-day QALYs 80 for influenza case – zanamivir treatment 21-day QALYs loss for influenza case – no treatment QALY 7576 (days) ITU LOS HRQoL parameters Expected cost of hospitalisation 77 for influenza case – no treatment 21-day QALYs 81 loss for influenza case – oseltamivir treatment QALY 82 loss for influenza case – zanamivir treatment QALY 84 Duration adverse events 83 Utility decrement – adverse events 8586 Utility decrement respiratory complication 87 Utility decrement cardiac complication 88 Utility decrement CNS complication 89 Utility decrement renal complication 90 Utility decrement otitis media complication 91 Utility decrement other complication 92 Duration respiratory complication (years) 93 Duration cardiac complication (years) 94 Duration CNS complication (years) 95 Duration renal complication (years) 96 Duration otitis media complication (years) 97 Duration other complication (years) 98 Utility general population 0–24 Utility general population 25–34

202 88 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 – – – 0.01 0.01 0.01 0.01 0.02 Parameter 2 Parameter 0.91 0.85 0.80 0.78 0.73 0.51 3.50% 24.74 Parameter 1 Parameter 0.91 0.85 0.80 0.78 0.73 0.51 3.50% 24.74 Mean Distribution Normal Normal Normal Normal Normal NA NA NA 75 No. description Parameter 99100 Utility general population 35–44 101 Utility general population 45–54 102 Utility general population 55–64 103 Utility general population 65–74 104 Utility general population > population female Percentage 105106 loss for premature death QALY Discount rate for QALYs 203

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – 0.24 0.44 0.60 0.17 1.23 20 86.11 12 800.78 237.89 200 100 199 281 859 1125 1256 2051 Parameter 2 Parameter 5 1.72 2 1 1 1 1 1 0.72 9 10.41 13.56 10 –1.56 –1.66 –2.26 –1.05 73.40 32.65 83 740 622 180 Parameter 1 Parameter 0.25 0.01 0.02 0.06 0.05 0.02 1 1 1 1 1 0.37 0.21 0.19 0.10 0.35 0.72 0.30 0.86 0.75 0.50 0.09 40 Mean Beta Beta Beta Beta Beta Beta NA NA NA Beta Beta Lognormal Lognormal Lognormal Lognormal Gamma NA Beta Beta Beta Distribution Healthy adults ILI event probabilities (treatment) 23 patient with ILI presents Probability 22 withdrawal – zanamivir prophylaxis Probability 21 withdrawal – oseltamivir prophylaxis Probability 20 withdrawal – amantadine prophylaxis Probability 19 adverse event – amantadine prophylaxis Probability Adverse events/withdrawals (prophylaxis) 18 adverse event – vaccination Probability 17 of influenza cases avoidable – zanamivir Percentage 16 influenza case avoidable – oseltamivir Probability 15 influenza case avoidable – amantadine (vaccination) Probability NA 14 influenza case avoidable – amantadine Probability 13 influenza case occurs within epidemic Probability 12 of amantadine resistance Probability 11 RR for influenza – zanamivir prophylaxis 10 RR for influenza – oseltamivir prophylaxis 9 RR for influenza – amantadine prophylaxis Effectiveness parameters (prevention) 8 RR for influenza – vaccine 7 Duration of influenza epidemic (days) 6 influenza is A Probability 5 influenza is A in B dominant years Probability Beta 4 influenza is A in dominant seasons Probability Beta 3 influenza A strain is dominant Probability 2 ILI is influenza within epidemic period Probability Baseline event probabilities (disease) 1 Baseline attack rate for influenza No. description Parameter

204 89 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – – – – – – – 0.16 0 86.11 800.78 668 6437 8579 5636 6515 6515 6515 6515 6515 6515 47,169 85,248 Parameter 2 Parameter 1.72 0.11 0.89 0 10 £4.80 £4.80 33 –0.36 –1 10 12 10.41 £10 £24.55 £16.36 £24.55 £16.36 237 253 501 102 104 6983 5637 6509 19811 Parameter 1 Parameter 0.01 0.81 0.42 0.04 0.04 0.08 0 0.02 0 0.87 0.70 0.40 0.08 0.01 0.02 0.11 0.89 0 0.16 10 £4.80 £4.80 £10 £24.55 £16.36 £24.55 £16.36 Mean NA NA NA NA NA NA NA Beta Beta Beta Beta Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Lognormal Lognormal Beta Beta Beta Beta Distribution 48 hours NA 50 Days per course – amantadine prophylaxis (prior vaccination) NA 49 Days per course – amantadine prophylaxis 48 Cost of zanamivir treatment course 47 Cost of oseltamivir treatment course 46 Cost of zanamivir prophylaxis course 45 Cost of oseltamivir prophylaxis course 44 Cost of amantadine prophylaxis course (with vaccine) Cost/resource parameters 43 Cost of amantadine prophylaxis course (without vaccine) 42 of influenza death | complication Probability 41 patient receives antibiotics | complication Probability 40 patient receives antibiotics | no complication Probability 39 respiratory complication is pneumonia Probability 38 complication is other Probability 37 complication is otitis media Probability 36 complication is renal Probability 35 complication is CNS Probability 34 complication is cardiac Probability 33 complication is respiratory Probability 32 Odds ratio complication – zanamivir treatment 31 Odds ratio complication – oseltamivir treatment 30 complication – no treatment Probability 29 adverse events – zanamivir treatment Probability 28 adverse events – oseltamivir treatment Probability 27 patient receives zanamivir | prescribed antiviral Probability NA 26 patient receives oseltamivir | prescribed antiviral Probability NA 25 patient given antiviral treatment | presents < Probability 24 patient presents within 48 hours of ILI onset Probability No. description Parameter 205

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – – – – – – – – – – – – 2.41 1 5.16 46 £31.95 453 674 270.11 674 270.11 100,000 Parameter 2 Parameter 5 0.97 8.35 0.97 8.35 11.60 16 22 £1.69 £6.80 56 56 £5.63 10 10 £25 £25 £30.73 £30.73 £95.56 £69 £25 £25 4146 £261.17 £4937.39 £1345.39 Parameter 1 Parameter 0.04 0.05 0.11 0.08 0.97 0.03 0.08 0.97 0.03 28 11.90 £1.69 £6.80 £5.63 10 10 £25 £25 £30.73 £30.73 £95.56 £69 £25 £25 £261.17 £4937.39 £1345.39 Mean Beta NA Gamma Normal Gamma Beta Beta Gamma NA NA NA NA NA NA NA NA NA NA NA Distribution Healthy adults (continued) HRQoL parameters 77 for influenza case – no treatment 21-day QALYs 76 Expected cost of hospitalisation 75 (days) ITU LOS 74 Cost of ITU day 73 (days) Inpatient LOS 72 ICU care | complication Probability 71 hospitalisation no treatment | complication Probability 70 Cost of inpatient episode 69 Cost of managing adverse events – amantadine prophylaxis NA 68 Cost of managing adverse events – vaccination 67 Cost of anti-emetics course (metaclopramide 7-day course) NA 66 Cost of antibiotics course 65 Cost of complicated influenza presentation 64 Cost of uncomplicated influenza presentation 63 home GP visit | presentation (complication) Probability Beta 62 GP attendance | patient presents (complication) Probability NA 61 A&E attendance | patient presents (complication) Probability Beta 60 home GP visit | presentation (no complication) Probability Beta 59 GP attendance | patient presents (no complication) Probability NA 58 A&E attendance | patient presents (no complication) Probability Beta 57 Cost of attendance at A&E 56 Cost of attendance at GP home visit 55 Cost of attendance at GP surgery consultation 54 Administration cost for vaccination 53 Acquisition cost for vaccination 52 Days per course – zanamivir prophylaxis 51 Days per course – oseltamivir prophylaxis No. description Parameter

206 89 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 – – – – – – 0.02 0.01 0.01 0.01 0.01 0.01 0.01 0.98 0.96 0.98 0.98 0.98 0.98 0.14 0.41 0.14 0.14 0.14 0.41 0 1000 100,000 100,000 Parameter 2 Parameter 3.50% 0.51 0.73 0.78 0.80 0.85 0.91 0.93 0.94 9.46 9.73 9.46 9.46 9.46 9.46 0.01 0.01 0.01 13.37 –0.99 –1.90 –0.99 –0.99 –0.99 –1.90 25 200 4247 4247 Parameter 1 Parameter 3.50% 0.51 0.73 0.78 0.80 0.85 0.91 0.93 0.94 0.03 0.03 0.03 0.03 0.03 0.03 0.37 0.15 0.37 0.37 0.37 0.15 0.01 0.20 0.01 0.01 0.01 0.04 0.04 13.37 Mean NA NA NA Normal Normal Normal Normal Normal Normal Normal Gamma Gamma Gamma Gamma Gamma Gamma Lognormal Lognormal Lognormal Lognormal Lognormal Lognormal Gamma Beta NA NA NA Beta Beta Distribution 75 106 Discount rate for QALYs 105 loss for premature death QALY 104 population female Percentage 103 Utility general population > 102 Utility general population 65–74 101 Utility general population 55–64 100 Utility general population 45–54 99 Utility general population 35–44 98 Utility general population 25–34 97 Utility general population 0–24 96 Duration other complication (years) 95 Duration otitis media complication (years) 94 Duration renal complication (years) 93 Duration CNS complication (years) 92 Duration cardiac complication (years) 91 Duration respiratory complication (years) 90 Utility decrement other complication 89 Utility decrement otitis media complication 88 Utility decrement renal complication 87 Utility decrement CNS complication 86 Utility decrement cardiac complication 85 Utility decrement respiratory complication 84 Duration adverse events 83 Utility decrement – adverse events 82 loss for influenza case – zanamivir treatment QALY 81 loss for influenza case – oseltamivir treatment QALY 80 loss for influenza case – no treatment QALY 79 for influenza case – zanamivir treatment 21-day QALYs 78 for influenza case – oseltamivir treatment 21-day QALYs No. description Parameter 207

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – 1.23 0.17 0.60 0.44 0.24 2.55 12 20 86.11 281 859 199 100 200 800.78 2051 1256 1125 Parameter 2 Parameter 0.72 9 1 1 1 1 1 2 0.37 5 1.72 –1.05 –2.26 –1.66 –1.56 32.65 83 10 73.40 10.41 180 622 740 Parameter 1 Parameter 0.09 0.72 0.50 0.75 0.86 0.30 0.35 0.10 0.19 0.21 1 1 1 1 1 0.02 0.05 0.15 0.25 0.37 0.02 0.01 40 Mean Distribution Beta NA Gamma Beta Beta Lognormal Lognormal Lognormal Lognormal Beta NA NA NA Beta Beta Beta Beta Beta Beta Beta Post-exposure prophylaxis: at-risk adults Post-exposure No. description Parameter Baseline event probabilities (disease) 1 Baseline attack rate for influenza 67 influenza is A Probability Duration of influenza epidemic (days) 23 ILI is influenza within epidemic period Probability 4 influenza A strain is dominant Probability 5 influenza is A in dominant seasons Probability influenza is A in B dominant years Probability Beta Effectiveness parameters (prevention) Beta 8 RR for influenza – vaccine 9 RR for influenza – amantadine prophylaxis 10 RR for influenza – oseltamivir prophylaxis 11 RR for influenza – zanamivir prophylaxis 1314 influenza case occurs within epidemic Probability 15 influenza case avoidable – amantadine Probability 16 influenza case avoidable – amantadine (vaccination) Probability 17 influenza case avoidable – oseltamivir Probability of influenza cases avoidable – zanamivir Adverse events/withdrawals (prophylaxis) Percentage NA 1819 adverse event – vaccination Probability 20 adverse event – amantadine prophylaxis Probability withdrawal – amantadine prophylaxis Probability ILI event probabilities (treatment) 23 patient with ILI presents Probability 12 of amantadine resistance Probability 2122 withdrawal – oseltamivir prophylaxis Probability withdrawal – zanamivir prophylaxis Probability

208 90 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – – – – – – – 0 0.38 86.11 800.78 668 2172 2172 2172 2172 2172 2172 1941 8579 2142 17,597 Parameter 2 Parameter 47,169 1 0.89 0.11 1.72 6 –1 –0.71 10.41 10 30 16 £4.80 67 62 16 £4.80 £16.36 £24.55 £16.36 £24.55 £10 104 111 2166 1942 6983 19811 Parameter 1 Parameter 0.12 0.40 0.01 0.49 0.16 1 0.89 0.11 0.02 0.89 0.01 0.01 0 0.05 0.03 0.03 0.42 0.81 0.01 10 £4.80 £4.80 £16.36 £24.55 £16.36 £24.55 £10 Mean Beta Lognormal Beta Lognormal NA NA NA NA NA Distribution Beta NA Beta Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet NA Dirichlet Beta Beta Beta Beta NA 48 hours NA 3031 complication – no treatment Probability Odds ratio complication – oseltamivir treatment 29 adverse events – zanamivir treatment Probability 32 Odds ratio complication – zanamivir treatment 4546 Cost of oseltamivir prophylaxis course 47 Cost of zanamivir prophylaxis course 48 Cost of oseltamivir treatment course 49 Cost of zanamivir treatment course 50 Days per course – amantadine prophylaxis Days per course – amantadine prophylaxis (prior vaccination) NA No. description Parameter 2425 patient presents within 48 hours of ILI onset Probability 26 patient given antiviral treatment | presents < Probability 27 patient receives oseltamivir | prescribed antiviral Probability 28 patient receives zanamivir | prescribed antiviral Probability adverse events – oseltamivir treatment Probability NA 3334 complication is respiratory Probability 35 complication is cardiac Probability 36 complication is CNS Probability 37 complication is renal Probability complication is otitis media Probability 44 Cost of amantadine prophylaxis course (with vaccine) 3839 complication is other Probability 40 respiratory complication is pneumonia Probability 41 patient receives antibiotics | no complication Probability 42 patient receives antibiotics | complication Probability Cost/resource parameters of influenza death | complication Probability 43 Cost of amantadine prophylaxis course (without vaccine) 209

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – – – – – – – – – – – – 5.16 1 2.41 95 270.11 674 270.11 674 453 £31.95 Parameter 2 Parameter 100,000 8.35 0.97 8.35 0.97 10 10 £5.63 56 56 £6.80 £1.69 15 22 16 11.60 £25 £25 £69 £95.56 £30.73 £30.73 £25 £25 £261.17 2820 £1345.39 £4937.39 Parameter 1 Parameter 0.03 0.97 0.08 0.03 0.97 0.08 0.16 0.05 0.03 10 10 £5.63 £6.80 £1.69 11.90 28 £25 £25 £69 £95.56 £30.73 £30.73 £25 £25 £261.17 Mean £1345.39 £4937.39 Distribution NA NA NA NA NA NA NA NA NA NA NA NA Gamma Beta Beta Gamma Normal Gamma NA Beta Post-exposure prophylaxis: at-risk adults (continued) Post-exposure No. description Parameter 51 Days per course – oseltamivir prophylaxis 52 Days per course – zanamivir prophylaxis 53 Acquisition cost for vaccination 54 Administration cost for vaccination 55 Cost of attendance at GP surgery consultation 56 Cost of attendance at GP home visit 57 Cost of attendance at A&E 58 A&E attendance | patient presents (no complication) Probability Beta 59 GP attendance | patient presents (no complication) Probability NA 60 home GP visit | presentation (no complication) Probability Beta 61 A&E attendance | patient presents (complication) Probability Beta 62 GP attendance | patient presents (complication) Probability NA 63 home GP visit | presentation (complication) Probability Beta 64 Cost of uncomplicated influenza presentation 65 Cost of complicated influenza presentation 66 Cost of antibiotics course 67 Cost of anti-emetics course (metaclopramide 7-day course) NA 68 Cost of managing adverse events – vaccination 69 Cost of managing adverse events – amantadine prophylaxis 70 Cost of inpatient episode 71 hospitalisation no treatment | complication Probability 72 ICU care | complication Probability 73 (days) Inpatient LOS 7475 Cost of ITU day (days) ITU LOS 76HRQoL parameters Expected cost of hospitalisation 77 for influenza case – no treatment 21-day QALYs

210 90 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 – – – – – – 0 0.41 0.14 0.14 0.14 0.41 0.14 0.85 0.85 0.85 0.85 0.96 0.85 0.01 0.01 0.01 0.01 0.01 0.01 0.02 1000 Parameter 2 Parameter 100,000 100,000 0.02 0.02 0.02 9.73 0.94 0.93 0.91 0.85 0.80 0.78 0.73 0.51 3.50% –1.90 –0.99 –0.99 –0.99 25 –1.90 –0.99 12.60 12.60 12.60 12.60 12.60 13.37 200 2977 2977 Parameter 1 Parameter 0.03 0.03 0.02 0.02 0.02 0.20 0.01 0.15 0.37 0.37 0.37 0.15 0.37 0.03 0.03 0.03 0.03 0.03 0.03 0.94 0.93 0.91 0.85 0.80 0.78 0.73 0.51 3.50% 13.37 Mean Distribution Beta Beta NA NA NA Beta Gamma Lognormal Lognormal Lognormal Lognormal Lognormal Lognormal Gamma Gamma Gamma Gamma Gamma Gamma Normal Normal Normal Normal Normal Normal Normal NA NA NA 75 No. description Parameter 78 for influenza case – oseltamivir treatment 21-day QALYs 79 for influenza case – zanamivir treatment 21-day QALYs 80 loss for influenza case – no treatment QALY 81 loss for influenza case – oseltamivir treatment QALY 82 loss for influenza case – zanamivir treatment QALY 83 Utility decrement – adverse events 84 Duration adverse events 85 Utility decrement respiratory complication 86 Utility decrement cardiac complication 87 Utility decrement CNS complication 88 Utility decrement renal complication 89 Utility decrement otitis media complication 90 Utility decrement other complication 91 Duration respiratory complication (years) 92 Duration cardiac complication (years) 93 Duration CNS complication (years) 94 Duration renal complication (years) 95 Duration otitis media complication (years) 96 Duration other complication (years) 97 Utility general population 0–24 98 Utility general population 25–34 99 Utility general population 35–44 100 Utility general population 45–54 101 Utility general population 55–64 102 Utility general population 65–74 103 Utility general population > 104 population female Percentage 105 loss for premature death QALY 106 Discount rate for QALYs 211

