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technology report HTA Granulocyte-Colony Stimulating Issue 115 Factor for Antiviral-Associated December 2008 Neutropenia: Systematic Review *An amendment was made in February 2009 and Economic Evaluation
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Cite as: Dryden DM, Fassbender K, Doucette K, Tandon P, Milne A, Vandermeer B, Durec T. Granulocyte-colony stimulating factor for antiviral-associated neutropenia: Systematic review and economic evaluation [Technology report number 115]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2008.
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Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation
Donna M. Dryden, PhD1 Konrad Fassbender, PhD2 Karen Doucette, MD, MSc, FRCPC3 Puneeta Tandon, MD, MSc, FRCPC4 Andrea Milne, BScN1 Ben Vandermeer, MSc1 Tamara Durec, BSc Pharm, MLIS1
December 2008
1 University of Alberta Evidence-based Practice Center, Edmonton, AB 2 Division of Palliative Care Medicine, Department of Oncology, University of Alberta, Edmonton, AB 3 Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, AB 4 Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB
Reviewers These individuals kindly provided comments on this report:
External Reviewers Tanya Horsley, PhD Peter Ghali, MD FRCPC MSc(Epid) Adjunct Faculty Assistant Professor of Medicine Epidemiology and Community Medicine McGill University Health Centre University of Ottawa Montréal, QC Ottawa, ON
Kevork M Peltekian, MD David Robinson, PhD Associate Professor, Medicine Associate Professor Dalhousie University Laurentian University Halifax, NS Sudbury, ON
Rick Audas, BBA MBA MA PhD Assistant Professor Memorial University St. John’s, NL
CADTH Peer Review Group Reviewers Chris Skedgel, MDE Jeffrey Barkun, MD MSc FRCSC Research Health Economist Chairman, Division of General Surgery Department of Medicine McGill University Health Centre Dalhousie University Montréal, QC Halifax, NS
Industry: Amgen Canada Inc. was provided with an opportunity to comment on an earlier version of this report. All comments that were received were considered when preparing the final report.
This report is a review of existing public literature, studies, materials, and other information and documentation (collectively the “source documentation”) that are available to CADTH. The accuracy of the contents of the source documentation on which this report is based is not warranted, assured, or represented in any way by CADTH and CADTH does not assume responsibility for the quality, propriety, inaccuracies, or reasonableness of any statements, information, or conclusions contained in the source documentation.
CADTH takes sole responsibility for the final form and content of this report. The statements and conclusions in this report are those of CADTH and not of its Panel members or reviewers.
i Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation Authorship Donna Dryden coordinated the project, selected trials, extracted data, performed quality assessment, summarized and interpreted data, and contributed to writing all sections of the report.
Konrad Fassbender, the lead for the economic analysis, developed the methods for the economic analysis; selected studies; extracted, tabulated, and analyzed data; and wrote the economic sections of the report.
Karen Doucette, a content expert in clinical medicine and hepatitis C, provided guidance on the development of the clinical and economic review methods, interpreted data, and contributed to writing all sections of the report.
Puneeta Tandon, a content expert in clinical medicine and hepatitis C, provided guidance on the development of the clinical and economic review methods, interpreted data, and contributed to writing all sections of the report.
Andrea Milne selected trials, extracted data, performed quality assessment, summarized data, and contributed to writing and formatting all sections of the report.
Ben Vandermeer performed the statistical analyses, provided methodological and statistical advice, and contributed to writing the analysis and results section of the report.
Tamara Durec designed and executed the literature search strategies, wrote the associated search strategy section of the report and appendix, and managed the bibliographic software.
All authors contributed to the revision of the report.
Acknowledgements The authors are grateful to Elizabeth Sumamo, Carol Spooner, Jennifer Seida, Kate O’Gorman, and Mohammad Karkhaneh for their assistance with the clinical review and to Lisa Tjosvold for her assistance with the literature search strategy.
Conflicts of Interest Karen Doucette received funding for consulting from Hoffman-La Roche Ltd. Schering-Plough Canada, and Astellas Pharma Inc.. Puneeta Tandon received funding in-kind from Novartis Pharmaceuticals Canada Inc. for conducting research. Funding received for both authors was unrelated to this topic. All other authors declared no conflict of interest.
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: ii Systematic Review and Economic Evaluation
iii Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation EXECUTIVE SUMMARY
Issue In Canada, the standard therapy for hepatitis C is pegylated interferon in combination with ribavirin. The goal of antiviral therapy is to achieve a sustained virological response (SVR), which is thought to represent a clinical cure. Given the appropriate dose and duration of pegylated interferon and ribavirin therapy, 42% to 46% of genotype 1 and 72% to 80% of genotype 2 or 3 patients will achieve SVR. To obtain optimal response rates, maximal treatment adherence to pegylated interferon and ribavirin is required. Side effects have resulted in the need to reduce the dose or discontinue therapy in up to 30% of patients. In clinical trials, neutropenia, a hematological disorder characterized by an abnormally low number of neutrophils (a type of white blood cell), is the most common reason for pegylated interferon dose reduction. The standard of care for controlling neutropenia is a dose reduction of pegylated interferon. To maintain full-dose antiviral therapy, the use of granulocyte-colony stimulating factor (G-CSF) has been proposed as a means to control neutropenia. There is uncertainty about the cost- effectiveness of G-CSF in comparison with dose reduction.
Objectives The aim was to evaluate the clinical efficacy, safety, and cost-effectiveness of G-CSF (filgrastim or pegfilgrastim) for the treatment of antiviral-associated neutropenia in adults with hepatitis C. To achieve these objectives, the following research questions were addressed: • What is the clinical-effectiveness of G-CSF in improving clinical markers (neutrophil count), patient outcomes (SVR, infection, survival), and health-related quality of life compared with interferon dose reduction or treatment discontinuation? • What, if any, differences in harm are there between G-CSF monotherapy and G-CSF plus epoetin (or darbepoetin) combination therapy? • What is the cost-effectiveness of G-CSF, and what is the impact on health resources of funding G-CSF compared with interferon dose reduction or treatment discontinuation? • Are there specific reimbursement criteria (for example, disease severity, hepatitis C virus genotype, type of interferon used) that would allow the optimal use of G-CSF in this population?
Clinical Review Methods: A systematic review was conducted to identify controlled trials and observational studies that assessed the effect of G-CSF or dose reduction strategies to control neutropenia in treatment- naïve adults with hepatitis C being treated with combination interferon and ribavirin. The outcomes were neutrophil count, early virological response, SVR, health-related quality of life, complications, and adverse effects of G-CSF. Data were summarized using descriptive statistics.
Results: Two small clinical trials of low methodological quality compared the effectiveness of filgrastim with interferon dose reduction to control neutropenia. One randomized controlled trial defined neutropenia as neutrophil counts less than 0.75×109/L and reported the rate of SVR for those receiving G-CSF as 54.5% [95% confidence interval (CI) 34.7 to 73.1] compared with 26.3% (95% CI 11.8 to 48.8) for dose reduction. One controlled clinical trial defined neutropenia as neutrophil counts less than 1.0×109/L and reported the rate of SVR for those receiving G-CSF
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: iv Systematic Review and Economic Evaluation as 30.0% (95% CI 14.5 to 51.9) compared with 21.1% (95% CI 8.5 to 43.3) for dose reduction. Based on these two trials, a relationship between SVR and G-CSF has not been shown. A retrospective cohort study compared patients who developed neutropenia and received G-CSF with patients who did not develop neutropenia and completed the full course of antiviral therapy. In the G-CSF group, 61.9% (95% CI 40.9 to 79.2) achieved SVR compared with 76.5% (95% CI 52.7 to 90.4) in the non-G-CSF group. This study provided evidence that patients who were treated with G-CSF may maintain the optimal dose and duration of antiviral therapy. The impact on SVR is not established.
The risk of adverse effects that was associated with G-CSF was low (14.1%; 95% CI 8.6 to 22.3). The most common adverse effects were bone pain, rash, body aches, headache, and splenomegaly. Overall, they were clinically mild and transient, required only supportive interventions, and caused no long-term consequences. The risk of infection that was associated with neutropenia (neutrophil counts less than 0.75×109/L) in patients with hepatitis C was low (1.9%; 95% CI 0.3 to 9.8). Infections that occurred were minor, did not lead to hospitalization, were treated with antibiotic or antifungal agents, and were resolved without long-term consequences.