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – 1.23 0.23 0.60 0.44 0.24 2.55 12 86.11 859 281 199 100 200 800.78 2051 1256 1125 Parameter 2 Parameter 9 0.72 1 1 1 1 1 2 0.37 1.72 –0.87 –2.26 –1.66 83 –1.56 32.65 73.40 10 10.41 180 622 740 Parameter 1 Parameter 0.09 0.50 0.75 0.86 0.30 0.72 0.42 0.10 0.19 0.21 0.37 1 1 1 1 1 0.02 0.05 0.15 0.02 0.01 40 Mean Distribution Beta Beta Beta NA Gamma Lognormal Lognormal Lognormal Lognormal Beta Beta NA NA NA Beta Beta Beta Beta Beta Post-exposure prophylaxis: healthy elderly Post-exposure No. description Parameter Baseline event probabilities (disease) 1 Baseline attack rate for influenza 2 ILI is influenza within epidemic period Probability 3 influenza A strain is dominant Probability 4 influenza is A in dominant seasons Probability Beta 5 influenza is A in B dominant years Probability Beta 6 influenza is A Probability 7 Duration of influenza epidemic (days) Effectiveness parameters (prevention) 8 RR for influenza – vaccine 9 RR for influenza – amantadine prophylaxis 10 RR for influenza – oseltamivir prophylaxis 11 RR for influenza – zanamivir prophylaxis 12 of amantadine resistance Probability 13 influenza case occurs within epidemic Probability 14 influenza case avoidable – amantadine Probability 15 influenza case avoidable – amantadine (vaccination) Probability NA 16 influenza case avoidable – oseltamivir Probability 17 of influenza cases avoidable – zanamivir Percentage Adverse events/withdrawals (prophylaxis) 18 adverse event – vaccination Probability 19 adverse event – amantadine prophylaxis Probability 20 withdrawal – amantadine prophylaxis Probability 21 withdrawal – oseltamivir prophylaxis Probability 22 withdrawal – zanamivir prophylaxis Probability

212 91 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – – – 0 0.16 20 86.11 164 800.78 948 948 948 948 948 948 819 981 1916 Parameter 2 Parameter 10,145 15,620 5 1 0.89 0.11 1.72 6 18.5 –1 –0.36 10.41 10 22 22 68 £4.80 £4.80 942 820 106 110 £16.36 £24.55 Parameter 1 Parameter 8544 1527 0.25 0.11 1 0.89 0.11 0.02 0.01 0.09 0.40 0.70 0.86 0.01 0.02 0.01 0.02 0.07 0.13 0.55 0.80 0.11 £4.80 £4.80 Mean £16.36 £24.55 Distribution Beta Beta NA Beta Beta Beta Lognormal Lognormal Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Beta Beta Beta Beta NA NA NA NA 48 hours NA No. description Parameter ILI event probabilities (treatment) 23 patient with ILI presents Probability 24 patient presents within 48 hours of ILI onset Probability 25 patient given antiviral treatment | presents < Probability 26 patient receives oseltamivir | prescribed antiviral Probability NA 27 patient receives zanamivir | prescribed antiviral Probability 28 adverse events – oseltamivir treatment Probability 29 adverse events – zanamivir treatment Probability 30 complication – no treatment Probability 31 Odds ratio complication – oseltamivir treatment 32 Odds ratio complication – zanamivir treatment 33 complication is respiratory Probability 34 complication is cardiac Probability 35 complication is CNS Probability 36 complication is renal Probability 37 complication is otitis media Probability 38 complication is other Probability 39 respiratory complication is pneumonia Probability 40 patient receives antibiotics | no complication Probability 41 patient receives antibiotics | complication Probability 42 of influenza death | complication Probability Cost/resource parameters 43 Cost of amantadine prophylaxis course (without vaccine) 44 Cost of amantadine prophylaxis course (with vaccine) 4546 Cost of oseltamivir prophylaxis course Cost of zanamivir prophylaxis course 213

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – – – – – – – – – – – – – – – 5.16 95 270.11 165 270.11 165 453 Parameter 2 Parameter 8.35 0.97 8.35 0.97 10 10 10 £5.63 62 62 £6.80 £1.69 15 22 £16.36 £24.55 £10 £25 £25 £69 £95.56 £43.20 £43.20 £25 £25 £261.17 Parameter 1 Parameter 0.03 0.97 0.38 0.03 0.97 0.38 0.16 0.05 10 10 10 £5.63 £6.80 £1.69 £16.36 £24.55 £10 £25 £25 £69 £95.56 £43.20 £43.20 £25 £25 £261.17 Mean Distribution NA NA NA NA NA NA NA NA NA NA Beta NA NA NA NA NA Gamma Beta Beta Post-exposure prophylaxis: healthy elderly (continued) Post-exposure No. description Parameter 47 Cost of oseltamivir treatment course 48 Cost of zanamivir treatment course 49 Days per course – amantadine prophylaxis 50 Days per course – amantadine prophylaxis (prior vaccination) NA 51 Days per course – oseltamivir prophylaxis 52 Days per course – zanamivir prophylaxis 53 Acquisition cost for vaccination 54 Administration cost for vaccination 55 Cost of attendance at GP surgery consultation 56 Cost of attendance at GP home visit 57 Cost of attendance at A&E 58 A&E attendance | patient presents (no complication) Probability Beta 59 GP attendance | patient presents (no complication) Probability NA 60 home GP visit | presentation (no complication) Probability Beta 61 A&E attendance | patient presents (complication) Probability Beta 62 GP attendance | patient presents (complication) Probability NA 63 home GP visit | presentation (complication) Probability 64 Cost of uncomplicated influenza presentation 65 Cost of complicated influenza presentation 66 Cost of antibiotics course 67 Cost of anti-emetics course (metaclopramide 7-day course) NA 68 Cost of managing adverse events – vaccination 69 Cost of managing adverse events – amantadine prophylaxis 70 Cost of inpatient episode 71 hospitalisation no treatment | complication Probability 72 ICU care | complication Probability

214 91 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – 1 2.41 0 0.41 0.14 0.14 0.14 0.41 0.14 0.83 0.83 0.83 0.83 0.96 0.83 0.01 0.01 £31.95 1000 Parameter 2 Parameter 100,000 100,000 100,000 0.02 0.01 0.01 9.73 0.94 0.93 25 11.60 –1.90 –0.99 –0.99 –0.99 25 –1.90 –0.99 13.15 13.15 13.15 13.15 13.15 200 2820 2977 2977 £1345.39 £5747.01 Parameter 1 Parameter 0.03 0.03 0.03 0.02 0.01 0.01 0.20 0.01 0.15 0.37 0.37 0.37 0.15 0.37 0.03 0.03 0.03 0.03 0.03 0.03 0.94 0.93 15 28 £1345.39 £5747.01 Mean Distribution Gamma Normal Gamma NA Beta Beta Beta NA NA NA Beta Gamma Lognormal Lognormal Lognormal Lognormal Lognormal Lognormal Gamma Gamma Gamma Gamma Gamma Gamma Normal Normal No. description Parameter 73 (days) Inpatient LOS 74 Cost of ITU day 75 (days) ITU LOS 76 Expected cost of hospitalisation HRQoL parameters 77 for influenza case – no treatment 21-day QALYs 78 for influenza case – oseltamivir treatment 21-day QALYs 79 for influenza case – zanamivir treatment 21-day QALYs 80 loss for influenza case – no treatment QALY 81 loss for influenza case – oseltamivir treatment QALY 82 loss for influenza case – zanamivir treatment QALY 83 Utility decrement – adverse events 84 Duration adverse events 85 Utility decrement respiratory complication 86 Utility decrement cardiac complication 87 Utility decrement CNS complication 88 Utility decrement renal complication 89 Utility decrement otitis media complication 90 Utility decrement other complication 91 Duration respiratory complication (years) 92 Duration cardiac complication (years) 93 Duration CNS complication (years) 94 Duration renal complication (years) 95 Duration otitis media complication (years) 96 Duration other complication (years) 97 Utility general population 0–24 98 Utility general population 25–34 215

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 Parameter 2 Parameter 0.01 0.01 0.01 0.01 0.02 – – – 0.91 0.85 0.80 0.78 0.73 0.51 2.95 3.50% Parameter 1 Parameter 0.91 0.85 0.80 0.78 0.73 0.51 2.95 3.50% Mean Distribution Normal Normal Normal Normal Normal NA NA NA 75 Post-exposure prophylaxis: healthy elderly (continued) Post-exposure No. description Parameter 99 Utility general population 35–44 100 Utility general population 45–54 101 Utility general population 55–64 102 Utility general population 65–74 103104 Utility general population > population female Percentage 105 loss for premature death QALY 106 Discount rate for QALYs

216 91 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – 1.23 0.23 0.60 0.44 0.24 2.55 12 86.11 859 281 199 100 200 800.78 2051 1256 1125 Parameter 2 Parameter 9 0.72 1 1 1 1 1 2 0.37 1.72 –0.87 –2.26 83 –1.66 –1.56 32.65 73.40 10 10.41 180 622 740 Parameter 1 Parameter 0.09 0.50 0.75 0.86 0.30 0.72 0.42 0.10 0.19 0.21 0.37 1 1 1 1 1 0.02 0.05 0.15 0.02 0.01 40 Mean Distribution Beta Beta Beta NA Gamma Lognormal Lognormal Lognormal Lognormal Beta Beta NA NA NA Beta Beta Beta Beta Beta Post-exposure prophylaxis: at-risk elderly Post-exposure No. description Parameter Baseline event probabilities (disease) 1 Baseline attack rate for influenza 2 ILI is influenza within epidemic period Probability 3 influenza A strain is dominant Probability 4 influenza is A in dominant seasons Probability Beta 5 influenza is A in B dominant years Probability Beta 6 influenza is A Probability 7 Duration of influenza epidemic (days) Effectiveness parameters (prevention) 8 RR for influenza – vaccine 9 RR for influenza – amantadine prophylaxis 10 RR for influenza – oseltamivir prophylaxis 11 RR for influenza – zanamivir prophylaxis 12 of amantadine resistance Probability 13 influenza case occurs within epidemic Probability 14 influenza case avoidable – amantadine Probability 15 influenza case avoidable – amantadine (vaccination) Probability NA 16 influenza case avoidable – oseltamivir Probability 17 of influenza cases avoidable – zanamivir Percentage Adverse events/withdrawals (prophylaxis) 18 adverse event – vaccination Probability 19 adverse event – amantadine prophylaxis Probability 20 withdrawal – amantadine prophylaxis Probability 21 withdrawal – oseltamivir prophylaxis Probability 22 withdrawal – zanamivir prophylaxis Probability

TABLE 92 TABLE 217

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – – – – – 0 0.38 20 86.11 164 800.78 914 914 914 914 914 914 754 936 7407 1916 15,620 Parameter 2 Parameter 5 1 0.89 0.11 1.72 18.5 –1 –0.71 10.41 60 24 13 12 50 97 £4.80 £4.80 908 755 114 £16.36 £24.55 £16.36 8544 1527 Parameter 1 Parameter 0.25 0.11 1 0.89 0.11 0.02 0.01 0.12 0.40 0.49 0.83 0.07 0.03 0.01 0.01 0.05 0.13 0.55 0.80 0.12 £4.80 £4.80 £16.36 £24.55 £16.36 Mean Distribution Beta Beta NA Beta Beta Beta Lognormal Lognormal Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Dirichlet Beta Beta Beta Beta NA NA NA NA NA 48 hours NA Post-exposure prophylaxis: at-risk elderly (continued) Post-exposure No. description Parameter ILI event probabilities (treatment) 23 patient with ILI presents Probability 24 patient presents within 48 hours of ILI onset Probability 25 patient given antiviral treatment | presents < Probability 26 patient receives oseltamivir | prescribed antiviral Probability NA 27 patient receives zanamivir | prescribed antiviral Probability 28 adverse events – oseltamivir treatment Probability 29 adverse events – zanamivir treatment Probability 30 complication – no treatment Probability 31 Odds ratio complication – oseltamivir treatment 32 Odds ratio complication – zanamivir treatment 33 complication is respiratory Probability 34 complication is cardiac Probability 35 complication is CNS Probability 36 complication is renal Probability 37 complication is otitis media Probability 38 complication is other Probability 39 respiratory complication is pneumonia Probability 40 patient receives antibiotics | no complication Probability 41 patient receives antibiotics | complication Probability 42 of influenza death | complication Probability Cost/resource parameters 43 Cost of amantadine prophylaxis course (without vaccine) 44 Cost of amantadine prophylaxis course (with vaccine) 45 Cost of oseltamivir prophylaxis course 46 Cost of zanamivir prophylaxis course 47 Cost of oseltamivir treatment course

218 92 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 continued – – – – – – – – – – – – – – – – – – 5.16 1 95 270.11 165 270.11 165 453 £31.95 Parameter 2 Parameter 8.35 0.97 8.35 0.97 10 10 10 £5.63 62 62 £6.80 £1.69 15 22 25 £24.55 £10 £25 £25 £69 £95.56 £43.20 £43.20 £25 £25 £261.17 £1345.39 Parameter 1 Parameter 0.03 0.97 0.38 0.03 0.97 0.38 0.16 0.05 10 10 10 £5.63 £6.80 £1.69 15 £24.55 £10 £25 £25 £69 £95.56 £43.20 £43.20 £25 £25 £261.17 £1345.39 Mean Distribution NA NA NA NA NA NA NA NA NA NA NA Beta NA NA NA NA NA NA Gamma Beta Beta Gamma Normal No. description Parameter 48 Cost of zanamivir treatment course 49 Days per course – amantadine prophylaxis 50 Days per course – amantadine prophylaxis (prior vac) 51 Days per course – oseltamivir prophylaxis 52 Days per course – zanamivir prophylaxis 53 Acquisition cost for vaccination 54 Administration cost for vaccination 55 Cost of attendance at GP surgery consultation 56 Cost of attendance at GP home visit 57 Cost of attendance at A&E 58 A&E attendance | patient presents (no complication) Probability Beta 59 GP attendance | patient presents (no complication) Probability NA 60 home GP visit | presentation (no complication) Probability Beta 61 A&E attendance | patient presents (complication) Probability Beta 62 GP attendance | patient presents (complication) Probability 63 home GP visit | presentation (complication) Probability 64 Cost of uncomplicated influenza presentation 65 Cost of complicated influenza presentation 66 Cost of antibiotics course 67 Cost of anti-emetics course (metaclopramide 7 day course) 68 Cost of managing adverse events – vaccination 69 Cost of managing adverse events – amantadine prophylaxis 70 Cost of inpatient episode 71 hospitalisation no treatment | complication Probability 72 ICU care | complication Probability 73 (days) Inpatient LOS 74 Cost of ITU day 219

© 2009 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 7 – – – – 2.41 0 0.41 0.14 0.14 0.14 0.41 0.14 0.83 0.83 0.83 0.83 0.96 0.83 0.01 0.01 0.01 1000 Parameter 2 Parameter 100,000 100,000 100,000 0.02 0.01 0.01 9.73 0.94 0.93 0.91 –1.90 –0.99 –0.99 –0.99 –1.90 –0.99 11.60 25 13.13 13.13 13.13 13.13 13.13 200 2820 2977 2977 £5747.01 Parameter 1 Parameter 0.03 0.03 0.03 0.02 0.01 0.01 0.20 0.01 0.15 0.37 0.37 0.37 0.15 0.37 0.03 0.03 0.03 0.03 0.03 0.03 0.94 0.93 0.91 28 £5747.01 Mean Distribution Gamma NA Beta Beta Beta NA NA NA Beta Gamma Lognormal Lognormal Lognormal Lognormal Lognormal Lognormal Gamma Gamma Gamma Gamma Gamma Gamma Normal Normal Normal Post-exposure prophylaxis: at-risk elderly (continued) Post-exposure No. description Parameter 7576 (days) ITU LOS HRQoL parameters Expected cost of hospitalisation 77 for influenza case – no treatment 21-day QALYs 78 for influenza case – oseltamivir treatment 21-day QALYs 79 for influenza case – zanamivir treatment 21-day QALYs 8081 loss for influenza case – no treatment QALY 82 loss for influenza case – oseltamivir treatment QALY 83 loss for influenza case – zanamivir treatment QALY 84 Utility decrement – adverse events 85 Duration adverse events Utility decrement respiratory complication 86 Utility decrement cardiac complication 87 Utility decrement CNS complication 88 Utility decrement renal complication 89 Utility decrement otitis media complication 90 Utility decrement other complication 9192 Duration respiratory complication (years) 93 Duration cardiac complication (years) 94 Duration CNS complication (years) 95 Duration renal complication (years) Duration otitis media complication (years) 9697 Duration other complication (years) Utility general population 0–24 98 Utility general population 25–34 99 Utility general population 35–44

220 92 TABLE DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11 – – – 0.02 0.01 0.01 0.01 Parameter 2 Parameter 0.73 0.51 2.95 3.50% 0.85 0.80 0.78 Parameter 1 Parameter 0.73 0.51 2.95 3.50% 0.85 0.80 0.78 Mean Normal NA NA NA Distribution Normal Normal Normal 75 104105 population female Percentage 106 loss for premature death QALY Discount rate for QALYs No. description Parameter 100 Utility general population 45–54 101 Utility general population 55–64 102 Utility general population 65–74 103 Utility general population > 221

DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Appendix 8 Cost-effectiveness acceptability curves (base-case analysis)

Cost-effectiveness acceptability curves for seasonal prophylaxis

1.00 0.90 0.80 0.70 0.60 0.50 0.40 0.30 No Px Amantadine Px 0.20 Oseltamivir Px Probability of being cost-effective Probability 0.10 Zanamivir Px 0.00 £10 £10,000 £20,000 £30,000 £40,000 £50,000 Value of ceiling ratio

FIGURE 6 Cost-effectiveness acceptability curves: seasonal prophylaxis, healthy children (no vaccination). Px, prophylaxis.

FIGURE 7 Cost-effectiveness acceptability curves: seasonal prophylaxis, healthy children (prior vaccination). Px, prophylaxis.

223

FIGURE 8 Cost-effectiveness acceptability curves: seasonal prophylaxis, at-risk children (no vaccination). Px, prophylaxis.

FIGURE 9 Cost-effectiveness acceptability curves: seasonal prophylaxis, at-risk children (prior vaccination). Px, prophylaxis.

224 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

FIGURE 10 Cost-effectiveness acceptability curves: seasonal prophylaxis, healthy adults (no vaccination). Px, prophylaxis.

FIGURE 11 Cost-effectiveness acceptability curves: seasonal prophylaxis, healthy adults (prior vaccination). Px, prophylaxis.

225

FIGURE 12 Cost-effectiveness acceptability curves: seasonal prophylaxis, at-risk adults (no vaccination). Px, prophylaxis.

FIGURE 13 Cost-effectiveness acceptability curves: seasonal prophylaxis, at-risk adults (prior vaccination). Px, prophylaxis.

226 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

FIGURE 14 Cost-effectiveness acceptability curves: seasonal prophylaxis, healthy elderly (no vaccination). Px, prophylaxis.

FIGURE 15 Cost-effectiveness acceptability curves: seasonal prophylaxis, healthy elderly (prior vaccination). Px, prophylaxis.

227

FIGURE 16 Cost-effectiveness acceptability curves: seasonal prophylaxis, at-risk elderly (no vaccination). Px, prophylaxis.

FIGURE 17 Cost-effectiveness acceptability curves: seasonal prophylaxis, at-risk elderly (prior vaccination). Px, prophylaxis.

228 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Cost-effectiveness acceptability curves for post-exposure prophylaxis

FIGURE 18 Cost-effectiveness acceptability curves: post-exposure prophylaxis, healthy children (no vaccination). Px, prophylaxis.

FIGURE 19 Cost-effectiveness acceptability curves: post-exposure prophylaxis, healthy children (prior vaccination). Px, prophylaxis.

229

FIGURE 20 Cost-effectiveness acceptability curves: post-exposure prophylaxis, at-risk children (no vaccination). Px, prophylaxis.

FIGURE 21 Cost-effectiveness acceptability curves: post-exposure prophylaxis, at-risk children (prior vaccination). Px, prophylaxis.

230 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

FIGURE 22 Cost-effectiveness acceptability curves: post-exposure prophylaxis, healthy adults (no vaccination). Px, prophylaxis.

FIGURE 23 Cost-effectiveness acceptability curves: post-exposure prophylaxis, healthy adults (prior vaccination). Px, prophylaxis.

231

FIGURE 24 Cost-effectiveness acceptability curves: post-exposure prophylaxis, at-risk adults (no vaccination). Px, prophylaxis.

FIGURE 25 Cost-effectiveness acceptability curves: post-exposure prophylaxis, at-risk adults (prior vaccination). Px, prophylaxis.

232 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

FIGURE 26 Cost-effectiveness acceptability curves: post-exposure prophylaxis, healthy elderly (no vaccination). Px, prophylaxis.

FIGURE 27 Cost-effectiveness acceptability curves: post-exposure prophylaxis, healthy elderly (prior vaccination). Px, prophylaxis.

233

FIGURE 28 Cost-effectiveness acceptability curves: post-exposure prophylaxis, at-risk elderly (no vaccination). Px, prophylaxis.

FIGURE 29 Cost-effectiveness acceptability curves: post-exposure prophylaxis, at-risk elderly (prior vaccination). Px, prophylaxis.

234 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Appendix 9 Cost-effectiveness acceptability curves (incorporating proposed price reduction for zanamivir)

Cost-effectiveness acceptability curves for seasonal prophylaxis

FIGURE 30 Cost-effectiveness acceptability curves: seasonal prophylaxis, healthy children (no vaccination). Px, prophylaxis.

FIGURE 31 Cost-effectiveness acceptability curves: seasonal prophylaxis, healthy children (prior vaccination). Px, prophylaxis.

235

FIGURE 32 Cost-effectiveness acceptability curves: seasonal prophylaxis, at-risk children (no vaccination). Px, prophylaxis.

FIGURE 33 Cost-effectiveness acceptability curves: seasonal prophylaxis, at-risk children (prior vaccination). Px, prophylaxis.

236 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

FIGURE 34 Cost-effectiveness acceptability curves: seasonal prophylaxis, healthy adults (no vaccination). Px, prophylaxis.

FIGURE 35 Cost-effectiveness acceptability curves: seasonal prophylaxis, healthy adults (prior vaccination). Px, prophylaxis.

237

FIGURE 36 Cost-effectiveness acceptability curves: seasonal prophylaxis, at-risk adults (no vaccination). Px, prophylaxis.

FIGURE 37 Cost-effectiveness acceptability curves: seasonal prophylaxis, at-risk adults (prior vaccination). Px, prophylaxis.

238 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

FIGURE 38 Cost-effectiveness acceptability curves: seasonal prophylaxis, healthy elderly (no vaccination). Px, prophylaxis.

FIGURE 39 Cost-effectiveness acceptability curves: seasonal prophylaxis, healthy elderly (prior vaccination). Px, prophylaxis.

239

FIGURE 40 Cost-effectiveness acceptability curves: seasonal prophylaxis, at-risk elderly (no vaccination). Px, prophylaxis.

FIGURE 41 Cost-effectiveness acceptability curves: seasonal prophylaxis, at-risk elderly (prior vaccination). Px, prophylaxis.

240 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Cost-effectiveness acceptability curves for post-exposure prophylaxis

FIGURE 42 Cost-effectiveness acceptability curves: post-exposure prophylaxis, healthy children (no vaccination). Px, prophylaxis.

FIGURE 43 Cost-effectiveness acceptability curves: post-exposure prophylaxis, healthy children (prior vaccination). Px, prophylaxis.

241

FIGURE 44 Cost-effectiveness acceptability curves: post-exposure prophylaxis, at-risk children (no vaccination). Px, prophylaxis.

FIGURE 45 Cost-effectiveness acceptability curves: post-exposure prophylaxis, at-risk children (prior vaccination). Px, prophylaxis.

242 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

FIGURE 46 Cost-effectiveness acceptability curves: post-exposure prophylaxis, healthy adults (no vaccination). Px, prophylaxis.

FIGURE 47 Cost-effectiveness acceptability curves: post-exposure prophylaxis, healthy adults (prior vaccination). Px, prophylaxis.

243

FIGURE 48 Cost-effectiveness acceptability curves: post-exposure prophylaxis, at-risk adults (no vaccination). Px, prophylaxis.

FIGURE 49 Cost-effectiveness acceptability curves: post-exposure prophylaxis, at-risk adults (prior vaccination). Px, prophylaxis.

244 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

FIGURE 50 Cost-effectiveness acceptability curves: post-exposure prophylaxis, healthy elderly (no vaccination). Px, prophylaxis.

FIGURE 51 Cost-effectiveness acceptability curves: post-exposure prophylaxis, healthy elderly (prior vaccination). Px, prophylaxis.

245

FIGURE 52 Cost-effectiveness acceptability curves: post-exposure prophylaxis, at-risk elderly (no vaccination). Px, prophylaxis.

FIGURE 53 Cost-effectiveness acceptability curves: post-exposure prophylaxis, at-risk elderly (prior vaccination). Px, prophylaxis.

246 DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Health Technology Assessment reports published to date

Volume 1, 1997 No. 11 No. 6 Newborn screening for inborn errors of Effectiveness of hip prostheses in No. 1 metabolism: a systematic review. primary total hip replacement: a critical Home parenteral nutrition: a systematic By Seymour CA, Thomason MJ, review of evidence and an economic review. Chalmers RA, Addison GM, Bain MD, model. By Richards DM, Deeks JJ, Sheldon Cockburn F, et al. By Faulkner A, Kennedy LG, Baxter TA, Shaffer JL. K, Donovan J, Wilkinson M, Bevan G. No. 12 No. 2 Routine preoperative testing: a No. 7 Diagnosis, management and screening systematic review of the evidence. Antimicrobial prophylaxis in colorectal of early localised prostate cancer. By Munro J, Booth A, Nicholl J. surgery: a systematic review of A review by Selley S, Donovan J, randomised controlled trials. Faulkner A, Coast J, Gillatt D. No. 13 By Song F, Glenny AM. Systematic review of the effectiveness of No. 3 laxatives in the elderly. No. 8 The diagnosis, management, treatment Bone marrow and peripheral By Petticrew M, Watt I, Sheldon T. and costs of prostate cancer in England blood stem cell transplantation for and Wales. malignancy. No. 14 A review by Chamberlain J, Melia J, A review by Johnson PWM, When and how to assess fast-changing Moss S, Brown J. Simnett SJ, Sweetenham JW, Morgan GJ, technologies: a comparative study of Stewart LA. No. 4 medical applications of four generic Screening for fragile X syndrome. technologies. No. 9 A review by Murray J, Cuckle H, A review by Mowatt G, Bower DJ, Screening for speech and language Taylor G, Hewison J. Brebner JA, Cairns JA, Grant AM, delay: a systematic review of the McKee L. literature. No. 5 By Law J, Boyle J, Harris F, A review of near patient testing in Harkness A, Nye C. primary care. Volume 2, 1998 By Hobbs FDR, Delaney BC, No. 10 Fitzmaurice DA, Wilson S, Hyde CJ, No. 1 Resource allocation for chronic Thorpe GH, et al. Antenatal screening for Down’s stable angina: a systematic review of effectiveness, costs and No. 6 syndrome. cost-effectiveness of alternative Systematic review of outpatient services A review by Wald NJ, Kennard A, interventions. for chronic pain control. Hackshaw A, McGuire A. By McQuay HJ, Moore RA, Eccleston By Sculpher MJ, Petticrew M, C, Morley S, de C Williams AC. No. 2 Kelland JL, Elliott RA, Holdright DR, Screening for ovarian cancer: a Buxton MJ. No. 7 systematic review. Neonatal screening for inborn errors of By Bell R, Petticrew M, Luengo S, No. 11 metabolism: cost, yield and outcome. Sheldon TA. Detection, adherence and control of A review by Pollitt RJ, Green A, hypertension for the prevention of McCabe CJ, Booth A, Cooper NJ, No. 3 stroke: a systematic review. Leonard JV, et al. Consensus development methods, By Ebrahim S. and their use in clinical guideline No. 12 No. 8 development. Postoperative analgesia and vomiting, Preschool vision screening. A review by Murphy MK, Black NA, with special reference to day-case A review by Snowdon SK, Lamping DL, McKee CM, Sanderson Stewart-Brown SL. surgery: a systematic review. CFB, Askham J, et al. By McQuay HJ, Moore RA. No. 9 No. 4 Implications of socio-cultural contexts No. 13 A cost–utility analysis of interferon beta for the ethics of clinical trials. Choosing between randomised and A review by Ashcroft RE, Chadwick for multiple sclerosis. nonrandomised studies: a systematic DW, Clark SRL, Edwards RHT, Frith L, By Parkin D, McNamee P, Jacoby A, review. Hutton JL. Miller P, Thomas S, Bates D. By Britton A, McKee M, Black N, McPherson K, Sanderson C, Bain C. No. 10 No. 5 A critical review of the role of neonatal Effectiveness and efficiency of methods No. 14 hearing screening in the detection of of dialysis therapy for end-stage renal Evaluating patient-based outcome congenital hearing impairment. disease: systematic reviews. measures for use in clinical trials. By Davis A, Bamford J, Wilson I, By MacLeod A, Grant A, Donaldson A review by Fitzpatrick R, Davey C, Ramkalawan T, Forshaw M, Wright S. C, Khan I, Campbell M, Daly C, et al. Buxton MJ, Jones DR. 247

No. 15 No. 4 No. 15 Ethical issues in the design and conduct A randomised controlled trial of Near patient testing in diabetes clinics: of randomised controlled trials. different approaches to universal appraising the costs and outcomes. antenatal HIV testing: uptake and A review by Edwards SJL, Lilford RJ, By Grieve R, Beech R, Vincent J, acceptability. Annex: Antenatal HIV Mazurkiewicz J. Braunholtz DA, Jackson JC, Hewison J, testing – assessment of a routine Thornton J. voluntary approach. By Simpson WM, Johnstone FD, No. 16 No. 16 Boyd FM, Goldberg DJ, Hart GJ, Positron emission tomography: Qualitative research methods in health Gormley SM, et al. establishing priorities for health technology assessment: a review of the technology assessment. literature. No. 5 A review by Robert G, Milne R. Methods for evaluating area-wide and By Murphy E, Dingwall R, organisation-based interventions in No. 17 (Pt 1) Greatbatch D, Parker S, Watson P. health and health care: a systematic The debridement of chronic wounds: a review. systematic review. No. 17 By Ukoumunne OC, Gulliford MC, By Bradley M, Cullum N, Sheldon T. The costs and benefits of paramedic Chinn S, Sterne JAC, Burney PGJ. skills in pre-hospital trauma care. No. 17 (Pt 2) By Nicholl J, Hughes S, Dixon S, No. 6 Assessing the costs of healthcare Systematic reviews of wound care Turner J, Yates D. technologies in clinical trials. management: (2) Dressings and topical A review by Johnston K, Buxton MJ, agents used in the healing of chronic No. 18 Jones DR, Fitzpatrick R. wounds. Systematic review of endoscopic By Bradley M, Cullum N, Nelson EA, ultrasound in gastro-oesophageal No. 7 Petticrew M, Sheldon T, Torgerson D. cancer. Cooperatives and their primary care emergency centres: organisation and By Harris KM, Kelly S, Berry E, No. 18 impact. Hutton J, Roderick P, Cullingworth J, By Hallam L, Henthorne K. A systematic literature review of et al. spiral and electron beam computed No. 8 tomography: with particular reference No. 19 Screening for cystic fibrosis. to clinical applications in hepatic Systematic reviews of trials and other A review by Murray J, Cuckle H, lesions, pulmonary embolus and studies. Taylor G, Littlewood J, Hewison J. coronary artery disease. By Sutton AJ, Abrams KR, Jones DR, By Berry E, Kelly S, Hutton J, No. 9 Sheldon TA, Song F. Harris KM, Roderick P, Boyce JC, et al. A review of the use of health status measures in economic evaluation. No. 20 By Brazier J, Deverill M, Green C, No. 19 Primary total hip replacement surgery: Harper R, Booth A. What role for statins? A review and a systematic review of outcomes economic model. and modelling of cost-effectiveness No. 10 By Ebrahim S, Davey Smith associated with different prostheses. Methods for the analysis of quality- G, McCabe C, Payne N, Pickin M, A review by Fitzpatrick R, Shortall of-life and survival data in health Sheldon TA, et al. technology assessment. E, Sculpher M, Murray D, Morris R, A review by Billingham LJ, No. 20 Lodge M, et al. Abrams KR, Jones DR. Factors that limit the quality, number No. 11 and progress of randomised controlled Volume 3, 1999 Antenatal and neonatal trials. haemoglobinopathy screening in the A review by Prescott RJ, Counsell CE, No. 1 UK: review and economic analysis. Gillespie WJ, Grant AM, Russell IT, By Zeuner D, Ades AE, Karnon J, Informed decision making: an Kiauka S, et al. Brown J, Dezateux C, Anionwu EN. annotated bibliography and systematic No. 21 review. No. 12 Antimicrobial prophylaxis in total hip By Bekker H, Thornton JG, Assessing the quality of reports of replacement: a systematic review. Airey CM, Connelly JB, Hewison J, randomised trials: implications for the By Glenny AM, Song F. Robinson MB, et al. conduct of meta-analyses. A review by Moher D, Cook DJ, No. 22 No. 2 Jadad AR, Tugwell P, Moher M, Jones A, et al. Health promoting schools and health Handling uncertainty when performing promotion in schools: two systematic economic evaluation of healthcare No. 13 reviews. interventions. ‘Early warning systems’ for identifying By Lister-Sharp D, Chapman S, A review by Briggs AH, Gray AM. new healthcare technologies. Stewart-Brown S, Sowden A. By Robert G, Stevens A, Gabbay J. No. 3 No. 23 No. 14 The role of expectancies in the placebo Economic evaluation of a primary A systematic review of the role of effect and their use in the delivery of human papillomavirus testing within a care-based education programme for health care: a systematic review. cervical screening programme. patients with osteoarthritis of the knee. By Crow R, Gage H, Hampson S, By Cuzick J, Sasieni P, Davies P, A review by Lord J, Victor C, 248 Hart J, Kimber A, Thomas H. Adams J, Normand C, Frater A, et al. Littlejohns P, Ross FM, Axford JS. DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Volume 4, 2000 No. 11 No. 21 Cost and outcome implications of the Systematic reviews of wound care No. 1 organisation of vascular services. management: (3) antimicrobial agents The estimation of marginal time By Michaels J, Brazier J, for chronic wounds; (4) diabetic foot preference in a UK-wide sample Palfreyman S, Shackley P, Slack R. ulceration. (TEMPUS) project. By O’Meara S, Cullum N, Majid M, A review by Cairns JA, No. 12 Sheldon T. van der Pol MM. Monitoring blood glucose control in diabetes mellitus: a systematic review. No. 22 No. 2 By Coster S, Gulliford MC, Seed PT, Using routine data to complement and enhance the results of randomised Geriatric rehabilitation following Powrie JK, Swaminathan R. controlled trials. fractures in older people: a systematic By Lewsey JD, Leyland AH, Murray review. No. 13 The effectiveness of domiciliary GD, Boddy FA. By Cameron I, Crotty M, Currie C, health visiting: a systematic review of Finnegan T, Gillespie L, Gillespie W, international studies and a selective No. 23 et al. review of the British literature. Coronary artery stents in the treatment By Elkan R, Kendrick D, Hewitt M, of ischaemic heart disease: a rapid and No. 3 Robinson JJA, Tolley K, Blair M, et al. systematic review. Screening for sickle cell disease and By Meads C, Cummins C, Jolly K, thalassaemia: a systematic review with No. 14 Stevens A, Burls A, Hyde C. supplementary research. The determinants of screening uptake By Davies SC, Cronin E, Gill M, and interventions for increasing uptake: No. 24 Greengross P, Hickman M, Normand C. a systematic review. Outcome measures for adult critical By Jepson R, Clegg A, Forbes C, care: a systematic review. No. 4 Lewis R, Sowden A, Kleijnen J. By Hayes JA, Black NA, Jenkinson C, Community provision of hearing aids Young JD, Rowan KM, Daly K, et al. and related audiology services. No. 15 A review by Reeves DJ, Alborz A, The effectiveness and cost-effectiveness No. 25 Hickson FS, Bamford JM. of prophylactic removal of wisdom A systematic review to evaluate the teeth. effectiveness of interventions to No. 5 A rapid review by Song F, O’Meara S, promote the initiation of breastfeeding. By Fairbank L, O’Meara S, False-negative results in screening Wilson P, Golder S, Kleijnen J. programmes: systematic review of Renfrew MJ, Woolridge M, Sowden AJ, impact and implications. No. 16 Lister-Sharp D. By Petticrew MP, Sowden AJ, Ultrasound screening in pregnancy: No. 26 Lister-Sharp D, Wright K. a systematic review of the clinical Implantable cardioverter defibrillators: effectiveness, cost-effectiveness and arrhythmias. A rapid and systematic No. 6 women’s views. review. By Bricker L, Garcia J, Henderson J, Costs and benefits of community By Parkes J, Bryant J, Milne R. postnatal support workers: a Mugford M, Neilson J, Roberts T, et al. randomised controlled trial. No. 27 No. 17 By Morrell CJ, Spiby H, Stewart P, Treatments for fatigue in multiple Walters S, Morgan A. A rapid and systematic review of the sclerosis: a rapid and systematic review. effectiveness and cost-effectiveness of By Brañas P, Jordan R, Fry-Smith A, No. 7 the taxanes used in the treatment of Burls A, Hyde C. Implantable contraceptives (subdermal advanced breast and ovarian cancer. implants and hormonally impregnated By Lister-Sharp D, McDonagh MS, No. 28 intrauterine systems) versus other Khan KS, Kleijnen J. Early asthma prophylaxis, natural forms of reversible contraceptives: two history, skeletal development and No. 18 systematic reviews to assess relative economy (EASE): a pilot randomised Liquid-based cytology in cervical effectiveness, acceptability, tolerability controlled trial. screening: a rapid and systematic and cost-effectiveness. By Baxter-Jones ADG, Helms PJ, review. By French RS, Cowan FM, Russell G, Grant A, Ross S, Cairns JA, By Payne N, Chilcott J, McGoogan E. Mansour DJA, Morris S, Procter T, et al. Hughes D, et al. No. 19 No. 29 Randomised controlled trial of non- Screening for hypercholesterolaemia No. 8 directive counselling, cognitive– versus case finding for familial An introduction to statistical methods behaviour therapy and usual general hypercholesterolaemia: a systematic for health technology assessment. practitioner care in the management of review and cost-effectiveness analysis. A review by White SJ, Ashby D, depression as well as mixed anxiety and By Marks D, Wonderling Brown PJ. depression in primary care. D, Thorogood M, Lambert H, By King M, Sibbald B, Ward E, Humphries SE, Neil HAW. No. 9 Bower P, Lloyd M, Gabbay M, et al. Disease-modifying drugs for multiple No. 30 sclerosis: a rapid and systematic review. No. 20 A rapid and systematic review of By Clegg A, Bryant J, Milne R. Routine referral for radiography of the clinical effectiveness and cost- patients presenting with low back pain: effectiveness of glycoprotein IIb/IIIa No. 10 is patients’ outcome influenced by GPs’ antagonists in the medical management Publication and related biases. referral for plain radiography? of unstable angina. A review by Song F, Eastwood AJ, By Kerry S, Hilton S, Patel S, By McDonagh MS, Bachmann LM, Gilbody S, Duley L, Sutton AJ. Dundas D, Rink E, Lord J. Golder S, Kleijnen J, ter Riet G. 249