Economic Analysis Methods: Cost-effectiveness and cost-utility analyses were conducted to evaluate the cost- effectiveness of G-CSF compared with pegylated interferon dose reduction strategies.
Results: G-CSF (filgrastim), when compared with pegylated interferon dose reduction strategies, yields an incremental cost-effectiveness ratio of $42,737 per SVR achieved or $7,785 per quality-adjusted life year (QALY) gained for patients with genotype 1 infection and $17,151 per SVR or $3,124 per QALY gained for patients with genotype 2 or 3.
Health Services Impact Based on base-case assumptions and the definition of neutropenia as neutrophil counts less than 0.75×109/L, an additional $11,881 per person is required to treat patients with genotype 1 infection, and an additional $4,065 per person is required for patients with genotype 2 or 3. An additional $1,333,584 is required to manage all cases of neutropenia in Canada. With a more conservative definition of neutropenia (neutrophil counts less than 0.5×109/L), an additional $236,451 is required to manage all cases of neutropenia.
Conclusion The clinical review did not show a superiority of G-CSF versus pegylated interferon dose reduction for achieving SVR. Whereas the administration of G-CSF may enable patients to stay on or resume optimal antiviral therapy compared with patients who receive a reduced pegylated interferon dose, the evidence that this improves outcomes is weak. At baseline values, G-CSF compared with pegylated interferon dose reduction may be perceived as cost-effective if decision makers pay $7,785 for a QALY. Concluding that G-CSF compared with pegylated interferon dose reduction is cost-effective may be premature in light of the weak clinical data. The economic analysis will focus future efforts in gathering additional evidence. In the meantime, techniques such as program-budgeting marginal-analysis are available to decision makers for evaluating this evidence and setting priorities.
v Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation ABBREVIATIONS
CCT controlled clinical trial CI confidence interval EVR early virological response G-CSF granulocyte-colony stimulating factor HCV hepatitis C virus HIV human immunodeficiency virus IQR interquartile range NOS Newcastle-Ottawa Scale OR odds ratio QALY quality-adjusted life year RCT randomized controlled trial RNA ribonucleic acid RR risk ratio RVR rapid virological response SVR sustained virological response
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: vi Systematic Review and Economic Evaluation
vii Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation TABLE OF CONTENTS
EXECUTIVE SUMMARY ...... iv
ABBREVIATIONS ...... vi
1 INTRODUCTION...... 1 1.1 Background ...... 1 1.2 Current Clinical Practice...... 1 1.3 Overview of Technology...... 2
2 THE ISSUE ...... 3
3 OBJECTIVES ...... 3
4 CLINICAL REVIEW ...... 4 4.1 Methods...... 4 4.1.1 Literature search strategy...... 4 4.1.2 Selection criteria and method...... 5 4.1.3 Data extraction...... 6 4.1.4 Strategy for quality assessment ...... 6 4.1.5 Data analysis methods ...... 7 4.2 Results ...... 8 4.2.1 Quantity of research available...... 8 4.2.2 Industry contact...... 10 4.2.3 Quality of included studies...... 11 4.2.4 Data analysis and synthesis...... 13
5 ECONOMIC ANALYSIS ...... 17 5.1 Review of Economic Evaluations: Methods ...... 17 5.1.1 Literature search strategy...... 17 5.1.2 Selection criteria and method...... 18 5.1.3 Data extraction strategy...... 19 5.1.4 Utilization information ...... 19 5.2 Review of Economic Evaluations: Results ...... 19 5.2.1 Literature search...... 19 5.2.2 Study characteristics...... 21 5.2.3 Utilization information ...... 22 5.3 Canadian Economic Evaluation: Methods...... 22 5.3.1 Type of economic evaluation...... 22 5.3.2 Target population...... 23 5.3.3 Comparators...... 23 5.3.4 Perspective...... 23 5.3.5 Resource use and costs...... 24 5.3.6 Discount rate ...... 25 5.3.7 Modelling assumptions...... 25 5.3.8 Valuing outcomes...... 27 5.3.9 Handling variability and uncertainty...... 29
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: viii Systematic Review and Economic Evaluation 5.4 Canadian Economic Evaluation: Results ...... 29 5.4.1 Base case: Expected costs ...... 29 5.4.2 Base case: Expected outcomes ...... 29 5.4.3 Base case: Cost-effectiveness analysis ...... 30 5.4.4 Sensitivity analysis...... 30
6 HEALTH SERVICES IMPACT...... 36 6.1 Population Impact...... 36 6.2 Budget Impact ...... 37 6.3 Ethical, Equity, and Psychosocial Issues ...... 38
7 DISCUSSION...... 38 7.1 Clinical Results...... 38 7.2 Effectiveness...... 39 7.3 Safety ...... 40 7.4 Economic Analysis...... 40 7.5 Limitations ...... 41 7.6 Generalizability of Findings ...... 42 7.7 Knowledge Gaps...... 43
8 CONCLUSIONS...... 43
9 REFERENCES...... 44
APPENDICES – available from CADTH’s website www.cadth.ca
APPENDIX 1 Literature Search Strategies APPENDIX 2: Excluded Studies — Clinical Review APPENDIX 3: Excluded Studies — Economic Review APPENDIX 4: Forms APPENDIX 5: General Characteristics of Effectiveness and Safety Studies APPENDIX 6: Participants, Antiviral Therapy, Neutropenia Therapy and Outcomes APPENDIX 7: Safety Outcomes for Patients with Neutropenia APPENDIX 8: Methodological Quality of Studies Included for Clinical Review
ix Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation 1 INTRODUCTION 1.1 Background
The prevalence of hepatitis C in Canada is estimated to be 0.8% (251,000 Canadians). Approximately 5,000 persons are newly infected each year.1 There are six genotypes of hepatitis C virus (HCV). Genotype 1 accounts for more than 60% of cases in Canada, followed by type 2 (11% to 16%), type 3 (6% to 14%), and types 4, 5, and 6 (less than 5%).2,3
Between 70% and 80% of people who are infected with HCV will develop chronic infection, which may lead to progressive liver fibrosis.2,4,5 Approximately 20% of those with chronic infection will develop cirrhosis, which will progress to liver failure and, less often, hepatocellular carcinoma.4,5 Hepatitis C is the leading indication for liver transplantation in Canada.6,7
Among prevalent HCV infections in Canada, exposure occurs though injection drug use (56%), followed by blood transfusions (13%), blood products for hemophilia (less than 1%), and other modes of transmission (30%).8 Many cases of incident hepatitis C infections in Canada result from injection drug use — up to 80% of new cases are related to substance abuse, with 10% to 20% of these persons being co-infected with HIV and other infections.9 A large proportion of the infections occur in vulnerable populations that include persons with low income and unstable housing.
1.2 Current Clinical Practice
The standard therapy for HCV is pegylated interferon in combination with ribavirin.10-13 In Canada, ribavirin and pegylated interferon are packaged together (Table 1). The two formulations of pegylated interferon, pegylated interferon-alpha-2a (Pegasys RBV, Hoffmann-La Roche Ltd., Canada), and pegylated interferon-alpha-2b (Pegetron, Schering-Plough Canada Inc.) differ in the size and configuration of the polyethylene glycol molecules that are bound to the interferon molecule. The two formulations seem to be equally effective in therapy.14
The goal of HCV therapy is to achieve a sustained virological response (SVR), which is the absence of serum HCV ribonucleic acid (RNA) 24 weeks after treatment. This is thought to represent clinical cure. Less than 1% of those achieving SVR are documented to have virologic relapse in long-term follow up.15 By measuring the HCV RNA level in the blood at different times, the early virological response (EVR) and rapid virological response (RVR) predict how likely a patient is to respond to therapy (obtain an SVR). EVR is defined as a 2 or greater log drop in HCV RNA or as being HCV RNA negative at week 12. RVR is being HCV RNA negative at week 4.