No. 31 Volume 5, 2001 No. 11 A randomised controlled trial Effectiveness of autologous chondrocyte of prehospital intravenous fluid No. 1 transplantation for hyaline cartilage replacement therapy in serious trauma. Clinical and cost-effectiveness defects in knees: a rapid and systematic By Turner J, Nicholl J, Webber L, of donepezil, rivastigmine and review. Cox H, Dixon S, Yates D. galantamine for Alzheimer’s disease: a By Jobanputra P, Parry D, Fry-Smith rapid and systematic review. A, Burls A. No. 32 By Clegg A, Bryant J, Nicholson T, No. 12 Intrathecal pumps for giving opioids in McIntyre L, De Broe S, Gerard K, et al. Statistical assessment of the learning chronic pain: a systematic review. curves of health technologies. No. 2 By Williams JE, Louw G, By Ramsay CR, Grant AM, Wallace The clinical effectiveness and cost- Towlerton G. SA, Garthwaite PH, Monk AF, Russell IT. effectiveness of riluzole for motor No. 33 neurone disease: a rapid and systematic No. 13 Combination therapy (interferon review. The effectiveness and cost-effectiveness alfa and ribavirin) in the treatment By Stewart A, Sandercock J, Bryan S, of temozolomide for the treatment of of chronic hepatitis C: a rapid and Hyde C, Barton PM, Fry-Smith A, et al. recurrent malignant glioma: a rapid systematic review. and systematic review. By Shepherd J, Waugh N, No. 3 By Dinnes J, Cave C, Huang S, Hewitson P. Equity and the economic evaluation of Major K, Milne R. healthcare. No. 34 By Sassi F, Archard L, Le Grand J. No. 14 A systematic review of comparisons of A rapid and systematic review of effect sizes derived from randomised No. 4 the clinical effectiveness and cost- and non-randomised studies. Quality-of-life measures in chronic effectiveness of debriding agents in treating surgical wounds healing by By MacLehose RR, Reeves BC, diseases of childhood. secondary intention. Harvey IM, Sheldon TA, Russell IT, By Eiser C, Morse R. By Lewis R, Whiting P, ter Riet G, Black AMS. No. 5 O’Meara S, Glanville J. Eliciting public preferences for No. 35 healthcare: a systematic review of No. 15 Intravascular ultrasound-guided techniques. Home treatment for mental health interventions in coronary artery By Ryan M, Scott DA, Reeves C, Bate problems: a systematic review. disease: a systematic literature review, A, van Teijlingen ER, Russell EM, et al. By Burns T, Knapp M, Catty J, with decision-analytic modelling, of Healey A, Henderson J, Watt H, et al. outcomes and cost-effectiveness. No. 6 No. 16 By Berry E, Kelly S, Hutton J, General health status measures for How to develop cost-conscious Lindsay HSJ, Blaxill JM, Evans JA, et al. people with cognitive impairment: guidelines. learning disability and acquired brain No. 36 By Eccles M, Mason J. injury. A randomised controlled trial to By Riemsma RP, Forbes CA, evaluate the effectiveness and cost- No. 17 Glanville JM, Eastwood AJ, Kleijnen J. effectiveness of counselling patients The role of specialist nurses in multiple sclerosis: a rapid and systematic review. with chronic depression. No. 7 By De Broe S, Christopher F, By Simpson S, Corney R, An assessment of screening strategies Waugh N. Fitzgerald P, Beecham J. for fragile X syndrome in the UK. By Pembrey ME, Barnicoat AJ, No. 18 No. 37 Carmichael B, Bobrow M, Turner G. A rapid and systematic review Systematic review of treatments for of the clinical effectiveness and atopic eczema. No. 8 cost-effectiveness of orlistat in the By Hoare C, Li Wan Po A, Issues in methodological research: management of obesity. Williams H. perspectives from researchers and By O’Meara S, Riemsma R, commissioners. Shirran L, Mather L, ter Riet G. No. 38 By Lilford RJ, Richardson A, Stevens Bayesian methods in health technology A, Fitzpatrick R, Edwards S, Rock F, et al. No. 19 assessment: a review. The clinical effectiveness and cost- By Spiegelhalter DJ, Myles JP, No. 9 effectiveness of pioglitazone for Jones DR, Abrams KR. Systematic reviews of wound type 2 diabetes mellitus: a rapid and systematic review. care management: (5) beds; By Chilcott J, Wight J, Lloyd Jones No. 39 (6) compression; (7) laser therapy, M, Tappenden P. The management of dyspepsia: a therapeutic ultrasound, electrotherapy systematic review. and electromagnetic therapy. No. 20 By Delaney B, Moayyedi P, Deeks J, By Cullum N, Nelson EA, Extended scope of nursing practice: Innes M, Soo S, Barton P, et al. Flemming K, Sheldon T. a multicentre randomised controlled trial of appropriately trained nurses No. 40 No. 10 and preregistration house officers in A systematic review of treatments for Effects of educational and psychosocial preoperative assessment in elective severe psoriasis. interventions for adolescents with general surgery. By Griffiths CEM, Clark CM, diabetes mellitus: a systematic review. By Kinley H, Czoski-Murray C, Chalmers RJG, Li Wan Po A, By Hampson SE, Skinner TC, Hart J, George S, McCabe C, Primrose J, 250 Williams HC. Storey L, Gage H, Foxcroft D, et al. Reilly C, et al. DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

No. 21 No. 31 No. 5 Systematic reviews of the effectiveness Design and use of questionnaires: a The clinical effectiveness and cost- of day care for people with severe review of best practice applicable to effectiveness of inhaler devices used mental disorders: (1) Acute day hospital surveys of health service staff and in the routine management of chronic versus admission; (2) Vocational patients. asthma in older children: a systematic rehabilitation; (3) Day hospital versus By McColl E, Jacoby A, Thomas L, review and economic evaluation. outpatient care. Soutter J, Bamford C, Steen N, et al. By Peters J, Stevenson M, Beverley C, By Marshall M, Crowther R, Lim J, Smith S. Almaraz- Serrano A, Creed F, Sledge W, No. 32 Kluiter H, et al. A rapid and systematic review of No. 6 the clinical effectiveness and cost- The clinical effectiveness and cost- No. 22 effectiveness of paclitaxel, docetaxel, effectiveness of sibutramine in the The measurement and monitoring of gemcitabine and vinorelbine in non- management of obesity: a technology surgical adverse events. small-cell lung cancer. assessment. By Bruce J, Russell EM, Mollison J, By Clegg A, Scott DA, Sidhu M, By O’Meara S, Riemsma R, Shirran Krukowski ZH. Hewitson P, Waugh N. L, Mather L, ter Riet G.

No. 23 No. 33 No. 7 Action research: a systematic review and Subgroup analyses in randomised The cost-effectiveness of magnetic guidance for assessment. controlled trials: quantifying the risks resonance angiography for carotid By Waterman H, Tillen D, Dickson R, of false-positives and false-negatives. artery stenosis and peripheral vascular de Koning K. By Brookes ST, Whitley E, Peters TJ, disease: a systematic review. Mulheran PA, Egger M, Davey Smith G. By Berry E, Kelly S, Westwood ME, No. 24 Davies LM, Gough MJ, Bamford JM, A rapid and systematic review of No. 34 et al. the clinical effectiveness and cost- Depot antipsychotic medication effectiveness of gemcitabine for the in the treatment of patients with No. 8 treatment of pancreatic cancer. schizophrenia: (1) Meta-review; (2) Promoting physical activity in South By Ward S, Morris E, Bansback N, Patient and nurse attitudes. Asian Muslim women through ‘exercise Calvert N, Crellin A, Forman D, et al. By David AS, Adams C. on prescription’. By Carroll B, Ali N, Azam N. No. 25 No. 35 No. 9 A rapid and systematic review of the A systematic review of controlled Zanamivir for the treatment of evidence for the clinical effectiveness trials of the effectiveness and cost- influenza in adults: a systematic review and cost-effectiveness of irinotecan, effectiveness of brief psychological and economic evaluation. oxaliplatin and raltitrexed for the treatments for depression. By Burls A, Clark W, Stewart T, treatment of advanced colorectal By Churchill R, Hunot V, Corney R, Preston C, Bryan S, Jefferson T, et al. cancer. Knapp M, McGuire H, Tylee A, et al. By Lloyd Jones M, Hummel S, No. 10 Bansback N, Orr B, Seymour M. No. 36 Cost analysis of child health A review of the natural history and surveillance. epidemiology of multiple sclerosis: No. 26 implications for resource allocation and Comparison of the effectiveness of By Sanderson D, Wright D, Acton C, Duree D. health economic models. inhaler devices in asthma and chronic By Richards RG, Sampson FC, obstructive airways disease: a systematic Beard SM, Tappenden P. review of the literature. By Brocklebank D, Ram F, Wright J, Volume 6, 2002 No. 11 Barry P, Cates C, Davies L, et al. Screening for gestational diabetes: No. 1 a systematic review and economic No. 27 A study of the methods used to select evaluation. The cost-effectiveness of magnetic review criteria for clinical audit. By Scott DA, Loveman E, McIntyre resonance imaging for investigation of By Hearnshaw H, Harker R, L, Waugh N. the knee joint. Cheater F, Baker R, Grimshaw G. By Bryan S, Weatherburn G, Bungay No. 12 H, Hatrick C, Salas C, Parry D, et al. No. 2 The clinical effectiveness and cost- Fludarabine as second-line therapy for effectiveness of surgery for people with No. 28 B cell chronic lymphocytic leukaemia: a morbid obesity: a systematic review and A rapid and systematic review of technology assessment. economic evaluation. the clinical effectiveness and cost- By Hyde C, Wake B, Bryan S, Barton By Clegg AJ, Colquitt J, Sidhu MK, effectiveness of topotecan for ovarian P, Fry-Smith A, Davenport C, et al. Royle P, Loveman E, Walker A. cancer. By Forbes C, Shirran L, Bagnall A-M, No. 3 No. 13 Duffy S, ter Riet G. Rituximab as third-line treatment for The clinical effectiveness of refractory or recurrent Stage III or IV trastuzumab for breast cancer: a No. 29 follicular non-Hodgkin’s lymphoma: systematic review. Superseded by a report published in a a systematic review and economic By Lewis R, Bagnall A-M, Forbes C, later volume. evaluation. Shirran E, Duffy S, Kleijnen J, et al. By Wake B, Hyde C, Bryan S, Barton No. 30 P, Song F, Fry-Smith A, et al. No. 14 The role of radiography in primary The clinical effectiveness and cost- care patients with low back pain of at No. 4 effectiveness of vinorelbine for breast least 6 weeks duration: a randomised A systematic review of discharge cancer: a systematic review and (unblinded) controlled trial. arrangements for older people. economic evaluation. By Kendrick D, Fielding K, Bentley By Parker SG, Peet SM, McPherson By Lewis R, Bagnall A-M, King S, E, Miller P, Kerslake R, Pringle M. A, Cannaby AM, Baker R, Wilson A, et al. Woolacott N, Forbes C, Shirran L, et al. 251

No. 15 No. 24 No. 33 A systematic review of the effectiveness A systematic review of the effectiveness The effectiveness and cost-effectiveness and cost-effectiveness of metal-on- of interventions based on a stages-of- of imatinib in chronic myeloid metal hip resurfacing arthroplasty for change approach to promote individual leukaemia: a systematic review. treatment of hip disease. behaviour change. By Garside R, Round A, Dalziel K, By Vale L, Wyness L, McCormack K, By Riemsma RP, Pattenden J, Bridle Stein K, Royle R. McKenzie L, Brazzelli M, Stearns SC. C, Sowden AJ, Mather L, Watt IS, et al. No. 34 No. 16 No. 25 A comparative study of hypertonic The clinical effectiveness and cost- A systematic review update of the saline, daily and alternate-day rhDNase effectiveness of bupropion and nicotine clinical effectiveness and cost- in children with cystic fibrosis. replacement therapy for smoking effectiveness of glycoprotein IIb/IIIa By Suri R, Wallis C, Bush A, cessation: a systematic review and antagonists. Thompson S, Normand C, Flather M, economic evaluation. By Robinson M, Ginnelly L, Sculpher et al. By Woolacott NF, Jones L, Forbes CA, M, Jones L, Riemsma R, Palmer S, et al. Mather LC, Sowden AJ, Song FJ, et al. No. 35 No. 26 A systematic review of the costs and No. 17 A systematic review of the effectiveness, effectiveness of different models of A systematic review of effectiveness cost-effectiveness and barriers to paediatric home care. and economic evaluation of new drug implementation of thrombolytic and By Parker G, Bhakta P, Lovett CA, treatments for juvenile idiopathic neuroprotective therapy for acute Paisley S, Olsen R, Turner D, et al. arthritis: etanercept. ischaemic stroke in the NHS. By Cummins C, Connock M, By Sandercock P, Berge E, Dennis M, Fry-Smith A, Burls A. Forbes J, Hand P, Kwan J, et al. Volume 7, 2003

No. 18 No. 27 No. 1 Clinical effectiveness and cost- A randomised controlled crossover trial How important are comprehensive effectiveness of growth hormone in of nurse practitioner versus doctor- literature searches and the assessment children: a systematic review and led outpatient care in a bronchiectasis of trial quality in systematic reviews? economic evaluation. clinic. Empirical study. By Bryant J, Cave C, Mihaylova B, By Caine N, Sharples LD, By Egger M, Jüni P, Bartlett C, Hollingworth W, French J, Keogan M, Chase D, McIntyre L, Gerard K, et al. Holenstein F, Sterne J. Exley A, et al. No. 19 No. 2 No. 28 Clinical effectiveness and cost- Systematic review of the effectiveness Clinical effectiveness and cost – effectiveness of growth hormone and cost-effectiveness, and economic consequences of selective serotonin in adults in relation to impact on evaluation, of home versus hospital or reuptake inhibitors in the treatment of quality of life: a systematic review and satellite unit haemodialysis for people sex offenders. economic evaluation. with end-stage renal failure. By Adi Y, Ashcroft D, Browne K, By Bryant J, Loveman E, Chase D, By Mowatt G, Vale L, Perez J, Wyness Beech A, Fry-Smith A, Hyde C. Mihaylova B, Cave C, Gerard K, et al. L, Fraser C, MacLeod A, et al. No. 29 No. 3 No. 20 Treatment of established osteoporosis: Systematic review and economic Clinical medication review by a a systematic review and cost–utility evaluation of the effectiveness of pharmacist of patients on repeat analysis. infliximab for the treatment of Crohn’s prescriptions in general practice: a By Kanis JA, Brazier JE, Stevenson disease. randomised controlled trial. M, Calvert NW, Lloyd Jones M. By Clark W, Raftery J, Barton P, By Zermansky AG, Petty DR, Raynor Song F, Fry-Smith A, Burls A. DK, Lowe CJ, Freementle N, Vail A. No. 30 Which anaesthetic agents are cost- No. 4 No. 21 effective in day surgery? Literature A review of the clinical effectiveness The effectiveness of infliximab and review, national survey of practice and and cost-effectiveness of routine anti-D etanercept for the treatment of randomised controlled trial. prophylaxis for pregnant women who rheumatoid arthritis: a systematic By Elliott RA Payne K, Moore JK, are rhesus negative. review and economic evaluation. Davies LM, Harper NJN, St Leger AS, By Chilcott J, Lloyd Jones M, Wight By Jobanputra P, Barton P, Bryan S, et al. J, Forman K, Wray J, Beverley C, et al. Burls A. No. 31 No. 5 No. 22 Screening for hepatitis C among Systematic review and evaluation of the A systematic review and economic injecting drug users and in use of tumour markers in paediatric evaluation of computerised cognitive genitourinary medicine clinics: oncology: Ewing’s sarcoma and behaviour therapy for depression and systematic reviews of effectiveness, neuroblastoma. anxiety. modelling study and national survey of By Riley RD, Burchill SA, By Kaltenthaler E, Shackley P, current practice. Abrams KR, Heney D, Lambert PC, Stevens K, Beverley C, Parry G, By Stein K, Dalziel K, Walker A, Jones DR, et al. Chilcott J. McIntyre L, Jenkins B, Horne J, et al. No. 6 No. 23 No. 32 The cost-effectiveness of screening for A systematic review and economic The measurement of satisfaction with Helicobacter pylori to reduce mortality evaluation of pegylated liposomal healthcare: implications for practice and morbidity from gastric cancer and doxorubicin hydrochloride for ovarian from a systematic review of the peptic ulcer disease: a discrete-event cancer. literature. simulation model. By Forbes C, Wilby J, Richardson G, By Crow R, Gage H, Hampson S, By Roderick P, Davies R, Raftery J, 252 Sculpher M, Mather L, Reimsma R. Hart J, Kimber A, Storey L, et al. Crabbe D, Pearce R, Bhandari P, et al. DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

No. 7 No. 16 No. 26 The clinical effectiveness and cost- Screening for fragile X syndrome: a Can randomised trials rely on existing effectiveness of routine dental checks: literature review and modelling. electronic data? A feasibility study to a systematic review and economic By Song FJ, Barton P, Sleightholme explore the value of routine data in evaluation. V, Yao GL, Fry-Smith A. health technology assessment. By Davenport C, Elley K, Salas By Williams JG, Cheung WY, C, Taylor-Weetman CL, Fry-Smith A, No. 17 Cohen DR, Hutchings HA, Longo MF, Bryan S, et al. Systematic review of endoscopic sinus Russell IT. surgery for nasal polyps. No. 8 No. 27 By Dalziel K, Stein K, Round A, A multicentre randomised controlled Evaluating non-randomised Garside R, Royle P. trial assessing the costs and benefits intervention studies. of using structured information and By Deeks JJ, Dinnes J, D’Amico R, No. 18 analysis of women’s preferences in the Sowden AJ, Sakarovitch C, Song F, et al. management of menorrhagia. Towards efficient guidelines: how to By Kennedy ADM, Sculpher MJ, monitor guideline use in primary care. No. 28 Coulter A, Dwyer N, Rees M, Horsley S, By Hutchinson A, McIntosh A, A randomised controlled trial to assess et al. Cox S, Gilbert C. the impact of a package comprising a patient-orientated, evidence-based self- No. 9 No. 19 help guidebook and patient-centred Clinical effectiveness and cost–utility Effectiveness and cost-effectiveness consultations on disease management of photodynamic therapy for wet of acute hospital-based spinal cord and satisfaction in inflammatory bowel age-related macular degeneration: injuries services: systematic review. disease. a systematic review and economic By Bagnall A-M, Jones L, Richardson By Kennedy A, Nelson E, Reeves D, evaluation. G, Duffy S, Riemsma R. Richardson G, Roberts C, Robinson A, By Meads C, Salas C, Roberts T, et al. Moore D, Fry-Smith A, Hyde C. No. 20 Prioritisation of health technology No. 29 No. 10 assessment. The PATHS model: The effectiveness of diagnostic tests for Evaluation of molecular tests for the assessment of shoulder pain due prenatal diagnosis of chromosome methods and case studies. to soft tissue disorders: a systematic abnormalities. By Townsend J, Buxton M, review. By Grimshaw GM, Szczepura A, Harper G. By Dinnes J, Loveman E, McIntyre L, Hultén M, MacDonald F, Nevin NC, Waugh N. Sutton F, et al. No. 21 Systematic review of the clinical No. 30 No. 11 effectiveness and cost-effectiveness of The value of digital imaging in diabetic First and second trimester antenatal tension-free vaginal tape for treatment retinopathy. screening for Down’s syndrome: of urinary stress incontinence. By Sharp PF, Olson J, Strachan F, the results of the Serum, Urine and By Cody J, Wyness L, Wallace S, Hipwell J, Ludbrook A, O’Donnell M, Ultrasound Screening Study (SURUSS). Glazener C, Kilonzo M, Stearns S, et al. By Wald NJ, Rodeck C, Hackshaw et al. AK, Walters J, Chitty L, Mackinson AM. No. 22 No. 31 The clinical and cost-effectiveness of No. 12 Lowering blood pressure to prevent patient education models for diabetes: The effectiveness and cost-effectiveness myocardial infarction and stroke: a new a systematic review and economic of ultrasound locating devices for preventive strategy. central venous access: a systematic evaluation. By Law M, Wald N, Morris J. review and economic evaluation. By Loveman E, Cave C, Green C, By Calvert N, Hind D, McWilliams Royle P, Dunn N, Waugh N. No. 32 RG, Thomas SM, Beverley C, Clinical and cost-effectiveness of Davidson A. No. 23 capecitabine and tegafur with uracil for The role of modelling in prioritising the treatment of metastatic colorectal No. 13 and planning clinical trials. cancer: systematic review and economic A systematic review of atypical By Chilcott J, Brennan A, Booth A, evaluation. antipsychotics in schizophrenia. Karnon J, Tappenden P. By Ward S, Kaltenthaler E, Cowan J, By Bagnall A-M, Jones L, Lewis R, Brewer N. Ginnelly L, Glanville J, Torgerson D, No. 24 et al. Cost–benefit evaluation of routine No. 33 Clinical and cost-effectiveness of new influenza immunisation in people and emerging technologies for early No. 14 65–74 years of age. localised prostate cancer: a systematic Prostate Testing for Cancer and By Allsup S, Gosney M, Haycox A, Treatment (ProtecT) feasibility study. review. Regan M. By Donovan J, Hamdy F, Neal D, By Hummel S, Paisley S, Morgan A, Peters T, Oliver S, Brindle L, et al. Currie E, Brewer N. No. 25 The clinical and cost-effectiveness of No. 15 No. 34 Early thrombolysis for the treatment pulsatile machine perfusion versus cold Literature searching for clinical and of acute myocardial infarction: a storage of kidneys for transplantation cost-effectiveness studies used in health systematic review and economic retrieved from heart-beating and non- technology assessment reports carried evaluation. heart-beating donors. out for the National Institute for By Boland A, Dundar Y, Bagust A, By Wight J, Chilcott J, Holmes M, Clinical Excellence appraisal system. Haycox A, Hill R, Mujica Mota R, et al. Brewer N. By Royle P, Waugh N. 253

No. 35 No. 2 No. 11 Systematic review and economic Systematic review and modelling of the The use of modelling to evaluate decision modelling for the prevention investigation of acute and chronic chest new drugs for patients with a chronic and treatment of influenza A and B. pain presenting in primary care. condition: the case of antibodies By Turner D, Wailoo A, Nicholson K, By Mant J, McManus RJ, Oakes RAL, against tumour necrosis factor in Cooper N, Sutton A, Abrams K. Delaney BC, Barton PM, Deeks JJ, et al. rheumatoid arthritis. By Barton P, Jobanputra P, Wilson J, No. 36 No. 3 Bryan S, Burls A. A randomised controlled trial The effectiveness and cost-effectiveness No. 12 to evaluate the clinical and cost- of microwave and thermal balloon Clinical effectiveness and cost- effectiveness of Hickman line insertions endometrial ablation for heavy effectiveness of neonatal screening in adult cancer patients by nurses. menstrual bleeding: a systematic review for inborn errors of metabolism using By Boland A, Haycox A, Bagust A, and economic modelling. tandem mass spectrometry: a systematic Fitzsimmons L. By Garside R, Stein K, Wyatt K, review. Round A, Price A. By Pandor A, Eastham J, Beverley C, No. 37 Chilcott J, Paisley S. Redesigning postnatal care: a No. 4 randomised controlled trial of protocol- A systematic review of the role of No. 13 based midwifery-led care focused bisphosphonates in metastatic disease. Clinical effectiveness and cost- on individual women’s physical and By Ross JR, Saunders Y, effectiveness of pioglitazone and psychological health needs. Edmonds PM, Patel S, Wonderling D, rosiglitazone in the treatment of type By MacArthur C, Winter HR, Normand C, et al. 2 diabetes: a systematic review and Bick DE, Lilford RJ, Lancashire RJ, economic evaluation. Knowles H, et al. No. 5 By Czoski-Murray C, Warren E, Systematic review of the clinical Chilcott J, Beverley C, Psyllaki MA, No. 38 effectiveness and cost-effectiveness Cowan J. Estimating implied rates of discount in of capecitabine (Xeloda®) for locally No. 14 healthcare decision-making. advanced and/or metastatic breast Routine examination of the newborn: By West RR, McNabb R, Thompson cancer. the EMREN study. Evaluation of an AGH, Sheldon TA, Grimley Evans J. By Jones L, Hawkins N, Westwood M, extension of the midwife role including Wright K, Richardson G, Riemsma R. a randomised controlled trial of No. 39 appropriately trained midwives and Systematic review of isolation policies No. 6 paediatric senior house officers. in the hospital management of Effectiveness and efficiency of guideline By Townsend J, Wolke D, Hayes J, methicillin-resistant Staphylococcus dissemination and implementation Davé S, Rogers C, Bloomfield L, et al. aureus: a review of the literature strategies. with epidemiological and economic By Grimshaw JM, Thomas RE, No. 15 modelling. MacLennan G, Fraser C, Ramsay CR, Involving consumers in research and By Cooper BS, Stone SP, Kibbler CC, Vale L, et al. development agenda setting for the Cookson BD, Roberts JA, Medley GF, NHS: developing an evidence-based et al. No. 7 approach. Clinical effectiveness and costs of the By Oliver S, Clarke-Jones L, Rees R, No. 40 Sugarbaker procedure for the treatment Milne R, Buchanan P, Gabbay J, et al. Treatments for spasticity and pain in of pseudomyxoma peritonei. No. 16 multiple sclerosis: a systematic review. By Bryant J, Clegg AJ, Sidhu MK, A multi-centre randomised controlled By Beard S, Hunn A, Wight J. Brodin H, Royle P, Davidson P. trial of minimally invasive direct coronary bypass grafting versus No. 41 No. 8 percutaneous transluminal coronary The inclusion of reports of randomised Psychological treatment for insomnia angioplasty with stenting for proximal trials published in languages other than in the regulation of long-term hypnotic stenosis of the left anterior descending English in systematic reviews. drug use. coronary artery. By Moher D, Pham B, Lawson ML, By Morgan K, Dixon S, Mathers N, By Reeves BC, Angelini GD, Bryan Klassen TP. Thompson J, Tomeny M. AJ, Taylor FC, Cripps T, Spyt TJ, et al.

No. 42 No. 9 No. 17 The impact of screening on future Improving the evaluation of Does early magnetic resonance imaging health-promoting behaviours and therapeutic interventions in multiple influence management or improve health beliefs: a systematic review. sclerosis: development of a patient- outcome in patients referred to By Bankhead CR, Brett J, Bukach C, based measure of outcome. secondary care with low back pain? A Webster P, Stewart-Brown S, Munafo M, By Hobart JC, Riazi A, Lamping DL, pragmatic randomised controlled trial. et al. Fitzpatrick R, Thompson AJ. By Gilbert FJ, Grant AM, Gillan MGC, Vale L, Scott NW, Campbell MK, et al. No. 10 A systematic review and economic Volume 8, 2004 No. 18 evaluation of magnetic resonance The clinical and cost-effectiveness No. 1 cholangiopancreatography compared of anakinra for the treatment of What is the best imaging strategy for with diagnostic endoscopic retrograde rheumatoid arthritis in adults: a acute stroke? cholangiopancreatography. systematic review and economic By Wardlaw JM, Keir SL, Seymour J, By Kaltenthaler E, Bravo Vergel Y, analysis. Lewis S, Sandercock PAG, Dennis MS, Chilcott J, Thomas S, Blakeborough T, By Clark W, Jobanputra P, Barton P, 254 et al. Walters SJ, et al. Burls A. DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

No. 19 No. 28 No. 37 A rapid and systematic review and Effectiveness and cost-effectiveness Rituximab (MabThera®) for economic evaluation of the clinical of imatinib for first-line treatment aggressive non-Hodgkin’s lymphoma: and cost-effectiveness of newer drugs of chronic myeloid leukaemia in systematic review and economic for treatment of mania associated with chronic phase: a systematic review and evaluation. bipolar affective disorder. economic analysis. By Knight C, Hind D, Brewer N, By Bridle C, Palmer S, Bagnall A-M, By Dalziel K, Round A, Stein K, Abbott V. Darba J, Duffy S, Sculpher M, et al. Garside R, Price A. No. 38 No. 20 No. 29 Clinical effectiveness and cost- VenUS I: a randomised controlled trial Liquid-based cytology in cervical effectiveness of clopidogrel and of two types of bandage for treating screening: an updated rapid and modified-release dipyridamole in the venous leg ulcers. systematic review and economic secondary prevention of occlusive By Iglesias C, Nelson EA, Cullum analysis. vascular events: a systematic review and By Karnon J, Peters J, Platt J, NA, Torgerson DJ, on behalf of the economic evaluation. Chilcott J, McGoogan E, Brewer N. VenUS Team. By Jones L, Griffin S, Palmer S, Main C, Orton V, Sculpher M, et al. No. 21 No. 30 Systematic review of the long-term Systematic review of the effectiveness No. 39 effects and economic consequences of and cost-effectiveness, and economic Pegylated interferon α-2a and -2b treatments for obesity and implications evaluation, of myocardial perfusion for health improvement. scintigraphy for the diagnosis and in combination with ribavirin in the By Avenell A, Broom J, Brown TJ, management of angina and myocardial treatment of chronic hepatitis C: Poobalan A, Aucott L, Stearns SC, et al. infarction. a systematic review and economic By Mowatt G, Vale L, Brazzelli M, evaluation. No. 22 Hernandez R, Murray A, Scott N, et al. By Shepherd J, Brodin H, Cave C, Autoantibody testing in children Waugh N, Price A, Gabbay J. with newly diagnosed type 1 diabetes No. 31 mellitus. A pilot study on the use of decision No. 40 By Dretzke J, Cummins C, theory and value of information Clopidogrel used in combination with analysis as part of the NHS Health Sandercock J, Fry-Smith A, Barrett T, aspirin compared with aspirin alone Technology Assessment programme. Burls A. in the treatment of non-ST-segment- By Claxton K, Ginnelly L, Sculpher elevation acute coronary syndromes: M, Philips Z, Palmer S. No. 23 a systematic review and economic Clinical effectiveness and cost- evaluation. No. 32 effectiveness of prehospital intravenous By Main C, Palmer S, Griffin S, Jones The Social Support and Family Health fluids in trauma patients. Study: a randomised controlled trial L, Orton V, Sculpher M, et al. By Dretzke J, Sandercock J, Bayliss and economic evaluation of two S, Burls A. alternative forms of postnatal support No. 41 for mothers living in disadvantaged Provision, uptake and cost of cardiac No. 24 inner-city areas. rehabilitation programmes: improving Newer hypnotic drugs for the short- By Wiggins M, Oakley A, Roberts I, services to under-represented groups. term management of insomnia: a Turner H, Rajan L, Austerberry H, et al. By Beswick AD, Rees K, Griebsch I, systematic review and economic Taylor FC, Burke M, West RR, et al. evaluation. No. 33 By Dündar Y, Boland A, Strobl J, Psychosocial aspects of genetic No. 42 Dodd S, Haycox A, Bagust A, et al. screening of pregnant women and Involving South Asian patients in newborns: a systematic review. clinical trials. No. 25 By Green JM, Hewison J, Bekker HL, By Hussain-Gambles M, Leese B, Development and validation of Bryant, Cuckle HS. Atkin K, Brown J, Mason S, Tovey P. methods for assessing the quality of diagnostic accuracy studies. No. 34 No. 43 By Whiting P, Rutjes AWS, Dinnes J, Evaluation of abnormal uterine Clinical and cost-effectiveness of Reitsma JB, Bossuyt PMM, Kleijnen J. bleeding: comparison of three continuous subcutaneous insulin outpatient procedures within cohorts infusion for diabetes. No. 26 defined by age and menopausal status. EVALUATE hysterectomy trial: By Colquitt JL, Green C, Sidhu MK, By Critchley HOD, Warner P, Lee AJ, Hartwell D, Waugh N. a multicentre randomised trial Brechin S, Guise J, Graham B. comparing abdominal, vaginal and No. 44 laparoscopic methods of hysterectomy. No. 35 Identification and assessment of By Garry R, Fountain J, Brown J, Coronary artery stents: a rapid ongoing trials in health technology Manca A, Mason S, Sculpher M, et al. systematic review and economic evaluation. assessment reviews. No. 27 By Hill R, Bagust A, Bakhai A, By Song FJ, Fry-Smith A, Davenport Methods for expected value of Dickson R, Dündar Y, Haycox A, et al. C, Bayliss S, Adi Y, Wilson JS, et al. information analysis in complex health economic models: developments on No. 36 No. 45 the health economics of interferon-β Review of guidelines for good practice Systematic review and economic and glatiramer acetate for multiple in decision-analytic modelling in health evaluation of a long-acting insulin sclerosis. technology assessment. analogue, insulin glargine By Tappenden P, Chilcott JB, By Philips Z, Ginnelly L, Sculpher M, By Warren E, Weatherley-Jones E, Eggington S, Oakley J, McCabe C. Claxton K, Golder S, Riemsma R, et al. Chilcott J, Beverley C. 255

No. 46 No. 4 No. 13 Supplementation of a home-based Randomised evaluation of alternative Cervical screening programmes: can exercise programme with a class- electrosurgical modalities to treat automation help? Evidence from based programme for people bladder outflow obstruction in men systematic reviews, an economic with osteoarthritis of the knees: a with benign prostatic hyperplasia. analysis and a simulation modelling randomised controlled trial and health By Fowler C, McAllister W, Plail R, exercise applied to the UK. By Willis BH, Barton P, Pearmain P, economic analysis. Karim O, Yang Q. Bryan S, Hyde C. By McCarthy CJ, Mills PM, Pullen R, No. 5 Richardson G, Hawkins N, Roberts CR, No. 14 A pragmatic randomised controlled et al. Laparoscopic surgery for inguinal trial of the cost-effectiveness of hernia repair: systematic review of No. 47 palliative therapies for patients with effectiveness and economic evaluation. Clinical and cost-effectiveness of once- inoperable oesophageal cancer. By McCormack K, Wake B, Perez J, daily versus more frequent use of same By Shenfine J, McNamee P, Steen N, Fraser C, Cook J, McIntosh E, et al. potency topical corticosteroids for Bond J, Griffin SM. atopic eczema: a systematic review and No. 15 economic evaluation. No. 6 Clinical effectiveness, tolerability and By Green C, Colquitt JL, Kirby J, Impact of computer-aided detection cost-effectiveness of newer drugs for Davidson P, Payne E. prompts on the sensitivity and epilepsy in adults: a systematic review specificity of screening mammography. and economic evaluation. No. 48 By Taylor P, Champness J, Given- By Wilby J, Kainth A, Hawkins N, Epstein D, McIntosh H, McDaid C, et al. Acupuncture of chronic headache Wilson R, Johnston K, Potts H. disorders in primary care: randomised No. 7 No. 16 controlled trial and economic analysis. A randomised controlled trial to By Vickers AJ, Rees RW, Zollman CE, Issues in data monitoring and interim analysis of trials. compare the cost-effectiveness of McCarney R, Smith CM, Ellis N, et al. tricyclic antidepressants, selective By Grant AM, Altman DG, Babiker serotonin reuptake inhibitors and AB, Campbell MK, Clemens FJ, No. 49 lofepramine. Generalisability in economic evaluation Darbyshire JH, et al. By Peveler R, Kendrick T, Buxton M, studies in healthcare: a review and case Longworth L, Baldwin D, Moore M, et al. studies. No. 8 By Sculpher MJ, Pang FS, Manca A, Lay public’s understanding of equipoise No. 17 and randomisation in randomised Drummond MF, Golder S, Urdahl H, Clinical effectiveness and cost- controlled trials. et al. effectiveness of immediate angioplasty By Robinson EJ, Kerr CEP, for acute myocardial infarction: No. 50 Stevens AJ, Lilford RJ, Braunholtz DA, systematic review and economic evaluation. Virtual outreach: a randomised Edwards SJ, et al. By Hartwell D, Colquitt J, Loveman controlled trial and economic No. 9 E, Clegg AJ, Brodin H, Waugh N, et al. evaluation of joint teleconferenced Clinical and cost-effectiveness of medical consultations. electroconvulsive therapy for depressive No. 18 By Wallace P, Barber J, Clayton W, illness, schizophrenia, catatonia A randomised controlled comparison of Currell R, Fleming K, Garner P, et al. and mania: systematic reviews and alternative strategies in stroke care. economic modelling studies. By Kalra L, Evans A, Perez I, Knapp M, Swift C, Donaldson N. By Greenhalgh J, Knight C, Hind D, Volume 9, 2005 Beverley C, Walters S. No. 19 The investigation and analysis of No. 1 No. 10 Randomised controlled multiple critical incidents and adverse events in Measurement of health-related quality healthcare. treatment comparison to provide a cost- of life for people with dementia: By Woloshynowych M, Rogers S, effectiveness rationale for the selection development of a new instrument Taylor-Adams S, Vincent C. of antimicrobial therapy in acne. (DEMQOL) and an evaluation of By Ozolins M, Eady EA, Avery A, current methodology. No. 20 Cunliffe WJ, O’Neill C, Simpson NB, By Smith SC, Lamping DL, Banerjee Potential use of routine databases in et al. S, Harwood R, Foley B, Smith P, et al. health technology assessment. By Raftery J, Roderick P, Stevens A. No. 2 No. 11 Do the findings of case series studies Clinical effectiveness and cost- No. 21 vary significantly according to effectiveness of drotrecogin alfa Clinical and cost-effectiveness of newer methodological characteristics? (activated) (Xigris®) for the treatment immunosuppressive regimens in renal By Dalziel K, Round A, Stein K, of severe sepsis in adults: a systematic transplantation: a systematic review and modelling study. Garside R, Castelnuovo E, Payne L. review and economic evaluation. By Woodroffe R, Yao GL, Meads C, By Green C, Dinnes J, Takeda A, Bayliss S, Ready A, Raftery J, et al. No. 3 Shepherd J, Hartwell D, Cave C, et al. Improving the referral process No. 22 for familial breast cancer genetic No. 12 A systematic review and economic counselling: findings of three A methodological review of how evaluation of alendronate, etidronate, randomised controlled trials of two heterogeneity has been examined in risedronate, raloxifene and teriparatide interventions. systematic reviews of diagnostic test for the prevention and treatment of By Wilson BJ, Torrance N, accuracy. postmenopausal osteoporosis. Mollison J, Wordsworth S, Gray JR, By Dinnes J, Deeks J, Kirby J, By Stevenson M, Lloyd Jones M, De 256 Haites NE, et al. Roderick P. Nigris E, Brewer N, Davis S, Oakley J. DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