Given the appropriate dose and duration of pegylated interferon and ribavirin, between 42% and 46% of genotype 1 patients who are treated for 48 weeks and between 72% and 80% of genotype 2 or 3 patients who are treated for 24 weeks will achieve a SVR.10-13 To maximize the response rates to HCV therapy, full treatment adherence to pegylated interferon and ribavirin is required.15 The side effects have resulted in a need to reduce the dose or discontinue therapy in up to 30% of patients.11-13,16,17
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 1 Systematic Review and Economic Evaluation Table 1: Antiviral Treatment of Hepatitis C in Canada Brand Name, PEG IFN Formulation, Ribavirin Dose Duration of Manufacturer PEG IFN Dose Therapy Genotype 1 Pegasys RBV, PEG IFN-alpha-2a, 1,000 mg to 1,200 mg/day given 48 weeks Hoffmann-La 180 µg sc weekly orally in 2 divided doses; dose Roche Ltd., depends on whether patient weighs Canada more or less than 75 kg Pegetron, PEG IFN-alpha-2b, 800 mg to 1,200 mg/day given 48 weeks Schering-Plough 1.5 µg/kg sc weekly orally in 2 divided doses; dose Canada, Inc. depends on patient’s weight (800 mg if <64 kg; 1,000 mg if 64 kg to <85 kg; 1,200 mg if >85 kg) Genotype 2 or 3 Pegasys RBV, PEG IFN-alpha-2a, 800 mg/day given orally in 2 equal 24 weeks Hoffmann-La 180 µg sc weekly doses Roche Ltd., Canada Pegetron, PEG IFN-alpha-2b, 800 mg/day given orally in 2 equal 24 weeks Schering-Plough 1.5 µg/kg sc weekly doses Canada, Inc.
PEG IFN=pegylated interferon; RBV=ribavirin; sc=subcutaneously.
In clinical trials, neutropenia is the most common cause of pegylated interferon dose reduction.10- 12,18 Between 30% and 50% of patients on HCV therapy experience a fall in neutrophil counts within the first two weeks of therapy.10-13,19 Although neutrophil counts can fall to levels that have been associated with an increased risk of bacterial infections, much of the research on this topic is based on oncology patients who are receiving chemotherapy. It is unclear whether patients with HCV without similar comorbidities have a similar risk of infection.20
Pegylated interferon dose reductions or the addition of granulocyte-colony stimulating factor (G- CSF) is recommended by most experts when the neutrophil count falls below 0.5×109/L.10,21 Although the package inserts for Pegasys RBV and Pegetron suggest dose reductions if the neutrophil count falls below 0.7×109/L and recommend discontinuation if the neutrophil count falls below 0.5×109/L, Canadian guidelines suggest that dose reductions are unnecessary until the neutrophil count falls below 0.5×109/L and that discontinuation occur only if the neutrophil count falls below 0.3×109/L.10 Because suboptimal doses of pegylated interferon have a negative impact on SVR rates, G-CSF has been used to maintain the pegylated interferon dose.10,21
1.3 Overview of Technology
In Canada, two hematopoietic growth factors act on granulocytes: filgrastim (Neupogen, Amgen Manufacturing Ltd., Thousand Oaks, California) and pegfilgrastim (Neulasta, Amgen Manufacturing Ltd., Thousand Oaks, California) (Table 2). G-CSF increases neutrophil production and enhances the phagocytic and cytotoxic functions of neutrophils. Pegfilgrastim is a new pegylated G-CSF agent with a longer duration of action than filgrastim.
2 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation Table 2: Granulocyte Colony Stimulating Factor in Canada Brand Name, Manufacturer Generic Name Formulation and Dosage Neupogen, Amgen Filgrastim 300 µg/1 mL vial; sc 1 to 3 times/week, Manufacturing Ltd. 480 µg/1 mL vial; sc 1 to 3 times/week Neulasta, Amgen Pegfilgrastim 6 mg/syringe; sc weekly Manufacturing Ltd.
sc=subcutaneous.
G-CSF seems to be well tolerated. The most common reported adverse effect is mild to moderate bone pain secondary to proliferation of neutrophils in the bone marrow.22 Local skin reactions may also occur with subcutaneous injection. The marked granulocytosis that may occur with prolonged therapy is unaccompanied by clinical morbidity and can be avoided with close monitoring. Rare occurrences of splenic rupture with G-CSF therapy have been documented in case reports.23
In Canada, the reimbursement policies of publicly funded drug plans for G-CSF are generally limited to patients with cancer who develop neutropenia. Yukon, Ontario, Québec, and New Brunswick provide reimbursement on a case-by-case basis for patients with chronic hepatitis C who develop neutropenia. Most jurisdictions do not have a reimbursement policy for this patient population.
2 THE ISSUE
In Canada, the current standard of care for controlling neutropenia during antiviral therapy for hepatitis C patients is dose reduction of interferon. Research has shown that the efficacy of antiviral therapy to achieve SVR is diminished as a result of dose reduction. To maintain full- dose therapy, the use of G-CSF has been proposed as a means to control neutropenia. There is uncertainty about the cost-effectiveness of G-CSF in comparison with dose reduction. To develop clinical guidelines and allocate resources, decision makers need to know if G-CSF is more effective and cost-effective than dose reduction of interferon in controlling neutropenia.
3 OBJECTIVES
A systematic review and primary economic analysis were performed to evaluate the clinical efficacy, safety, and cost-effectiveness of G-CSF monotherapy (filgrastim or pegfilgrastim) for the treatment of antiviral-associated neutropenia in treatment-naïve (not previously treated with antiviral therapy) adults with chronic hepatitis C infection.
To achieve these objectives, the following research questions were addressed: • What is the clinical efficacy of G-CSF in improving clinical markers (for example, neutrophil count) compared with interferon dose reduction or treatment discontinuation?
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 3 Systematic Review and Economic Evaluation • What is the clinical-effectiveness of G-CSF in improving patient outcomes (for example, SVR, infection, survival) compared with interferon dose reduction or treatment discontinuation? • What is the clinical-effectiveness of G-CSF in improving health-related quality of life compared with interferon dose reduction or treatment discontinuation? • What, if any, differences in harm are there between G-CSF monotherapy and G-CSF plus epoetin (or darbepoetin) combination therapy? • What is the cost-effectiveness of adding G-CSF compared with interferon dose reduction or treatment discontinuation? • What is the impact on health resources (including publicly funded drug plan budgets) of funding filgrastim or pegfilgrastim compared with interferon dose reduction or treatment discontinuation? • Are there specific reimbursement criteria (for example, disease severity, HCV genotype, type of interferon used) that would allow the optimal use of G-CSF in this population?
4 CLINICAL REVIEW 4.1 Methods
The methods for this systematic review were described in a protocol that was developed a priori.
4.1.1 Literature search strategy
Comprehensive searches were developed by an information specialist (TD) who used pre- defined search terms (Appendices 1.1 and 1.2). Searches were conducted in the following electronic databases: ABI/INFORM Global (ProQuest) (1971 to 2007), Academic Search Premier (1975 to 2007), BIOSIS Previews (1969 to 2007), CINAHL Plus with Full Text (through EBSCOhost) (1937 to 2007), Cochrane Central Register of Controlled Trials (1900 to 2007), Cochrane Database of Systematic Reviews (4th Quarter, 2007), Database of Abstracts of Reviews of Effects (1994 to 2007), EMBASE (1988 to 2008 Week 12), Health Source: Nursing/Academic Edition (1975 to 2007), Health Technology Assessment Database (HTA) through The Cochrane Library (4th Quarter 2007), International Pharmaceutical Abstracts (1970 to October 2007), Ovid HealthSTAR (1966 to September 2007), Ovid MEDLINE (1950 to March Week 3 2008), Ovid MEDLINE In-Process & Other Non-Indexed Citations (March 27, 2008), Pascal (1987 to September 2007), PubMed, Science Citation Index Expanded (1900 to 2008), and Social Sciences Citation Index (1956 to 2008). We also searched for studies of adverse effects in the US National Library of Medicine’s TOXLINE (1965 to 2007) and Health Canada’s Adverse Drug Reaction Database. No language restrictions were applied.
Grey literature was identified by searching other specialized databases and websites for conference abstracts, theses, dissertations, and health technology assessments (Appendices 1.1, 1.2, and 1.3). As needed, authors of included studies were contacted for additional information.
Electronic searches were supplemented by manual searches of reference lists of included studies and hand-searching scientific meeting abstracts for the last five years in Hepatology, Journal of
4 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation Viral Hepatitis, Canadian Journal of Gastroenterology, Journal of Viral Hepatology, and Journal of Hepatology (Appendix 1.3).