No. 23 No. 32 No. 40 A systematic review to examine Longer term clinical and economic A randomised controlled trial and the impact of psycho-educational benefits of offering acupuncture care to cost-effectiveness study of systematic interventions on health outcomes patients with chronic low back pain. screening (targeted and total and costs in adults and children with By Thomas KJ, MacPherson population screening) versus routine difficult asthma. H, Ratcliffe J, Thorpe L, Brazier J, practice for the detection of atrial By Smith JR, Mugford M, Holland Campbell M, et al. fibrillation in people aged 65 and over. R, Candy B, Noble MJ, Harrison BDW, The SAFE study. et al. No. 33 By Hobbs FDR, Fitzmaurice DA, Cost-effectiveness and safety of Mant J, Murray E, Jowett S, Bryan S, No. 24 epidural steroids in the management et al. An evaluation of the costs, effectiveness of sciatica. and quality of renal replacement No. 41 By Price C, Arden N, Coglan L, therapy provision in renal satellite units Displaced intracapsular hip fractures Rogers P. in England and Wales. in fit, older people: a randomised By Roderick P, Nicholson T, Armitage comparison of reduction and fixation, No. 34 A, Mehta R, Mullee M, Gerard K, et al. bipolar hemiarthroplasty and total hip The British Rheumatoid Outcome arthroplasty. No. 25 Study Group (BROSG) randomised By Keating JF, Grant A, Masson M, Imatinib for the treatment of patients controlled trial to compare the Scott NW, Forbes JF. with unresectable and/or metastatic effectiveness and cost-effectiveness of gastrointestinal stromal tumours: aggressive versus symptomatic therapy No. 42 systematic review and economic in established rheumatoid arthritis. Long-term outcome of cognitive evaluation. By Symmons D, Tricker K, Roberts C, behaviour therapy clinical trials in By Wilson J, Connock M, Song F, Davies L, Dawes P, Scott DL. central Scotland. Yao G, Fry-Smith A, Raftery J, et al. By Durham RC, Chambers JA, No. 35 Power KG, Sharp DM, Macdonald RR, No. 26 Conceptual framework and systematic Major KA, et al. Indirect comparisons of competing review of the effects of participants’ interventions. and professionals’ preferences in No. 43 By Glenny AM, Altman DG, Song F, randomised controlled trials. The effectiveness and cost-effectiveness Sakarovitch C, Deeks JJ, D’Amico R, By King M, Nazareth I, Lampe F, of dual-chamber pacemakers compared et al. Bower P, Chandler M, Morou M, et al. with single-chamber pacemakers for bradycardia due to atrioventricular No. 27 No. 36 block or sick sinus syndrome: systematic Cost-effectiveness of alternative review and economic evaluation. The clinical and cost-effectiveness of strategies for the initial medical By Castelnuovo E, Stein K, Pitt M, implantable cardioverter defibrillators: management of non-ST elevation acute Garside R, Payne E. a systematic review. coronary syndrome: systematic review and decision-analytical modelling. By Bryant J, Brodin H, Loveman E, No. 44 By Robinson M, Palmer S, Sculpher Payne E, Clegg A. Newborn screening for congenital heart M, Philips Z, Ginnelly L, Bowens A, et al. defects: a systematic review and cost- No. 37 effectiveness analysis. No. 28 A trial of problem-solving by By Knowles R, Griebsch I, Outcomes of electrically stimulated community mental health nurses for Dezateux C, Brown J, Bull C, Wren C. gracilis neosphincter surgery. anxiety, depression and life difficulties By Tillin T, Chambers M, Feldman R. among general practice patients. The No. 45 CPN-GP study. The clinical and cost-effectiveness of No. 29 By Kendrick T, Simons L, left ventricular assist devices for end- The effectiveness and cost-effectiveness Mynors-Wallis L, Gray A, Lathlean J, stage heart failure: a systematic review of pimecrolimus and tacrolimus for Pickering R, et al. and economic evaluation. atopic eczema: a systematic review and By Clegg AJ, Scott DA, Loveman E, economic evaluation. No. 38 Colquitt J, Hutchinson J, Royle P, et al. By Garside R, Stein K, Castelnuovo The causes and effects of socio- E, Pitt M, Ashcroft D, Dimmock P, et al. demographic exclusions from clinical No. 46 trials. The effectiveness of the Heidelberg No. 30 Retina Tomograph and laser diagnostic By Bartlett C, Doyal L, Ebrahim S, Systematic review on urine albumin glaucoma scanning system (GDx) in Davey P, Bachmann M, Egger M, et al. testing for early detection of diabetic detecting and monitoring glaucoma. complications. By Kwartz AJ, Henson DB, Harper No. 39 By Newman DJ, Mattock MB, RA, Spencer AF, McLeod D. Is hydrotherapy cost-effective? Dawnay ABS, Kerry S, McGuire A, A randomised controlled trial of Yaqoob M, et al. No. 47 combined hydrotherapy programmes Clinical and cost-effectiveness of No. 31 compared with physiotherapy land autologous chondrocyte implantation Randomised controlled trial of the cost- techniques in children with juvenile for cartilage defects in knee joints: effectiveness of water-based therapy for idiopathic arthritis. systematic review and economic lower limb osteoarthritis. By Epps H, Ginnelly L, Utley M, evaluation. By Cochrane T, Davey RC, Southwood T, Gallivan S, Sculpher M, By Clar C, Cummins E, McIntyre L, Matthes Edwards SM. et al. Thomas S, Lamb J, Bain L, et al. 257

No. 48 No. 6 No. 15 Systematic review of effectiveness of Systematic review and evaluation Measurement of the clinical and cost- different treatments for childhood of methods of assessing urinary effectiveness of non-invasive diagnostic retinoblastoma. incontinence. testing strategies for deep vein By McDaid C, Hartley S, Bagnall By Martin JL, Williams KS, Abrams thrombosis. A-M, Ritchie G, Light K, Riemsma R. KR, Turner DA, Sutton AJ, Chapple C, By Goodacre S, Sampson F, et al. Stevenson M, Wailoo A, Sutton A, No. 49 Thomas S, et al. Towards evidence-based guidelines No. 7 The clinical effectiveness and cost- for the prevention of venous No. 16 thromboembolism: systematic effectiveness of newer drugs for Systematic review of the effectiveness reviews of mechanical methods, oral children with epilepsy. A systematic and cost-effectiveness of HealOzone® anticoagulation, dextran and regional review. for the treatment of occlusal pit/fissure anaesthesia as thromboprophylaxis. By Connock M, Frew E, Evans B-W, By Roderick P, Ferris G, Wilson K, Bryan S, Cummins C, Fry-Smith A, et al. caries and root caries. Halls H, Jackson D, Collins R, et al. By Brazzelli M, McKenzie L, Fielding No. 8 S, Fraser C, Clarkson J, Kilonzo M, et al. No. 50 Surveillance of Barrett’s oesophagus: exploring the uncertainty through The effectiveness and cost-effectiveness No. 17 systematic review, expert workshop and of parent training/education Randomised controlled trials of economic modelling. programmes for the treatment conventional antipsychotic versus By Garside R, Pitt M, Somerville M, of conduct disorder, including new atypical drugs, and new atypical Stein K, Price A, Gilbert N. oppositional defiant disorder, in drugs versus clozapine, in people with children. No. 9 schizophrenia responding poorly to, or By Dretzke J, Frew E, Davenport C, Topotecan, pegylated liposomal intolerant of, current drug treatment. Barlow J, Stewart-Brown S, Sandercock J, doxorubicin hydrochloride and By Lewis SW, Davies L, Jones PB, et al. paclitaxel for second-line or subsequent Barnes TRE, Murray RM, Kerwin R, treatment of advanced ovarian cancer: et al. a systematic review and economic Volume 10, 2006 evaluation. No. 18 By Main C, Bojke L, Griffin S, Diagnostic tests and algorithms used No. 1 Norman G, Barbieri M, Mather L, et al. in the investigation of haematuria: The clinical and cost-effectiveness of systematic reviews and economic donepezil, rivastigmine, galantamine No. 10 evaluation. Evaluation of molecular techniques and memantine for Alzheimer’s By Rodgers M, Nixon J, Hempel S, disease. in prediction and diagnosis Aho T, Kelly J, Neal D, et al. By Loveman E, Green C, Kirby J, of cytomegalovirus disease in Takeda A, Picot J, Payne E, et al. immunocompromised patients. By Szczepura A, Westmoreland D, No. 19 Cognitive behavioural therapy in No. 2 Vinogradova Y, Fox J, Clark M. FOOD: a multicentre randomised trial addition to antispasmodic therapy for evaluating feeding policies in patients No. 11 irritable bowel syndrome in primary admitted to hospital with a recent Screening for thrombophilia in high- care: randomised controlled trial. stroke. risk situations: systematic review By Kennedy TM, Chalder T, By Dennis M, Lewis S, Cranswick G, and cost-effectiveness analysis. The McCrone P, Darnley S, Knapp M, Forbes J. Thrombosis: Risk and Economic Jones RH, et al. Assessment of Thrombophilia No. 3 Screening (TREATS) study. No. 20 The clinical effectiveness and cost- By Wu O, Robertson L, Twaddle S, A systematic review of the Lowe GDO, Clark P, Greaves M, et al. effectiveness of computed tomography clinical effectiveness and cost- screening for lung cancer: systematic effectiveness of enzyme replacement No. 12 reviews. A series of systematic reviews to inform therapies for Fabry’s disease and By Black C, Bagust A, Boland A, a decision analysis for sampling and mucopolysaccharidosis type 1. Walker S, McLeod C, De Verteuil R, et al. treating infected diabetic foot ulcers. By Connock M, Juarez-Garcia A, By Nelson EA, O’Meara S, Craig D, Frew E, Mans A, Dretzke J, Fry-Smith A, No. 4 Iglesias C, Golder S, Dalton J, et al. et al. A systematic review of the effectiveness and cost-effectiveness of neuroimaging No. 13 No. 21 assessments used to visualise the seizure Randomised clinical trial, observational Health benefits of antiviral therapy for focus in people with refractory epilepsy study and assessment of cost- mild chronic hepatitis C: randomised being considered for surgery. effectiveness of the treatment of controlled trial and economic By Whiting P, Gupta R, Burch J, varicose veins (REACTIV trial). evaluation. Mujica Mota RE, Wright K, Marson A, By Michaels JA, Campbell WB, By Wright M, Grieve R, Roberts J, et al. Brazier JE, MacIntyre JB, Palfreyman SJ, Main J, Thomas HC, on behalf of the Ratcliffe J, et al. No. 5 UK Mild Hepatitis C Trial Investigators. Comparison of conference abstracts No. 14 and presentations with full-text articles The cost-effectiveness of screening for No. 22 in the health technology assessments of oral cancer in primary care. Pressure relieving support surfaces: a rapidly evolving technologies. By Speight PM, Palmer S, Moles DR, randomised evaluation. By Dundar Y, Dodd S, Dickson R, Downer MC, Smith DH, Henriksson M, By Nixon J, Nelson EA, Cranny G, 258 Walley T, Haycox A, Williamson PR. et al. Iglesias CP, Hawkins K, Cullum NA, et al. DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

No. 23 No. 31 No. 40 A systematic review and economic Etanercept and infliximab for the What are the clinical outcome and cost- model of the effectiveness and cost- treatment of psoriatic arthritis: a effectiveness of endoscopy undertaken effectiveness of methylphenidate, systematic review and economic by nurses when compared with doctors? dexamfetamine and atomoxetine evaluation. A Multi-Institution Nurse Endoscopy for the treatment of attention deficit By Woolacott N, Bravo Vergel Y, Trial (MINuET). Hawkins N, Kainth A, Khadjesari Z, hyperactivity disorder in children and By Williams J, Russell I, Durai D, Misso K, et al. adolescents. Cheung W-Y, Farrin A, Bloor K, et al. By King S, Griffin S, Hodges Z, No. 32 Weatherly H, Asseburg C, Richardson G, No. 41 et al. The cost-effectiveness of testing for hepatitis C in former injecting drug The clinical and cost-effectiveness of oxaliplatin and capecitabine for the No. 24 users. adjuvant treatment of colon cancer: The clinical effectiveness and cost- By Castelnuovo E, Thompson-Coon systematic review and economic effectiveness of enzyme replacement J, Pitt M, Cramp M, Siebert U, Price A, et al. therapy for Gaucher’s disease: a evaluation. systematic review. By Pandor A, Eggington S, Paisley S, No. 33 By Connock M, Burls A, Frew E, Tappenden P, Sutcliffe P. Computerised cognitive behaviour Fry-Smith A, Juarez-Garcia A, McCabe C, therapy for depression and anxiety et al. No. 42 update: a systematic review and A systematic review of the effectiveness economic evaluation. of adalimumab, etanercept and No. 25 By Kaltenthaler E, Brazier J, infliximab for the treatment of Effectiveness and cost-effectiveness De Nigris E, Tumur I, Ferriter M, of salicylic acid and cryotherapy for Beverley C, et al. rheumatoid arthritis in adults and cutaneous warts. An economic decision an economic evaluation of their cost- model. No. 34 effectiveness. By Thomas KS, Keogh-Brown MR, Cost-effectiveness of using prognostic By Chen Y-F, Jobanputra P, Barton P, Chalmers JR, Fordham RJ, Holland RC, information to select women with breast Jowett S, Bryan S, Clark W, et al. Armstrong SJ, et al. cancer for adjuvant systemic therapy. By Williams C, Brunskill S, Altman D, No. 43 No. 26 Briggs A, Campbell H, Clarke M, et al. Telemedicine in dermatology: a A systematic literature review of the randomised controlled trial. effectiveness of non-pharmacological No. 35 By Bowns IR, Collins K, Walters SJ, interventions to prevent wandering in Psychological therapies including McDonagh AJG. dementia and evaluation of the ethical dialectical behaviour therapy for implications and acceptability of their borderline personality disorder: a No. 44 use. systematic review and preliminary Cost-effectiveness of cell salvage and By Robinson L, Hutchings D, Corner economic evaluation. alternative methods of minimising L, Beyer F, Dickinson H, Vanoli A, et al. By Brazier J, Tumur I, Holmes M, Ferriter M, Parry G, Dent-Brown K, et al. perioperative allogeneic blood No. 27 transfusion: a systematic review and A review of the evidence on the effects No. 36 economic model. and costs of implantable cardioverter Clinical effectiveness and cost- By Davies L, Brown TJ, Haynes S, defibrillator therapy in different effectiveness of tests for the diagnosis Payne K, Elliott RA, McCollum C. patient groups, and modelling of cost- and investigation of urinary tract effectiveness and cost–utility for these infection in children: a systematic No. 45 groups in a UK context. review and economic model. Clinical effectiveness and cost- By Buxton M, Caine N, Chase D, By Whiting P, Westwood M, Bojke L, effectiveness of laparoscopic surgery Connelly D, Grace A, Jackson C, et al. Palmer S, Richardson G, Cooper J, et al. for colorectal cancer: systematic reviews and economic evaluation. No. 37 No. 28 By Murray A, Lourenco T, de Verteuil Cognitive behavioural therapy Adefovir dipivoxil and pegylated R, Hernandez R, Fraser C, McKinley A, in chronic fatigue syndrome: a interferon alfa-2a for the treatment of randomised controlled trial of an et al. chronic hepatitis B: a systematic review outpatient group programme. and economic evaluation. By O’Dowd H, Gladwell P, Rogers No. 46 By Shepherd J, Jones J, Takeda A, CA, Hollinghurst S, Gregory A. Etanercept and efalizumab for the Davidson P, Price A. treatment of psoriasis: a systematic No. 38 review. No. 29 A comparison of the cost-effectiveness By Woolacott N, Hawkins N, An evaluation of the clinical and cost- of five strategies for the prevention Mason A, Kainth A, Khadjesari Z, Bravo effectiveness of pulmonary artery of nonsteroidal anti-inflammatory Vergel Y, et al. catheters in patient management in drug-induced gastrointestinal toxicity: intensive care: a systematic review and a a systematic review with economic No. 47 randomised controlled trial. modelling. By Harvey S, Stevens K, Harrison D, Systematic reviews of clinical decision By Brown TJ, Hooper L, Elliott RA, tools for acute abdominal pain. Young D, Brampton W, McCabe C, et al. Payne K, Webb R, Roberts C, et al. By Liu JLY, Wyatt JC, Deeks JJ, No. 30 No. 39 Clamp S, Keen J, Verde P, et al. Accurate, practical and cost-effective The effectiveness and cost-effectiveness assessment of carotid stenosis in the of computed tomography screening No. 48 UK. for coronary artery disease: systematic Evaluation of the ventricular assist By Wardlaw JM, Chappell FM, review. device programme in the UK. Stevenson M, De Nigris E, Thomas S, By Waugh N, Black C, Walker S, By Sharples L, Buxton M, Caine N, Gillard J, et al. McIntyre L, Cummins E, Hillis G. Cafferty F, Demiris N, Dyer M, et al. 259