The original searches were performed from October 29 to November 2, 2007. In March 2008, the searches were updated using the original search strategies in MEDLINE, EMBASE, and Web of Science. The citations were managed using Reference Manager, Version 11 bibliographic software (Thomson ISI ResearchSoft, Carlsbad, CA).
Amgen Canada Inc. was contacted by the Canadian Agency for Drugs and Technologies in Health (CADTH) for information about unpublished, completed, or ongoing studies that examined the efficacy or safety of filgrastim (Neupogen) or pegfilgrastim (Neulasta) for the treatment of antiviral-associated neutropenia in patients with hepatitis C.
4.1.2 Selection criteria and method
a) Selection criteria Screening criteria A study was considered to be not relevant if it met one of the following criteria: • letter, editorial, or lay press article • more than 50% of participants younger than 18 years old (data reported separately) • patients did not have hepatitis C (for example, hepatitis B patients, cancer patients without diagnosed hepatitis C) • patients were not receiving pegylated or non-pegylated interferon in combination with ribavirin • patients did not have neutropenia.
The original inclusion criteria for the intervention were modified after the completion of preliminary screening. In the protocol, a study was required to compare the administration of G- CSF with dose reduction or discontinuation of antiviral therapy due to neutropenia. Because this was considered to be too restrictive, the inclusion criteria were broadened so that one of the three interventions to manage neutropenia (G-CSF, dose reduction, or discontinuation of antiviral therapy) was sufficient.
Inclusion criteria To be included, a study must have met all the following criteria: • Publication type: report of primary research (clinical investigations were performed to collect primary data) • Study design: clinical trial, controlled before-and-after study, prospective or retrospective observational study (cohort, interrupted time series, case series, case control) • Population: more than 50% adult patients (data pertaining to adults 18 years of age or older reported separately) who are treatment-naïve for antiviral therapy, who are receiving combination antiviral therapy (pegylated or non-pegylated interferon in combination with ribavirin), and who have antiviral-induced neutropenia (as defined by the study authors). Non- treatment-naïve patients form a heterogeneous group with lower SVR rates than treatment- naïve patients. Treatment-naïve patients were selected as the focus for this report to gain a clear understanding of the potential efficacy and safety of G-CSF exclusive of other possible confounders such as lower SVR rates.
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 5 Systematic Review and Economic Evaluation • Intervention: administration of G-CSF (filgrastim or pegfilgrastim), dose reduction of antiviral therapy due to neutropenia, or discontinuation of antiviral therapy due to neutropenia; no restrictions on the dose of G-CSF or on the strategy for dose reduction • Outcome: numeric data on at least one outcome of interest (neutrophil count, RVR, EVR, SVR, health-related quality of life as measured by the study authors, complications such as bacterial or fungal infections, other complications as defined by the study authors, or adverse effects of G-CSF as defined by the study authors).
b) Selection method The screening that was based on the titles, abstracts, and keywords of each study was conducted by one of four reviewers (DD, ES, JS, AM). The screening criteria were applied as broadly as possible to ensure that only irrelevant studies were excluded. The full-text reports of all potentially relevant articles and of articles that were designated as “unclear” were retrieved for review. The level of agreement between the reviewers was evaluated using the Kappa (κ) statistic. A κ score in the range from 0.0 to 0.40 was considered to be poor agreement; 0.41 to 0.60 moderate agreement, and 0.61 to 0.80 substantial agreement.24 This phase was repeated on 10% samples until moderate agreement was reached.
Two of five reviewers (DD, ES, JS, AM, CS) independently examined the full text of all the studies that were classified as “potentially relevant” and “unclear” using a standard form (Appendix 4) containing the inclusion and exclusion criteria. Disagreements were initially resolved by consensus between two reviewers. When this was not possible, a third party (PT, KD) arbitrated. The decision to exclude a study was documented (Appendix 2).
4.1.3 Data extraction
Data were extracted by one of five reviewers (ES, AM, CS, MK, KO) using a pre-tested data extraction form (Appendix 4). A second reviewer verified the data before entering them into a Microsoft Word (2003) table (Microsoft Corporation, Redmond, WA). The data that were extracted included study design, population characteristics, antiviral therapy, definition of neutropenia, practice pattern for the treatment of neutropenia (for example, type, dosage and duration of G-CSF, protocol for dose reduction or discontinuation of antiviral therapy), measures of efficacy, and any reported adverse events that were related to G-CSF or infections.
The tables that summarize the characteristics of the included studies include information on the source of the article, study design, setting, treatment groups, inclusion and exclusion criteria, sample size, study quality, and outcomes with effect sizes.
4.1.4 Strategy for quality assessment
The methodological quality of each study depends on internal and external validity. Internal validity, which is considered to be the most important element of study quality, is the confidence that the design, conduct, and report of a trial prevent or reduce bias in the outcomes.25
Four tools were used to assess the randomized controlled trials (RCTs), non-randomized controlled clinical trials (CCTs), cohort studies, and case series studies (Appendix 4). The methodological quality of RCTs was assessed using the Jadad scale26 and the Schulz criteria for
6 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation allocation concealment.25 The former is a validated five-point scale with three items that require a yes or a no answer and that are related to internal validity: randomization, double-blinding, and a description of withdrawals and dropouts. The Schulz tool is based on empirical evidence of a strong relationship between concealment of allocation and biased estimates of effect.25
CCTs were assessed using a modified Jadad scale. The scale includes two items that require a yes or a no answer and that are related to internal validity: double-blinding and a description of withdrawals and dropouts. The reliability and validity of this scale have not been formally tested. Therefore, the components of the scale were reported for each study, and no overall indicator of quality was calculated.
Cohort studies were assessed using the Newcastle-Ottawa Scale (NOS).27 The scale is used to assess the methodological quality of studies across sample selection, comparability of study groups, and ascertainment of the outcome of interest. The NOS identifies eight components in prospective observational designs. The scale’s face and content validity and inter-rater reliability have been established. The components of the scale were reported for each study, and no overall indicator of quality was calculated.
For the case series, we developed a 14-item tool that focused on the risk of selection bias (six questions), attrition bias (one question), detection bias (four questions), and assessment bias (three questions). The reliability and validity of this tool have not been formally tested. Preliminary evaluation shows that it captures information about the features of a well-conducted case series study.28
Two reviewers (CS, AM) independently evaluated the methodological quality of each included study. Disagreements were resolved by consensus between the two reviewers or adjudicated by a third party (DD), when necessary.
4.1.5 Data analysis methods
Data were summarized using descriptive statistics [for example, proportions and percentages for categorical data, means and standard deviations, or medians with interquartile ranges (IQRs) for continuous data]. When a standard deviation was not reported, it was calculated from the standard error. For dichotomous outcomes, the risk ratio (RR) was calculated with 95% confidence intervals (CIs). For continuous outcomes, the weighted mean difference (WMD) or standardized mean difference (SMD) was calculated. Evidence tables summarize study characteristics; study populations; antiviral therapy; definition of neutropenia; type, dose, and duration of G-CSF administration; dose reduction strategies; patient outcomes; and adverse events.
Adverse events risks and 95% CIs were calculated from individual studies. CIs were computed using the normal scores method. Subtotals comparing trial data with observational studies and a pooled estimate for all studies that contributed data were provided. Studies that did not report data for adverse events were excluded. No assumption was made that if an event was not reported it did not occur.
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 7 Systematic Review and Economic Evaluation We planned to use meta-analyses to derive pooled estimates.29 Because the definition of neutropenia was inconsistent across studies, it was inappropriate to combine the studies. Therefore, data from the included studies were synthesized qualitatively. Dichotomous summaries between groups were compared using Fisher’s exact test.30 We planned to use a quantitative assessment of publication bias, but there were too few included studies to conduct the rank correlation test, weighted regression, and the trim and fill method.31
4.2 Results
4.2.1 Quantity of research available
The searches of electronic databases resulted in the identification of 9,372 records. Of these, 9,194 were excluded. The full texts of the 178 potentially relevant studies were assessed using more detailed inclusion criteria (Appendix 4). Fifty-six additional studies were identified through the grey literature searches and hand-searching. The updated search identified an additional 591 citations from which 26 potentially relevant citations were identified during screening. The overall level of agreement among reviewers for this phase was moderate (κ=0.45).
Of the 260 potentially relevant reports, 20 studies were considered to be relevant.32-51 Of these, five47-51 were considered to be multiple publications of other published studies,33,37-39 yielding 15 unique studies to address the effectiveness35,36,39,40,44-46 and safety32-34,37,38,41-43 research questions. Figure 1 shows the process of study selection.
a) Study characteristics Fifteen studies were included in this clinical review: one RCT,40 one CCT,36 two retrospective cohort studies,35,37 and 11 case series with no controls32-34,38,39,41-46 (Appendix 5). The studies were published between 1999 and 2007 (median year of publication was 2004). Most of the studies (9/15) were conducted in the United States, with others being conducted in France, Georgia, Germany, Greece, Italy, and Mexico (one study each). The number of study participants ranged from eight to 255. Ten studies33-35,37,40,42-46 were published as full manuscripts, and five were published only in abstract form.32,36,38,39,41
b) Study funding and setting One study reported receiving industry funding.43 The remaining studies did not report their funding source. Ten studies were conducted in one centre,34,35,38-42,44-46 and four were multi- centre studies.33,36,37,43 One study did not report the study setting.32 Ten studies35-38,40,41,43-46 occurred in university or teaching hospitals, two in a community or outpatient setting,34,42 and three did not specify the setting32,33,39 (Appendix 5).
c) Antiviral therapy The formulation of combination antiviral therapy varied across studies (Appendix 6). For interferon, the formulations included pegylated interferon-alpha-2a,33,34,40 pegylated interferon- alpha-2b,36,38,43-45 pegylated interferon not otherwise specified,39,41 and pegylated interferon- alpha-2a or pegylated interferon-alpha-2b.35,37,46 In two studies, the formulation of interferon was not provided.32,42 For ribavirin, dosages included 800 mg per day,34,39,46 1,000 to 1,200 mg per day,33,34,37,38,40,42 800 to 1,200 mg per day,35 800 to 1,400 mg per day,36,39,43 600 to 1,200 mg per day,44 and 400 to 1,000 mg per day.45
8 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation Figure 1: Clinical Literature Search Results
Number of citations from electronic searches and retrieved for screening: 9,372
Excluded: 9,194
Potentially relevant studies for inclusion: 178
Grey literature and Total potentially relevant hand-searching: 56 studies for inclusion: 234
Search update Excluded: 240 (March 2008) • Ineligible study design (58) 260 • Not correct population (122) (591 citations studies retrieved): 26 • Not correct intervention (26) • No outcomes of interest (13) • Insufficient data (12) • Unavailable (9)
Included studies: 20 (5 multiple publications) N=15 unique studies
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 9 Systematic Review and Economic Evaluation d) Neutropenia The definition of neutropenia varied across studies (Table 3 and Appendix 7). In six studies, patients were considered to have neutropenia when their neutrophil count fell below 0.75×109/L.32,33,38-40,43 In five studies they were considered to have neutropenia when their neutrophil count fell below 1.0×109/L.35-37,41,46 In two studies, neutropenia was defined as neutrophil counts below 1.5×109/L. The administration of G-CSF or the modification of antiviral therapy was not triggered until neutrophil counts fell below 0.75×109/L.34,42 In one study neutropenia was defined as a white blood cell count less than 3,000/µL.44 In another, it was defined as a white blood cell count less than 2,000/nL.45
e) Granulocyte-colony stimulating factor products Of the 11 studies that examined patients who were receiving G-CSF, seven33,35,36,39,44-46 did not specify the product that was used (Table 3 and Appendix 7). Four studies reported using filgrastim.32,40,41,43 G-CSF was administered subcutaneously. The dose and schedule varied across studies: 300 μg per week,35,40 300 μg two times per week,39 150 μg to 300 μg two times per week,36 150 μg to 200 μg three times per week,43 300 μg to 480 μg weekly to three times per week,41 300 μg per day,44 and 5 μg per kilogram two times per week.45 Three studies did not report the dosage.32,33,46 Based on the reported dosages, we assumed filgrastim was the G-CSF product that was administered.
f) Populations Participants ranged in age from 21 to 68 years. Five studies33,34,36,38,43 reported the mean and standard deviation of patients’ age. One reported mean and range.42 One study reported only the mean,35 three the median and range,44-46 one the median and IQR,37 one only the median,32 and one only the range.40 In two studies, the age was not reported.39,41 The median of the reported mean ages among the seven studies was 47 years (IQR 46 to 48).
Thirteen (86.7%) studies reported the distribution of patients by sex.32-38,40,42-46 The proportion of male patients ranged from 46% to 83% (median 68.8%; IQR 53.8 to 77.0). Eleven studies (73.3%) provided information on genotype.33-36,38,40,42-46 The proportion of patients who were genotype 1 ranged from 50%38 to 100%33,36,40 (median 77.1%; IQR 72.0 to 90.5) (Appendix 5). Three (20.0%) studies focused on liver transplant recipients with hepatitis C recurrence after transplantation.44-46 No included studies examined the use of G-CSF by hepatitis C patients who were co-infected with HIV.
g) Resources No data were reported regarding personnel involved or resources used in treating or monitoring patients with neutropenia. As part of the protocol regarding therapy for hepatitis C, patients were scheduled for regular follow-up visits in an outpatient setting to monitor the efficacy, safety, and tolerance of the antiviral therapy.34,35,39,40,43,45
4.2.2 Industry contact
Because Neupogen and Neulasta are not indicated for the treatment of antiviral-therapy-induced neutropenia in patients with hepatitis C, Amgen Canada Inc. did not provide relevant clinical or utilization data for this report.
10 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation 4.2.3 Quality of included studies
a) Randomized controlled trial The methodological quality of the RCT40 was low (Jadad score 2/5). The RCT lacked a description of the method of randomization. Double-blinding was not reported. The trial reported withdrawals or dropouts and accounted for all participants. The concealment of allocation was unclear (Appendix 8 and Table 1).
b) Controlled clinical trial The methodological quality of the CCT36 was low based on the NOS score. The trial reported withdrawals or dropouts and accounted for all participants. Double-blinding was not reported (Appendix 8 and Table 2).
c) Cohort studies The quality of the two retrospective cohort studies35,37 was considered to be good based on the NOS scores (Appendix 8 and Table 3). In both studies, the participants were considered to be representative of hepatitis C patients with antiviral-associated neutropenia, and selection bias was minimized by the choice of a comparison group from the same population as the exposed group. The exposure for both groups was ascertained using medical records, and all patients were free of the outcome of interest at the start of the investigation. Both studies reported that groups were similar in baseline characteristics, and both studies conducted multivariate analyses to control for confounders. In both studies, the assessment of outcome was independent and blinded. The follow-up period was considered to be long enough for the outcomes of interest to occur, and there was a complete follow-up of patients.
d) Case series studies with no controls The quality of the 11 case series studies32-34,38,39,41-46 was assessed using risk of bias criteria. The median number of items that were positively identified (a lower risk of bias) was 11/14 (IQR 9 to 11). All 11 case series fulfilled at least half of the risk of bias criteria, and six (54.5%) satisfied 11 or more (Appendix 8 and Table 4). Six questions that were related to selection bias were examined in each study. The source population for the included patients was indicated in 10 studies, and seven specified the inclusion criteria. Four studies reported that the study population consisted of a consecutive series of patients. The reporting of patient characteristics ranged from 72.7% (8/11) for genotype and 81.8% (9/11) for age. The risk of attrition bias was based on reporting losses to follow-up and dropout. All 11 studies reported losses to follow-up of less than 10%. In terms of detection bias, 10 studies described the trigger point for managing neutropenia, and seven described the protocol for managing neutropenia. Five studies reported adverse effects, and five reported on infections due to neutropenia. Regarding assessment bias, all studies stated the primary outcome, and 10 described how the primary outcome was assessed. All studies reported the impact that neutropenia had on the course of antiviral therapy.