No. 49 No. 7 No. 16 A systematic review and economic Glucocorticoid-induced osteoporosis: Additional therapy for young model of the clinical and cost- a systematic review and cost–utility children with spastic cerebral palsy: a analysis. effectiveness of immunosuppressive randomised controlled trial. By Kanis JA, Stevenson M, therapy for renal transplantation in McCloskey EV, Davis S, Lloyd-Jones M. By Weindling AM, Cunningham CC, children. Glenn SM, Edwards RT, Reeves DJ. By Yao G, Albon E, Adi Y, Milford D, No. 8 Bayliss S, Ready A, et al. Epidemiological, social, diagnostic and No. 17 economic evaluation of population Screening for type 2 diabetes: literature No. 50 screening for genital chlamydial review and economic modelling. Amniocentesis results: investigation of infection. By Waugh N, Scotland G, McNamee By Low N, McCarthy A, Macleod J, anxiety. The ARIA trial. P, Gillett M, Brennan A, Goyder E, et al. By Hewison J, Nixon J, Fountain J, Salisbury C, Campbell R, Roberts TE, et al. Cocks K, Jones C, Mason G, et al. No. 18 No. 9 The effectiveness and cost-effectiveness Methadone and buprenorphine for the of cinacalcet for secondary Volume 11, 2007 management of opioid dependence: hyperparathyroidism in end-stage renal a systematic review and economic disease patients on dialysis: a systematic No. 1 evaluation. review and economic evaluation. Pemetrexed disodium for the treatment By Connock M, Juarez-Garcia A, By Garside R, Pitt M, Anderson R, of malignant pleural mesothelioma: Jowett S, Frew E, Liu Z, Taylor RJ, et al. Mealing S, Roome C, Snaith A, et al. a systematic review and economic evaluation. No. 10 Exercise Evaluation Randomised No. 19 By Dundar Y, Bagust A, Dickson R, Trial (EXERT): a randomised trial The clinical effectiveness and cost- Dodd S, Green J, Haycox A, et al. comparing GP referral for leisure effectiveness of gemcitabine for centre-based exercise, community-based metastatic breast cancer: a systematic No. 2 walking and advice only. review and economic evaluation. A systematic review and economic By Isaacs AJ, Critchley JA, See Tai model of the clinical effectiveness S, Buckingham K, Westley D, Harridge By Takeda AL, Jones J, Loveman E, and cost-effectiveness of docetaxel SDR, et al. Tan SC, Clegg AJ. in combination with prednisone or prednisolone for the treatment of No. 11 No. 20 hormone-refractory metastatic prostate Interferon alfa (pegylated and non- A systematic review of duplex pegylated) and ribavirin for the cancer. ultrasound, magnetic resonance treatment of mild chronic hepatitis angiography and computed By Collins R, Fenwick E, Trowman R, C: a systematic review and economic Perard R, Norman G, Light K, et al. evaluation. tomography angiography for By Shepherd J, Jones J, Hartwell D, the diagnosis and assessment of No. 3 Davidson P, Price A, Waugh N. symptomatic, lower limb peripheral A systematic review of rapid diagnostic arterial disease. tests for the detection of tuberculosis No. 12 By Collins R, Cranny G, Burch J, infection. Systematic review and economic Aguiar-Ibáñez R, Craig D, Wright K, evaluation of bevacizumab and By Dinnes J, Deeks J, Kunst H, et al. Gibson A, Cummins E, Waugh N, et al. cetuximab for the treatment of metastatic colorectal cancer. By Tappenden P, Jones R, Paisley S, No. 21 No. 4 Carroll C. The clinical effectiveness and cost- The clinical effectiveness and cost- effectiveness of treatments for children effectiveness of strontium ranelate for No. 13 with idiopathic steroid-resistant the prevention of osteoporotic fragility A systematic review and economic nephrotic syndrome: a systematic fractures in postmenopausal women. evaluation of epoetin alfa, epoetin review. By Stevenson M, Davis S, Lloyd-Jones beta and darbepoetin alfa in anaemia By Colquitt JL, Kirby J, Green C, M, Beverley C. associated with cancer, especially that attributable to cancer treatment. Cooper K, Trompeter RS. No. 5 By Wilson J, Yao GL, Raftery J, No. 22 A systematic review of quantitative and Bohlius J, Brunskill S, Sandercock J, et al. A systematic review of the routine qualitative research on the role and monitoring of growth in children of effectiveness of written information No. 14 primary school age to identify growth- available to patients about individual A systematic review and economic related conditions. medicines. evaluation of statins for the prevention By Raynor DK, Blenkinsopp of coronary events. By Fayter D, Nixon J, Hartley S, A, Knapp P, Grime J, Nicolson DJ, By Ward S, Lloyd Jones M, Pandor A, Rithalia A, Butler G, Rudolf M, et al. Pollock K, et al. Holmes M, Ara R, Ryan A, et al. No. 23 No. 6 No. 15 Systematic review of the effectiveness of A systematic review of the effectiveness Oral naltrexone as a treatment for preventing and treating Staphylococcus and cost-effectiveness of different aureus carriage in reducing peritoneal relapse prevention in formerly opioid- models of community-based respite dependent drug users: a systematic care for frail older people and their catheter-related infections. review and economic evaluation. carers. By McCormack K, Rabindranath K, By Adi Y, Juarez-Garcia A, Wang D, By Mason A, Weatherly H, Spilsbury Kilonzo M, Vale L, Fraser C, McIntyre L, 260 Jowett S, Frew E, Day E, et al. K, Arksey H, Golder S, Adamson J, et al. et al. DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

No. 24 No. 32 No. 40 The clinical effectiveness and cost Current practice, accuracy, effectiveness Taxanes for the adjuvant treatment of of repetitive transcranial magnetic and cost-effectiveness of the school early breast cancer: systematic review stimulation versus electroconvulsive entry hearing screen. and economic evaluation. therapy in severe depression: a By Bamford J, Fortnum H, Bristow K, By Ward S, Simpson E, Davis S, Hind multicentre pragmatic randomised Smith J, Vamvakas G, Davies L, et al. D, Rees A, Wilkinson A. controlled trial and economic analysis. By McLoughlin DM, Mogg A, Eranti No. 33 No. 41 S, Pluck G, Purvis R, Edwards D, et al. The clinical effectiveness and cost- The clinical effectiveness and cost- effectiveness of inhaled insulin in effectiveness of screening for open No. 25 diabetes mellitus: a systematic review angle glaucoma: a systematic review A randomised controlled trial and and economic evaluation. and economic evaluation. economic evaluation of direct versus By Black C, Cummins E, Royle P, By Burr JM, Mowatt G, Hernández indirect and individual versus group Philip S, Waugh N. R, Siddiqui MAR, Cook J, Lourenco T, modes of speech and language therapy et al. for children with primary language No. 34 impairment. Surveillance of cirrhosis for No. 42 By Boyle J, McCartney E, Forbes J, hepatocellular carcinoma: systematic Acceptability, benefit and costs of early O’Hare A. review and economic analysis. screening for hearing disability: a study By Thompson Coon J, Rogers G, of potential screening tests and models. No. 26 Hewson P, Wright D, Anderson R, By Davis A, Smith P, Ferguson M, Hormonal therapies for early breast Cramp M, et al. Stephens D, Gianopoulos I. cancer: systematic review and economic evaluation. No. 35 No. 43 By Hind D, Ward S, De Nigris E, The Birmingham Rehabilitation Contamination in trials of educational Uptake Maximisation Study (BRUM). Simpson E, Carroll C, Wyld L. interventions. Homebased compared with hospital- By Keogh-Brown MR, Bachmann No. 27 based cardiac rehabilitation in a multi- MO, Shepstone L, Hewitt C, Howe A, Cardioprotection against the toxic ethnic population: cost-effectiveness Ramsay CR, et al. effects of anthracyclines given to and patient adherence. children with cancer: a systematic By Jolly K, Taylor R, Lip GYH, No. 44 review. Greenfield S, Raftery J, Mant J, et al. Overview of the clinical effectiveness of By Bryant J, Picot J, Levitt G, positron emission tomography imaging Sullivan I, Baxter L, Clegg A. No. 36 in selected cancers. A systematic review of the clinical, By Facey K, Bradbury I, Laking G, No. 28 public health and cost-effectiveness of Payne E. Adalimumab, etanercept and infliximab rapid diagnostic tests for the detection for the treatment of ankylosing and identification of bacterial intestinal No. 45 spondylitis: a systematic review and pathogens in faeces and food. The effectiveness and cost-effectiveness economic evaluation. By Abubakar I, Irvine L, Aldus CF, of carmustine implants and By McLeod C, Bagust A, Boland A, Wyatt GM, Fordham R, Schelenz S, et al. temozolomide for the treatment of Dagenais P, Dickson R, Dundar Y, et al. No. 37 newly diagnosed high-grade glioma: No. 29 A randomised controlled trial a systematic review and economic Prenatal screening and treatment examining the longer-term outcomes evaluation. strategies to prevent group B of standard versus new antiepileptic By Garside R, Pitt M, Anderson R, streptococcal and other bacterial drugs. The SANAD trial. Rogers G, Dyer M, Mealing S, et al. infections in early infancy: cost- By Marson AG, Appleton R, Baker effectiveness and expected value of GA, Chadwick DW, Doughty J, Eaton B, No. 46 information analyses. et al. Drug-eluting stents: a systematic review By Colbourn T, Asseburg C, Bojke L, and economic evaluation. Philips Z, Claxton K, Ades AE, et al. No. 38 By Hill RA, Boland A, Dickson R, Clinical effectiveness and cost- Dündar Y, Haycox A, McLeod C, et al. No. 30 effectiveness of different models Clinical effectiveness and cost- of managing long-term oral anti- No. 47 effectiveness of bone morphogenetic coagulation therapy: a systematic The clinical effectiveness and proteins in the non-healing of fractures review and economic modelling. cost-effectiveness of cardiac and spinal fusion: a systematic review. By Connock M, Stevens C, Fry-Smith resynchronisation (biventricular pacing) By Garrison KR, Donell S, Ryder J, A, Jowett S, Fitzmaurice D, Moore D, for heart failure: systematic review and Shemilt I, Mugford M, Harvey I, et al. et al. economic model. By Fox M, Mealing S, Anderson R, No. 31 No. 39 Dean J, Stein K, Price A, et al. A randomised controlled trial of A systematic review and economic postoperative radiotherapy following model of the clinical effectiveness No. 48 breast-conserving surgery in a and cost-effectiveness of interventions Recruitment to randomised trials: minimum-risk older population. The for preventing relapse in people with strategies for trial enrolment and PRIME trial. bipolar disorder. participation study. The STEPS study. By Prescott RJ, Kunkler IH, Williams By Soares-Weiser K, Bravo Vergel Y, By Campbell MK, Snowdon C, LJ, King CC, Jack W, van der Pol M, Beynon S, Dunn G, Barbieri M, Duffy S, Francis D, Elbourne D, McDonald AM, et al. et al. Knight R, et al. 261

No. 49 No. 4 No. 12 Cost-effectiveness of functional Does befriending by trained lay workers The clinical effectiveness and cost- cardiac testing in the diagnosis and improve psychological well-being and effectiveness of central venous catheters management of coronary artery quality of life for carers of people treated with anti-infective agents in disease: a randomised controlled trial. with dementia, and at what cost? A preventing bloodstream infections: The CECaT trial. randomised controlled trial. a systematic review and economic By Sharples L, Hughes V, Crean A, By Charlesworth G, Shepstone L, evaluation. Dyer M, Buxton M, Goldsmith K, et al. Wilson E, Thalanany M, Mugford M, By Hockenhull JC, Dwan K, Boland Poland F. A, Smith G, Bagust A, Dundar Y, et al. No. 50 No. 13 Evaluation of diagnostic tests when No. 5 Stepped treatment of older adults on there is no gold standard. A review of A multi-centre retrospective cohort laxatives. The STOOL trial. methods. study comparing the efficacy, safety By Mihaylov S, Stark C, McColl E, By Rutjes AWS, Reitsma and cost-effectiveness of hysterectomy Steen N, Vanoli A, Rubin G, et al. JB, Coomarasamy A, Khan KS, and uterine artery embolisation for Bossuyt PMM. the treatment of symptomatic uterine No. 14 fibroids. The HOPEFUL study. A randomised controlled trial of No. 51 By Hirst A, Dutton S, Wu O, Briggs cognitive behaviour therapy in Systematic reviews of the clinical A, Edwards C, Waldenmaier L, et al. adolescents with major depression effectiveness and cost-effectiveness of treated by selective serotonin reuptake proton pump inhibitors in acute upper No. 6 inhibitors. The ADAPT trial. gastrointestinal bleeding. Methods of prediction and prevention By Goodyer IM, Dubicka B, By Leontiadis GI, Sreedharan of pre-eclampsia: systematic reviews of Wilkinson P, Kelvin R, Roberts C, A, Dorward S, Barton P, Delaney B, accuracy and effectiveness literature Byford S, et al. Howden CW, et al. with economic modelling. By Meads CA, Cnossen JS, Meher S, No. 15 No. 52 Juarez-Garcia A, ter Riet G, Duley L, The use of irinotecan, oxaliplatin A review and critique of modelling in et al. and raltitrexed for the treatment of prioritising and designing screening advanced colorectal cancer: systematic programmes. No. 7 review and economic evaluation. By Karnon J, Goyder E, Tappenden The use of economic evaluations in By Hind D, Tappenden P, Tumur I, P, McPhie S, Towers I, Brazier J, et al. NHS decision-making: a review and Eggington E, Sutcliffe P, Ryan A. empirical investigation. No. 16 No. 53 By Williams I, McIver S, Moore D, Ranibizumab and pegaptanib for An assessment of the impact of the Bryan S. the treatment of age-related macular NHS Health Technology Assessment degeneration: a systematic review and Programme. No. 8 economic evaluation. By Hanney S, Buxton M, Green C, Stapled haemorrhoidectomy By Colquitt JL, Jones J, Tan SC, Coulson D, Raftery J. (haemorrhoidopexy) for the treatment Takeda A, Clegg AJ, Price A. of haemorrhoids: a systematic review and economic evaluation. No. 17 Volume 12, 2008 By Burch J, Epstein D, Baba-Akbari Systematic review of the clinical A, Weatherly H, Fox D, Golder S, et al. effectiveness and cost-effectiveness No. 1 of 64-slice or higher computed A systematic review and economic No. 9 tomography angiography as an model of switching from The clinical effectiveness of diabetes alternative to invasive coronary nonglycopeptide to glycopeptide education models for Type 2 diabetes: a angiography in the investigation of antibiotic prophylaxis for surgery. systematic review. coronary artery disease. By Cranny G, Elliott R, Weatherly H, By Loveman E, Frampton GK, By Mowatt G, Cummins E, Waugh N, Chambers D, Hawkins N, Myers L, et al. Clegg AJ. Walker S, Cook J, Jia X, et al.

No. 2 No. 10 No. 18 ‘Cut down to quit’ with nicotine Payment to healthcare professionals for Structural neuroimaging in psychosis: replacement therapies in smoking patient recruitment to trials: systematic a systematic review and economic cessation: a systematic review of review and qualitative study. evaluation. By Albon E, Tsourapas A, Frew E, effectiveness and economic analysis. By Raftery J, Bryant J, Powell J, Davenport C, Oyebode F, Bayliss S, et al. By Wang D, Connock M, Barton P, Kerr C, Hawker S. Fry-Smith A, Aveyard P, Moore D. No. 19 No. 11 Systematic review and economic No. 3 Cyclooxygenase-2 selective non- analysis of the comparative A systematic review of the effectiveness steroidal anti-inflammatory drugs effectiveness of different inhaled of strategies for reducing fracture risk (etodolac, meloxicam, celecoxib, corticosteroids and their usage with in children with juvenile idiopathic rofecoxib, etoricoxib, valdecoxib and long-acting beta2 agonists for the arthritis with additional data on long- lumiracoxib) for osteoarthritis and treatment of chronic asthma in adults term risk of fracture and cost of disease rheumatoid arthritis: a systematic and children aged 12 years and over. management. review and economic evaluation. By Shepherd J, Rogers G, Anderson By Thornton J, Ashcroft D, O’Neill T, By Chen Y-F, Jobanputra P, Barton P, R, Main C, Thompson-Coon J, 262 Elliott R, Adams J, Roberts C, et al. Bryan S, Fry-Smith A, Harris G, et al. Hartwell D, et al. DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

No. 20 No. 29 No. 2 Systematic review and economic analysis Absorbent products for urinary/faecal Thrombophilia testing in people with of the comparative effectiveness of incontinence: a comparative evaluation venous thromboembolism: systematic different inhaled corticosteroids and of key product categories. review and cost-effectiveness analysis. their usage with long-acting beta By Fader M, Cottenden A, Getliffe K, 2 By Simpson EL, Stevenson MD, agonists for the treatment of chronic Gage H, Clarke-O’Neill S, Jamieson K, Rawdin A, Papaioannou D. asthma in children under the age of 12 et al. years. By Main C, Shepherd J, Anderson R, No. 30 No. 3 Rogers G, Thompson-Coon J, Liu Z, et al. A systematic review of repetitive Surgical procedures and non-surgical functional task practice with modelling devices for the management of non- No. 21 of resource use, costs and effectiveness. apnoeic snoring: a systematic review of Ezetimibe for the treatment of By French B, Leathley M, Sutton C, clinical effects and associated treatment hypercholesterolaemia: a systematic McAdam J, Thomas L, Forster A, et al. costs. review and economic evaluation. By Main C, Liu Z, Welch K, Weiner By Ara R, Tumur I, Pandor A, Duenas No. 31 G, Quentin Jones S, Stein K. A, Williams R, Wilkinson A, et al. The effectiveness and cost-effectivness of minimal access surgery amongst No. 4 No. 22 people with gastro-oesophageal reflux Topical or oral ibuprofen for chronic disease – a UK collaborative study. The Continuous positive airway pressure knee pain in older people. The TOIB r e f l u x trial. devices for the treatment of obstructive study. By Grant A, Wileman S, Ramsay C, sleep apnoea–hypopnoea syndrome: a By Underwood M, Ashby D, Carnes Bojke L, Epstein D, Sculpher M, et al. systematic review and economic analysis. D, Castelnuovo E, Cross P, Harding G, By McDaid C, Griffin S, Weatherly H, et al. No. 32 Durée K, van der Burgt M, van Hout S, Time to full publication of studies of Akers J, et al. No. 23 anti-cancer medicines for breast cancer A prospective randomised comparison and the potential for publication bias: a No. 5 short systematic review. of minor surgery in primary and Use of classical and novel biomarkers secondary care. The MiSTIC trial. By Takeda A, Loveman E, Harris P, By George S, Pockney P, Primrose J, Hartwell D, Welch K. as prognostic risk factors for localised Smith H, Little P, Kinley H, et al. prostate cancer: a systematic review. No. 33 By Sutcliffe P, Hummel S, Simpson E, No. 24 Performance of screening tests for Young T, Rees A, Wilkinson A, et al. A review and critical appraisal child physical abuse in accident and of measures of therapist–patient emergency departments. No. 6 interactions in mental health settings. By Woodman J, Pitt M, Wentz R, The harmful health effects of By Cahill J, Barkham M, Hardy G, Taylor B, Hodes D, Gilbert RE. recreational ecstasy: a systematic review Gilbody S, Richards D, Bower P, et al. of observational evidence. No. 34 By Rogers G, Elston J, Garside R, No. 25 Curative catheter ablation in atrial Roome C, Taylor R, Younger P, et al. The clinical effectiveness and cost- fibrillation and typical atrial flutter: effectiveness of screening programmes systematic review and economic for amblyopia and strabismus in evaluation. No. 7 children up to the age of 4–5 years: By Rodgers M, McKenna C, Palmer S, Systematic review of the clinical a systematic review and economic Chambers D, Van Hout S, Golder S, et al. effectiveness and cost-effectiveness evaluation. of oesophageal Doppler monitoring By Carlton J, Karnon J, Czoski- No. 35 in critically ill and high-risk surgical Murray C, Smith KJ, Marr J. Systematic review and economic patients. modelling of effectiveness and cost By Mowatt G, Houston G, Hernández No. 26 utility of surgical treatments for men R, de Verteuil R, Fraser C, Cuthbertson A systematic review of the clinical with benign prostatic enlargement. B, et al. effectiveness and cost-effectiveness and By Lourenco T, Armstrong N, N’Dow economic modelling of minimal incision J, Nabi G, Deverill M, Pickard R, et al. total hip replacement approaches in No. 8 the management of arthritic disease of No. 36 The use of surrogate outcomes in the hip. Immunoprophylaxis against respiratory model-based cost-effectiveness analyses: By de Verteuil R, Imamura M, Zhu S, syncytial virus (RSV) with palivizumab a survey of UK Health Technology Glazener C, Fraser C, Munro N, et al. in children: a systematic review and Assessment reports. economic evaluation. By Taylor RS, Elston J. No. 27 By Wang D, Cummins C, Bayliss S, A preliminary model-based assessment Sandercock J, Burls A. No. 9 of the cost–utility of a screening Controlling Hypertension and programme for early age-related Hypotension Immediately Post Stroke macular degeneration. Volume 13, 2009 (CHHIPS) – a randomised controlled By Karnon J, Czoski-Murray C, Smith K, Brand C, Chakravarthy U, Davis S, trial. No. 1 By Potter J, Mistri A, Brodie F, et al. Deferasirox for the treatment of iron Chernova J, Wilson E, Jagger C, et al. overload associated with regular No. 28 blood transfusions (transfusional Intravenous magnesium sulphate haemosiderosis) in patients suffering No. 10 and sotalol for prevention of atrial with chronic anaemia: a systematic Routine antenatal anti-D prophylaxis fibrillation after coronary artery review and economic evaluation. for RhD-negative women: a systematic bypass surgery: a systematic review and By McLeod C, Fleeman N, Kirkham review and economic evaluation. economic evaluation. J, Bagust A, Boland A, Chu P, et al. By Pilgrim H, Lloyd-Jones M, Rees A. By Shepherd J, Jones J, Frampton GK, Tanajewski L, Turner D, Price A. 263

DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Health Technology Assessment Programme

Director, Deputy Director, Professor Tom Walley, Professor Jon Nicholl, Director, NIHR HTA Director, Medical Care Research Programme, Professor of Unit, University of Sheffield Clinical Pharmacology, University of Liverpool

Prioritisation Strategy Group Members

Chair, Dr Andrew Cook, Professor Paul Glasziou, Ms Lynn Kerridge, Professor Tom Walley, Consultant Advisor, NCCHTA Professor of Evidence-Based Chief Executive Officer, Director, NIHR HTA Medicine, University of Oxford NETSCC and NCCHTA Programme, Professor of Dr Peter Davidson, Clinical Pharmacology, Director of Science Support, Dr Nick Hicks, Dr Ruairidh Milne, University of Liverpool NCCHTA Director of NHS Support, Director of Strategy and NCCHTA Development, NETSCC Deputy Chair, Professor Robin E Ferner, Professor Jon Nicholl, Consultant Physician and Dr Edmund Jessop, Ms Kay Pattison, Director, Medical Care Research Director, West Midlands Centre Medical Adviser, National Section Head, NHS R&D Unit, University of Sheffield for Adverse Drug Reactions, Specialist, National Programme, Department of City Hospital NHS Trust, Commissioning Group (NCG), Health Dr Bob Coates, Birmingham Department of Health, London Consultant Advisor, NCCHTA Ms Pamela Young, Specialist Programme Manager, NCCHTA

HTA Commissioning Board Members

Programme Director, Professor Deborah Ashby, Professor Freddie Hamdy, Professor Ian Roberts, Professor Tom Walley, Professor of Medical Statistics, Professor of Urology, Professor of Epidemiology & Director, NIHR HTA Queen Mary, University of University of Sheffield Public Health, London School Programme, Professor of London of Hygiene and Tropical Clinical Pharmacology, Professor Allan House, Medicine University of Liverpool Professor John Cairns, Professor of Liaison Psychiatry, Professor of Health Economics, University of Leeds Professor Mark Sculpher, Chair, London School of Hygiene and Professor of Health Economics, Professor Jon Nicholl, Tropical Medicine Dr Martin J Landray, University of York Director, Medical Care Research Reader in Epidemiology, Unit, University of Sheffield Professor Peter Croft, Honorary Consultant Physician, Professor Helen Smith, Director of Primary Care Clinical Trial Service Unit, Professor of Primary Care, Deputy Chair, Sciences Research Centre, Keele University of Oxford University of Brighton Dr Andrew Farmer, University Senior Lecturer in General Professor Stuart Logan, Professor Kate Thomas, Practice, Department of Professor Nicky Cullum, Director of Health & Social Professor of Complementary & Primary Health Care, Director of Centre for Evidence- Care Research, The Peninsula Alternative Medicine Research, University of Oxford Based Nursing, University of Medical School, Universities of University of Leeds York Exeter and Plymouth Professor Ann Ashburn, Professor David John Professor of Rehabilitation Professor Jenny Donovan, Dr Rafael Perera, Torgerson, and Head of Research, Professor of Social Medicine, Lecturer in Medical Statisitics, Director of York Trials Unit, Southampton General Hospital University of Bristol Department of Primary Health University of York Care, Univeristy of Oxford Professor Steve Halligan, Professor Hywel Williams, Professor of Gastrointestinal Professor of Dermato- Radiology, University College Epidemiology, University of Hospital, London Nottingham

Observers

Ms Kay Pattison, Dr Morven Roberts, Section Head, NHS R&D Clinical Trials Manager, Programmes, Research and Medical Research Council Development Directorate, Department of Health 265

Diagnostic Technologies & Screening Panel Members

Chair, Dr Stephanie Dancer, Dr Anne Mackie, Dr W Stuart A Smellie, Professor Paul Glasziou, Consultant Microbiologist, Director of Programmes, UK Consultant in Chemical Professor of Evidence-Based Hairmyres Hospital, East National Screening Committee Pathology, Bishop Auckland Medicine, University of Oxford Kilbride General Hospital Dr Michael Millar, Deputy Chair, Professor Glyn Elwyn, Consultant Senior Lecturer in Dr Nicholas Summerton, Dr David Elliman, Primary Medical Care Research Microbiology, Barts and The Consultant Clinical and Public Consultant Paediatrician and Group, Swansea Clinical School, London NHS Trust, Royal Health Advisor, NICE Honorary Senior Lecturer, University of Wales London Hospital Great Ormond Street Hospital, Ms Dawn Talbot, London Dr Ron Gray, Mr Stephen Pilling, Service User Representative Consultant Clinical Director, Centre for Outcomes, Professor Judith E Adams, Epidemiologist, Department Research & Effectiveness, Dr Graham Taylor, Consultant Radiologist, of Public Health, University of Joint Director, National Scientific Advisor, Regional Manchester Royal Infirmary, Oxford Collaborating Centre for DNA Laboratory, St James’s Central Manchester & Mental Health, University University Hospital, Leeds Manchester Children’s Professor Paul D Griffiths, College London Professor of Radiology, Professor Lindsay Wilson University Hospitals NHS Turnbull, Trust, and Professor of University of Sheffield Mrs Una Rennard, Service User Representative Scientific Director of the Diagnostic Radiology, Imaging Dr Jennifer J Kurinczuk, Centre for Magnetic Resonance Science and Biomedical Consultant Clinical Dr Phil Shackley, Investigations and YCR Engineering, Cancer & Epidemiologist, National Senior Lecturer in Health Professor of Radiology, Hull Imaging Sciences, University of Perinatal Epidemiology Unit, Economics, School of Royal Infirmary Manchester Oxford Population and Health Ms Jane Bates, Sciences, University of Dr Susanne M Ludgate, Newcastle upon Tyne Consultant Ultrasound Medical Director, Medicines & Practitioner, Ultrasound Healthcare Products Regulatory Department, Leeds Teaching Agency, London Hospital NHS Trust

Observers

Dr Tim Elliott, Dr Catherine Moody, Dr Ursula Wells, Team Leader, Cancer Programme Manager, Principal Research Officer, Screening, Department of Neuroscience and Mental Department of Health Health Health Board

Pharmaceuticals Panel Members

Chair, Dr Peter Elton, Professor Jonathan Ledermann, Dr Martin Shelly, Professor Robin Ferner, Director of Public Health, Professor of Medical Oncology General Practitioner, Leeds, Consultant Physician and Bury Primary Care Trust and Director of the Cancer and Associate Director, NHS Director, West Midlands Centre Research UK and University Clinical Governance Support for Adverse Drug Reactions, Dr Ben Goldacre, College London Cancer Trials Team, Leicester City Hospital NHS Trust, Research Fellow, Division of Centre Birmingham Psychological Medicine and Dr Gillian Shepherd, Psychiatry, King’s College Dr Yoon K Loke, Director, Health and Clinical Deputy Chair, London Senior Lecturer in Clinical Excellence, Merck Serono Ltd Professor Imti Choonara, Pharmacology, University of Professor in Child Health, Mrs Barbara Greggains, East Anglia Mrs Katrina Simister, University of Nottingham Service User Representative Assistant Director New Professor Femi Oyebode, Medicines, National Prescribing Mrs Nicola Carey, Dr Bill Gutteridge, Consultant Psychiatrist Centre, Liverpool Senior Research Fellow, Medical Adviser, London and Head of Department, School of Health and Social Strategic Health Authority University of Birmingham Mr David Symes, Service User Representative Care, The University of Dr Dyfrig Hughes, Reading Dr Andrew Prentice, Reader in Pharmacoeconomics Senior Lecturer and Consultant Dr Lesley Wise, Mr John Chapman, and Deputy Director, Centre Obstetrician and Gynaecologist, Unit Manager, Service User Representative for Economics and Policy in The Rosie Hospital, University Pharmacoepidemiology Health, IMSCaR, Bangor of Cambridge Research Unit, VRMM, University Medicines & Healthcare Products Regulatory Agency Observers Mr Simon Reeve, Dr Heike Weber, Dr Ursula Wells, Ms Kay Pattison, Head of Clinical and Cost- Programme Manager, Principal Research Officer, Section Head, NHS R&D Effectiveness, Medicines, Medical Research Council Department of Health Programme, Department of Pharmacy and Industry Group, Health 266 Department of Health

Current and past membership details of all HTA Programme ‘committees’ are available from the HTA website (www.hta.ac.uk) DOI: 10.3310/hta13110 Health Technology Assessment 2009; Vol. 13: No. 11

Therapeutic Procedures Panel Members

Chair, Mrs Val Carlill, Mr Paul Hilton, Dr Kate Radford, Dr John C Pounsford, Service User Representative Consultant Gynaecologist Senior Lecturer (Research), Consultant Physician, North and Urogynaecologist, Royal Clinical Practice Research Bristol NHS Trust Mrs Anthea De Barton-Watson, Victoria Infirmary, Newcastle Unit, University of Central Service User Representative upon Tyne Lancashire, Preston Deputy Chair, Professor Scott Weich, Mr Mark Emberton, Professor Nicholas James, Mr Jim Reece Professor of Psychiatry, Division Senior Lecturer in Oncological Professor of Clinical Oncology, Service User Representative of Health in the Community, Urology, Institute of Urology, University of Birmingham, University of Warwick, Coventry University College Hospital, and Consultant in Clinical Dr Karen Roberts, London Oncology, Queen Elizabeth Nurse Consultant, Dunston Hill Professor Jane Barlow, Hospital Hospital Cottages Professor of Public Health in Professor Steve Goodacre, the Early Years, Health Sciences Professor of Emergency Dr Peter Martin, Research Institute, Warwick Medicine, University of Consultant Neurologist, Medical School, Coventry Sheffield Addenbrooke’s Hospital, Cambridge Ms Maree Barnett, Professor Christopher Griffiths, Acting Branch Head of Vascular Professor of Primary Care, Barts Programme, Department of and The London School of Health Medicine and Dentistry

Observers

Dr Phillip Leech, Dr Morven Roberts, Professor Tom Walley, Dr Ursula Wells, Principal Medical Officer for Clinical Trials Manager, Director, NIHR HTA Principal Research Officer, Primary Care, Department of Medical Research Council Programme, Professor of Department of Health Health Clinical Pharmacology, University of Liverpool Ms Kay Pattison, Section Head, NHS R&D Programme, Department of Health Disease Prevention Panel Members Chair, Dr John Jackson, Dr Julie Mytton, Dr Kieran Sweeney, Dr Edmund Jessop, General Practitioner, Parkway Locum Consultant in Public Honorary Clinical Senior Medical Adviser, National Medical Centre, Newcastle Health Medicine, Bristol Lecturer, Peninsula College Specialist, National upon Tyne Primary Care Trust of Medicine and Dentistry, Commissioning Group (NCG), Universities of Exeter and London Professor Mike Kelly, Miss Nicky Mullany, Plymouth Director, Centre for Public Service User Representative Deputy Chair, Health Excellence, NICE, Professor Carol Tannahill, Dr David Pencheon, London Professor Ian Roberts, Glasgow Centre for Population Director, NHS Sustainable Professor of Epidemiology and Health Development Unit, Cambridge Dr Chris McCall, Public Health, London School General Practitioner, The of Hygiene & Tropical Medicine Professor Margaret Thorogood, Dr Elizabeth Fellow-Smith, Hadleigh Practice, Corfe Professor of Epidemiology, Medical Director, West London Mullen, Dorset Professor Ken Stein, University of Warwick Medical Mental Health Trust, Middlesex Senior Clinical Lecturer in School, Coventry Ms Jeanett Martin, Public Health, University of Director of Nursing, BarnDoc Exeter Limited, Lewisham Primary Care Trust

Observers

Ms Christine McGuire, Dr Caroline Stone, Research & Development, Programme Manager, Medical Department of Health Research Council

267

Expert Advisory Network Members Professor Alan Horwich, Professor Miranda Mugford, Mr Jonothan Earnshaw, Professor Douglas Altman, Dean and Section Chairman, Professor of Health Economics Consultant Vascular Surgeon, Professor of Statistics in The Institute of Cancer and Group Co-ordinator, Gloucestershire Royal Hospital, Medicine, Centre for Statistics Research, London University of East Anglia in Medicine, University of Gloucester Oxford Professor Allen Hutchinson, Professor Jim Neilson, Professor Martin Eccles, Director of Public Health and Head of School of Reproductive Professor of Clinical Professor John Bond, Deputy Dean of ScHARR, & Developmental Medicine Effectiveness, Centre for Health Professor of Social Gerontology University of Sheffield and Professor of Obstetrics Services Research, University of & Health Services Research, and Gynaecology, University of Newcastle upon Tyne University of Newcastle upon Professor Peter Jones, Liverpool Tyne Professor of Psychiatry, Professor Pam Enderby, University of Cambridge, Mrs Julietta Patnick, Dean of Faculty of Medicine, Professor Andrew Bradbury, Cambridge National Co-ordinator, NHS Institute of General Practice Professor of Vascular Surgery, Cancer Screening Programmes, and Primary Care, University of Solihull Hospital, Birmingham Professor Stan Kaye, Sheffield Sheffield Cancer Research UK Professor Mr Shaun Brogan, of Medical Oncology, Royal Professor Robert Peveler, Professor Gene Feder, Chief Executive, Ridgeway Marsden Hospital and Institute Professor of Liaison Psychiatry, Professor of Primary Care Primary Care Group, Aylesbury of Cancer Research, Surrey Royal South Hants Hospital, Research & Development, Southampton Mrs Stella Burnside OBE, Centre for Health Sciences, Dr Duncan Keeley, Chief Executive, Regulation Barts and The London School General Practitioner (Dr Burch Professor Chris Price, and Improvement Authority, of Medicine and Dentistry & Ptnrs), The Health Centre, Director of Clinical Research, Belfast Thame Bayer Diagnostics Europe, Mr Leonard R Fenwick, Stoke Poges Ms Tracy Bury, Chief Executive, Freeman Dr Donna Lamping, Project Manager, World Hospital, Newcastle upon Tyne Research Degrees Programme Professor William Rosenberg, Confederation for Physical Director and Reader in Professor of Hepatology Mrs Gillian Fletcher, Therapy, London Psychology, Health Services and Consultant Physician, Antenatal Teacher and Tutor Research Unit, London School University of Southampton Professor Iain T Cameron, and President, National of Hygiene and Tropical Professor of Obstetrics and Childbirth Trust, Henfield Medicine, London Professor Peter Sandercock, Gynaecology and Head of the Professor of Medical Neurology, Professor Jayne Franklyn, School of Medicine, University Mr George Levvy, Department of Clinical Professor of Medicine, of Southampton Chief Executive, Motor Neurosciences, University of University of Birmingham Dr Christine Clark, Neurone Disease Association, Edinburgh Mr Tam Fry, Northampton Medical Writer and Consultant Dr Susan Schonfield, Honorary Chairman, Child Pharmacist, Rossendale Professor James Lindesay, Consultant in Public Health, Growth Foundation, London Professor Collette Clifford, Professor of Psychiatry for the Hillingdon Primary Care Trust, Professor of Nursing and Professor Fiona Gilbert, Elderly, University of Leicester Middlesex Consultant Radiologist and Head of Research, The Professor Julian Little, Dr Eamonn Sheridan, NCRN Member, University of Medical School, University of Professor of Human Genome Consultant in Clinical Genetics, Aberdeen Birmingham Epidemiology, University of St James’s University Hospital, Professor Barry Cookson, Professor Paul Gregg, Ottawa Leeds Professor of Orthopaedic Director, Laboratory of Hospital Professor Alistaire McGuire, Dr Margaret Somerville, Surgical Science, South Tees Infection, Public Health Professor of Health Economics, Director of Public Health Hospital NHS Trust Laboratory Service, London London School of Economics Learning, Peninsula Medical Bec Hanley, School, University of Plymouth Dr Carl Counsell, Professor Rajan Madhok, Co-director, TwoCan Associates, Clinical Senior Lecturer in Medical Director and Director Professor Sarah Stewart-Brown, West Sussex Neurology, University of of Public Health, Directorate Professor of Public Health, Aberdeen Dr Maryann L Hardy, of Clinical Strategy & Public Division of Health in the Professor Howard Cuckle, Senior Lecturer, University of Health, North & East Yorkshire Community, University of Professor of Reproductive Bradford & Northern Lincolnshire Warwick, Coventry Epidemiology, Department Health Authority, York Mrs Sharon Hart, Professor Ala Szczepura, of Paediatrics, Obstetrics & Healthcare Management Professor Alexander Markham, Professor of Health Service Gynaecology, University of Consultant, Reading Director, Molecular Medicine Research, Centre for Health Leeds Unit, St James’s University Services Studies, University of Professor Robert E Hawkins, Dr Katherine Darton, Hospital, Leeds Warwick, Coventry CRC Professor and Director Information Unit, MIND – The of Medical Oncology, Christie Dr Peter Moore, Mrs Joan Webster, Mental Health Charity, London CRC Research Centre, Freelance Science Writer, Consumer Member, Southern Professor Carol Dezateux, Christie Hospital NHS Trust, Ashtead Derbyshire Community Health Manchester Council Professor of Paediatric Dr Andrew Mortimore, Epidemiology, Institute of Child Professor Richard Hobbs, Public Health Director, Professor Martin Whittle, Health, London Head of Department of Primary Southampton City Primary Clinical Co-director, National Mr John Dunning, Care & General Practice, Care Trust Co-ordinating Centre for Consultant Cardiothoracic University of Birmingham Women’s and Children’s Dr Sue Moss, Health, Lymington Surgeon, Papworth Hospital Associate Director, Cancer NHS Trust, Cambridge Screening Evaluation Unit, Institute of Cancer Research, Sutton 268

Current and past membership details of all HTA Programme ‘committees’ are available from the HTA website (www.hta.ac.uk)

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