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 11 Systematic Review and Economic Evaluation Table 3: Effectiveness Outcomes for Patients with Neutropenia Author Number of Number in Treatment Comparison Group (IFN DR Outcomes for Patients with Neutropenia Patients with Group (G-CSF); Type of or no treatment) N (%) Neutropenia (%), G-CSF; Dose of G-CSF Definition of Neutropenia Koirala35 30 (50%), neutrophil 30; NR; 300 µg sc 1/week 30 did not have neutropenia EVR 23/30 (76.7) (G-CSF) versus 27/30 (90.0) count <1.0× 109/L (DR as needed for (no treatment); SVR 13/21 (61.9) (G-CSF) 8/30 patients) versus 13/17 (76.5) (no treatment) Koskinas36 39 (100%), 20; NR; 150 to 300 µg sc 19 escalating DR for 2 weeks or EVR 12/20 (60.0) (G-CSF) versus 9/19 (47.4) neutrophil count 2/week DC for 1 to 2 weeks in (DR/DC); SVR 6/20 (30) versus 4/19 (21.0) <1.0× 109/L unresolved cases (DR/DC) Senkbeil39 10 (20%), neutrophil 9; NR; 300 µg 2/week+DR NA 8/9 resumed full dose of PEG IFN; SVR 2/8 count <0.75× 109/L of PEG IFN by 0.5 µg/kg (25) until neutrophil count >1.25×109/L Sharvadze40 41 (100%), 22; filgrastim; 300 µg sc 19 PEG IFN DR when SVR 12/22 (54.4) G-CSF versus 5/19 (26.3) neutrophil count 1/week neutrophil count <0.75×109/L, DR/DC, DC AVT 0/22 (0) <0.75× 109/L DC when neutrophil count <0.5× 109/L until neutrophil count >1.0×109/L Liver transplant recipients Gopal44 10 (83.3), white 7/10; NR; 300 µg sc 3 IFN DR 7/7 (G-CSF) resumed full dose of IFN; SVR 1/7 blood cell count (14.3) <3,000/µL Neumann45 15 (60.0), white 11 IFN DR+G-CSF; NR; 4 PEG IFN DR to 0.5 mg/kg SVR 6/15 (40.0); 5/11 (45.5) (G-CSF+DR) blood cell count 5 μg/kg 2/week 2/week versus 1/4 (25.0) (DR only) <2,000/nL Sharma46 21 (60.0), neutrophil 6 IFN DR+G-CSF; NR; NR 10 PEG IFN DR SVR 9/21 (42.9) (patient with neutropenia); 3/6 count <1.0× 109/L (50.0) (G-CSF+DR); no data for DR group AVT=antiviral therapy; DC=discontinued; DR=dose reduction; EVR=early virological response; IFN=interferon; G-CSF=granulocyte-colony stimulating factor; NA=not applicable; NR=not reported; PEG=pegylated; pt=patient; sc=subcutaneously; SVR=sustained virological response.
12 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation e) Summary Overall, the quality of the included studies was low. The RCT was given a Jadad score that indicated low methodological quality, and the concealment of allocation was unclear. The CCT received a point for one component of the Jadad scale. The methodological quality of the observational studies (cohort and case series) was generally good. Observational studies, however, have a higher risk of bias because of their design. Therefore, the strength of the conclusions of this systematic review must be interpreted in light of the quality of the primary literature.
4.2.4 Data analysis and synthesis
a) Clinical-effectiveness analysis G-CSF versus interferon dose reduction (neutrophil count less than 0.75×109/L) One RCT40 involving 41 participants with neutropenia [G-CSF (filgrastim) = 22, pegylated interferon dose reduction or temporary discontinuation = 19] provided data comparing the effect of G-CSF versus interferon dose reduction on SVR (Table 3). All patients in this trial had genotype 1 infection. No patients who received G-CSF required dose reduction or discontinuation of pegylated interferon. The rate of SVR among patients who received G-CSF was higher than for patients who had a dose reduction. The RR was 2.07; 95% CI 0.89 to 4.82 [12/22 (54.5%; 95% CI 34.7 to 73.1) versus 5/19 (26.3%; 95% CI 11.8 to 48.8), P=0.12].
In a case series39 of 50 patients receiving a standard course of antiviral therapy, 10 (20.0%) developed neutropenia and required a dose reduction of pegylated interferon (Table 3). Nine patients were also given G-CSF. Of these, eight were able to resume a full dose of interferon. The rate of SVR for those who resumed their pegylated interferon was 2/8 (25.0%; 95% CI 7.1 to 59.1) versus 0/2 (0.0%; 95% CI 0.0 to 77.6) for those who did not resume full pegylated interferon therapy (P=1.00). The rate of SVR for the 27 patients who did not require any dose reduction of antiviral therapy was 14/27 (51.9%). No data were reported for genotype.
G-CSF versus interferon dose reduction (neutrophil count less than 1.0×109/L) In Koskinas et al.’s36 CCT, 20 patients with neutropenia were assigned to receive G-CSF and 19 patients were assigned to undergo dose reduction or temporary discontinuation of pegylated interferon (Table 3). All patients had genotype 1. The rates of EVR and SVR among patients who received G-CSF were higher than those for patients who had a dose reduction. The differences were not statistically significant — EVR RR=1.27; 95% CI 0.70 to 2.29 [12/20 (60.0%; 95% CI 38.7 to 78.1) versus 9/19 (47.4%; 95% CI 27.38 to 68.3), P=0.53]; SVR RR=1.43; 95% CI 0.48, 4.27 [6/20 (30.0%; 95% CI 14.5 to 51.9) versus 4/19 (21.1%; 95% CI 8.5 to 43.3), P=0.72].
In Koirala et al.’s35 cohort study, 30 patients who developed neutropenia and received G-CSF were compared with 30 patients who did not develop neutropenia and completed the full course of pegylated interferon and ribavirin (Table 3). Overall, 70% of the cohort had genotype 1. The outcomes were not reported by genotype. At the end of antiviral therapy, 23/30 (76.7%; 95% CI 59.1 to 88.2) of the G-CSF patients had achieved EVR compared with 27/30 (90.0%; 95% CI 74.4 to 96.5) of the non-G-CSF group (RR=0.85; 95% CI 0.68 to 1.07). The difference between groups was not statistically significant (P=0.30). Six months after completion of antiviral therapy, 13/21 (61.9%; 95% CI 40.9 to 79.2) in the G-CSF group achieved SVR compared with
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 13 Systematic Review and Economic Evaluation 13/17 (76.5%; 95% CI 52.7 to 90.4) in the non-G-CSF group (RR=0.81; 95% CI 0.53 to 1.24). The difference between groups was not statistically significant (P=0.49). Among the patients who received G-CSF, two discontinued antiviral therapy because of severe depression, pancreatitis, and thrombocytopenia.
Other outcomes None of the included studies reported data on health-related quality of life or on long-term survival (beyond 24 weeks after completion of antiviral treatment). None of the deaths that were reported in the studies were attributed to neutropenia, infections, or G-CSF.
Liver transplant recipients Three case series studies examined liver transplant patients with recurrent hepatitis C (Table 3).44-46 In Gopal et al.’s study,44 12 patients were treated with pegylated interferon and ribavirin. Ten (83.3%) patients were diagnosed with neutropenia (white blood cell count less than 3,000/µL) and required a dose reduction of pegylated interferon. Seven (70.0%) patients also received G-CSF, and all seven were able to resume taking full dose pegylated interferon. One patient in the case series achieved SVR. This patient had received G-CSF.
In Neumann et al.’s case series,45 15 of 25 patients (60.0%) developed a white blood cell count below 2,000/nL and required a dose reduction of pegylated interferon. Eleven (73.3%) patients also received G-CSF. SVR was achieved in 45.5% (5/11) of the patients who received G-CSF. Among the four patients who had pegylated interferon dose reduction but no G-CSF, one (25.0%) achieved SVR.
Sharma et al.46 reported that 21 of 35 patients (60.0%) had neutropenia (neutrophil count less than 1.0×109/L). Of these, six were treated with G-CSF plus a dose reduction of pegylated interferon, and four had a dose reduction of pegylated interferon. Nine of 21 (42.9%) patients with neutropenia achieved SVR. Three of the six patients who received G-CSF plus a dose reduction achieved SVR.
Summary Two clinical trials compared the effectiveness of G-CSF and interferon dose reduction to control neutropenia in patients who received combination antiviral therapy. Different definitions of neutropenia were used. This precluded the pooling of data in a meta-analysis. One RCT defined neutropenia as neutrophil counts less than 0.75×109/L and reported the rate of SVR for those receiving G-CSF as 54.5% compared with 26.3% for dose reduction (P=0.12). One CCT defined neutropenia as neutrophil counts less than 1.0×109/L and reported the rate of SVR for those receiving G-CSF as 30.0% compared with 21.1% for dose reduction (P=0.72). Based on these two trials, the relationship between SVR and G-CSF has not been demonstrated.
b) Safety analysis Total adverse effects related to G-CSF Five studies (one RCT,40 one CCT,36 three observational32,41,43) provided data on the safety of G- CSF (Appendix 7). In one study,35 the number of patients who reported adverse effects is unknown. Therefore, the data are not included in the analysis (Table 4). The pooled risk of an adverse effect that was related to G-CSF was 14.1 (95% CI 8.6 to 22.3). All estimates came from the observational studies.
14 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation The adverse effects that were related to G-CSF included bone pain,35,43 rash,35 body aches,43 headache,41 and an enlarged spleen.43 Most studies indicated that the adverse effects were clinically insignificant, were transient, only required supportive interventions, and caused no follow-up sequelae. Two studies reported that one patient each discontinued G-CSF treatment because of rash35 and severe headache.41
Table 4: Risk of Adverse Effects Associated with G-CSF Author Proportion with Event (n/N) Absolute Risk (95% CI) Clinical trials Koskinas36 0/20 0.0 (0.0 to 11.9) Sharvadze40 0/22 0.0 (0.0 to 11.0) Sub-total 0/42 0.0 (0.0 to 6.1) Observational studies Ball32 0/7 0.0 (0.0 to 27.9) Sood41 1/12 8.3 (1.5 to 35.4) Younossi43 13/38 34.2 (21.2 to 50.1) Subtotal 14/57 24.6 (15.2 to 37.1) Total 14/99 14.1 (8.6 to 22.3)
CI=confidence interval; G-CSF=granulocyte-colony stimulating factor.
Total adverse effects related to G-CSF plus epoetin or darbepoetin One study43 provided data on the safety of G-CSF (filgrastim) plus darbepoetin alpha (26 patients). Adverse effects included gastric disturbance (1/26; 3.8%), musculoskeletal symptoms (bone pain, joint pain, body aches) (8/26; 30.1%), splenomegaly (1/26; 3.8%), and nonspecific symptoms (dizziness after injection, dyspnea, fatigue, insomnia) (5/26; 19.2%). None of the adverse effects was considered to be serious, and none required hospitalization.
Infections due to neutropenia Seven studies (one CCT,36 six observational33-35,37,38,42) provided data on the risk of infection among patients with neutropenia. The rates of infections were evaluated for patients with neutrophil counts less than 0.75×109/L33,34,38,42 and neutrophil counts less than 1.0×109/L34-37,42 (Tables 5 and 6). The pooled risk of an infection for patients with neutrophil counts less than 0.75×109/L was 1.9 (95% CI 0.3 to 9.8). The pooled risk of an infection for patients with neutrophil counts less than 1.0×109/L was 9.6 (95% CI 6.6 to 13.9). All infections were reported in observational studies.
In Soza et al.’s case series,42 a bacterial infection was reported by 22 of 119 (18.5%) patients who received antiviral treatment. Episodes of infection were defined as a confirmed (by bacterial culture or positive radiograph) or suspected infection, which led to oral or parenteral antibiotic therapy up to four weeks after stopping therapy. None of the patients who developed an infection had pre-existing neutropenia (neutrophil counts less than 1.5×109/L) and none developed neutropenia (neutrophil counts less than 1.0×109/L) during antiviral treatment. The authors reported that neutropenia was not associated with infection in univariate or multivariate analyses.
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 15 Systematic Review and Economic Evaluation Table 5: Risk of Infection among Patients with Neutropenia (neutrophil count less than 0.75x109/L) Author Proportion with Event (n/N) Absolute Risk (95% CI) Observational studies Jeffers33 0/34 0.0 (0.0 to 7.4) Juarez-Navarro34 1/3 33.3 (6.1 to 79.2) Renou38 0/4 0.0 (0.0 to 40.4) Soza42 0/13 0.0 (0.0 to 17.2) Total 1/54 1.9 (0.3 to 9.8)
CI=confidence interval.
Table 6: Risks of Infection among Patients with Neutropenia (neutrophil count <1.0x109/L) Author Proportion with Event (n/N) Absolute Risk (95% CI) CCT Koskinas36 0/39 0.0 (0.0 to 6.5) Subtotal 0/39 0.0 (0.0 to 6.5) Observational studies Juarez-Navarro34 16/95 16.8 (10.6 to 25.6) Koirala35 0/30 0.0 (0.0 to 8.3) Puoti37 8/85 9.4 (4.8 to 17.5) Subtotal 24/210 11.4 (7.8 to 16.4) Total 24/249 9.6 (6.6 to 13.9)
CCT=controlled clinical trial; CI=confidence interval.
In Puoti et al.’s retrospective cohort study,37 31 infections were recorded in 255 (12.2%) patients who were treated with ribavirin plus standard interferon (103 patients) and pegylated interferon (152 patients). Infections were defined as confirmed (by bacterial culture or positive chest x-ray) or suspected localized or systemic febrile events, which led to oral or parenteral antibiotic therapy up to four weeks after stopping therapy. Eight of the infections were diagnosed in patients with neutrophil counts less than 1.0×109/L (8/85, 9.4%), and all eight were upper or lower respiratory infections. None of the non-respiratory infections was observed in patients with neutropenia. The infections were successfully managed on an outpatient basis. In a stratified Cox’s proportional hazards regression analysis, the authors reported that neutropenia was associated with a higher risk of respiratory infection (hazard ratio=5.6; 95% CI 1.5 to 24.4, adjusted for pegylated interferon usage).
In Juarez-Navarro et al.’s case series,34 a bacterial infection was documented in 33 of 209 (15.8%) patients who received antiviral treatment. All were classified as mild infection, and all resolved with a short course of oral antibiotic or antifungal agent. Of the 33 infections, 16 (48.5%) occurred in patients with neutrophil counts less than 1.5×109/L. Of these 16, one patient had neutrophil counts less than 0.75×109/L. The authors concluded that neutropenia is not associated with a higher rate of infection or with severe infections in patients who are on combined therapy with pegylated interferon and ribavirin.
16 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation The four remaining studies reported that there were no serious infections among the patients with neutropenia. They did not provide details about how infections were identified or classified.
Summary Patients with neutropenia as a result of antiviral therapy were at low risk of infection. When infections occurred, most were of minor consequence and did not lead to hospitalization or modification of antiviral therapy.
5 ECONOMIC ANALYSIS
The economic analysis involved a review of economic literature and an economic evaluation. The methods were described in an a priori protocol.
5.1 Review of Economic Evaluations: Methods
5.1.1 Literature search strategy
Comprehensive searches were developed by an information specialist who used predefined search terms (Appendices 1.1 and 1.2). Searches were conducted in the following electronic databases: Academic Search Premier (1975 to 2007), BIOSIS Previews (1969 to 2007), CINAHL Plus with Full Text (through EBSCOhost) (1937 to 2007), Cochrane Central Register of Controlled Trials (1900 to 2007), Cochrane Database of Systematic Reviews (4th Quarter, 2007), Database of Abstracts of Reviews of Effects (1994 to 2007), EMBASE (1988 to 2008 Week 12), Health Source: Nursing/Academic Edition (1975 to 2007), Health Technology Assessment Database (HTA) through The Cochrane Library (4th Quarter 2007), International Pharmaceutical Abstracts (1970 to October 2007), Ovid HealthSTAR (1966 to September 2007), Ovid MEDLINE (1950 to March Week 3 2008), Ovid MEDLINE In-Process & Other Non- Indexed Citations (March 27, 2008), Pascal (1987 to September 2007), PubMed, Science Citation Index Expanded (1900 to 2008) and Social Sciences Citation Index (1956 to 2008). We also searched for studies of adverse effects in the National Library of Medicine’s TOXLINE (1965 to 2007) and Health Canada’s Adverse Drug Reaction Database. No language restrictions were applied.
Grey literature was identified by searching other specialized databases and websites for conference abstracts, theses, dissertations, and health technology assessment (Appendix 1.1, Appendix 1.2, Appendix 1.3).
Electronic searches were supplemented by manual searches of reference lists of included studies and hand-searching scientific meeting abstracts for the last five years in Hepatology, Journal of Viral Hepatitis, Canadian Journal of Gastroenterology, Journal of Viral Hepatology, and Journal of Hepatology (Appendix 1.3).
The original searches were performed October 29 to November 2, 2007. In March 2008, the searches were updated using the original search strategies in MEDLINE, EMBASE, and Web of
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 17 Systematic Review and Economic Evaluation Science. The citations were managed using Reference Manager, Version 11 bibliographic software (Thomson ISI ResearchSoft, Carlsbad, CA).
5.1.2 Selection criteria and method
a) Selection criteria Screening criteria A study was considered to be not relevant if it met one of the following criteria: • letter, editorial, or lay press article • more than 50% of participants who were younger than 18 years old (data to be reported separately) • patients did not have hepatitis C (for example, patients with hepatitis B, patients who had cancer without diagnosed hepatitis C) • patients were not receiving interferon (pegylated or non-pegylated) in combination with ribavirin • patients did not have neutropenia.
Inclusion and exclusion criteria To be included, a study must have met one of the following criteria: • Population: more than 50% adult patients (data pertaining to adults 18 years of age and older to be reported separately) who are treatment-naïve for antiviral therapy, who are receiving combination antiviral therapy (pegylated or non-pegylated interferon in combination with ribavirin), and who have antiviral-induced neutropenia (as defined by the study authors) • Intervention: administration of G-CSF (filgrastim or pegfilgrastim), dose reduction of antiviral therapy due to neutropenia, or discontinuation of antiviral therapy due to neutropenia; no restrictions on the dose of G-CSF or strategy for dose reduction • Outcome: numeric data on at least one outcome of interest (neutrophil count, RVR, EVR, SVR, health-related quality of life as measured by the study authors, complications such as bacterial or fungal infections, other complications as defined by the study authors), adverse effects of G-CSF (as defined by the study authors).
b) Selection method The electronic and grey literature searches for the economic review produced the same results as those produced for the clinical review. Therefore, the literature selection was done concurrently with the selection for the clinical review. The screening that was based on the titles and abstracts of each study was conducted by one of four reviewers (DD, ES, JS, AM). The screening criteria were applied as broadly as possible to the titles, abstracts, and keywords to ensure that only irrelevant studies were excluded. The full texts of all potentially relevant articles and of articles that were designated as “unclear” were retrieved for review. The level of agreement between the reviewers was evaluated using the Kappa (κ) statistic. A κ score from 0.0 to 0.40 was considered to be poor agreement; 0.41 to 0.60 moderate agreement; and 0.61 to 0.80 substantial agreement.24
Two of five reviewers (DD, ES, JS, AM, CS) independently appraised the full text of all the studies that were classified as “potentially relevant” and “unclear” using the inclusion and exclusion criteria that were listed on a standard form. Disagreements about the inclusion or exclusion of studies were initially resolved by consensus between two reviewers. When this was
18 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation not possible, a third party arbitrated (PT, KD). The decision to exclude a study was documented (Appendix 3).
5.1.3 Data extraction strategy
Data were extracted by one of a possible five reviewers (ES, AM, CS, MK, KO) using a pre- tested data extraction form (Appendix 4). A second reviewer verified the data before entry into a Microsoft Word (2003) table (Microsoft Corporation, Redmond, WA). Data on study design, population characteristics, treatment outcomes, adverse events, and resource use and costs were extracted.
5.1.4 Utilization information
CADTH contacted Brogan Inc. to obtain an analysis of hepatitis C patients who were using G- CSF (filgrastim or pegfilgrastim) concurrently with antiviral therapy (Pegetron or Pegasys RBV). Brogan Inc. has access to claim data from two public drug plans (Ontario Drug Benefits and Alberta Health and Wellness) and maintains the Brogan Inc. Private Payer database of drug benefits claims that are paid by private insurers. It is estimated that the database includes approximately 65% of private drug plan prescription activity in Canada.
The study period for the analysis was July 1, 2002 to March 31, 2008. Treatment-naïve patients were identified by examining the claims history to confirm that the patient did not have any claims for antiviral therapy six months before the initial claim during the index period (January 1, 2003 to December 31, 2006). For each year (2003 to 2006) treatment-naïve patients were identified from the initial claim and tracked for the following 15 months. Treatment-naïve patients were included in the cohort if they had a claim for antiviral therapy and at least one claim for G-CSF within one year of the initial claim for antiviral therapy.
5.2 Review of Economic Evaluations: Results
5.2.1 Literature search
Figure 2 shows the process of study selection. The electronic searches resulted in 9,372 citations. No additional citations were identified through the economic searches beyond those captured through the searches for the clinical review. Of the 9,372 citations, 9,194 were considered to be “obviously irrelevant” and were excluded. The full text of the 178 potentially relevant citations was assessed using more detailed inclusion criteria. An additional 56 studies were identified through grey literature searches and hand-searching. The updated search identified an additional 591 citations from which screening identified 26 potentially relevant citations. The level of agreement among reviewers for the inclusion and exclusion phase was moderate (κ=0.45). Of the 260 potentially relevant reports, 23 studies11,12,32-43,47-55 were considered to be relevant to a cost- effectiveness evaluation of G-CSF for the treatment of antiviral-therapy-induced neutropenia in patients with hepatitis C. Of these, five47-51 were considered to be multiple publications of other published studies, yielding 18 unique studies.
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 19 Systematic Review and Economic Evaluation Figure 2: Economic Literature Search Results
Studies retrieved from electronic searches for screening: 9,372
Excluded: 9,194
Potentially relevant studies for inclusion: 178
Grey literature and Total potentially relevant hand-searching: 56 studies for inclusion: 234
Excluded: 237 Search update • Ineligible study design (56) • Not correct population (122) (March 2008) 260 • Not correct intervention (26) (591 citations retrieved): 26 studies • No outcomes of interest (11) • Insufficient data (13) • Unavailable (9)
Included 23 (5 multiple publications): 18 unique studies
Health economic evaluation: 1 Cost and probability data: 17 unique studies
20 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation 5.2.2 Study characteristics a) General characteristics There was one economic evaluation.53 Of the remaining studies, 1232-43 were included in the clinical review, and five11,12,52,54,55 provided additional probability data that allowed us to construct a model of resource use and rates of SVR that were associated with the use of G-CSF and dose reduction in the control of neutropenia. b) Summary of economic evaluation Chapko and Dominitz53 evaluated the cost-effectiveness of G-CSF as an alternative to standard pegylated interferon dose reduction strategies in patients with neutropenia (Table 7). The base- case analysis reported the cost per additional SVR using G-CSF instead of dose reduction was $115,870 for patients with genotype 1 and $134,628 for patients with genotype 2 or 3. The cost per QALY gained was $16,247 for genotype 1 and $18,877 for genotype 2 or 3 patients. The authors found that the cost per added SVR increased when pegylated interferon dose reduction had a smaller effect on SVR. Their results were also sensitive to the use of different sources for cost estimates.
Table 7: Characteristics of Economic Evaluation of G-CSF Source Chapko and Dominitz53 Study objective* Evaluate cost-effectiveness of G-CSF as alternative to standard PEG IFN dose reduction strategies in patients with neutropenia during anti-hepatitis C therapy Alternative compared Dose reduction of PEG IFN Methods Source of Relationship between dose reduction and EVR or SVR: 2 RCTs effectiveness QALYs gained once SVR is achieved: cost-effectiveness analysis of data IFN+ribavirin for treatment of chronic hepatitis C Primary 1. Total prescription drug cost per patient treated outcomes 2. Cost of G-CSF per additional SVR 3. Cost of G-CSF per additional QALY Cost analysis Categories of cost and unit costs reported. Unit cost data derived from http://www.Drugstore.com. Price year was 2004. Analysis of Using US Veterans Administration pharmacy costs versus uncertainty http://www.Drugstore.com; varying estimates of future cost of hepatitis C if antiviral therapy is not effective in achieving SVR; varying estimates of QALYs gained from achieving SVR; varying probability that G-CSF controls neutropenia Results Genotype 1 patients: cost per additional SVR using G-CSF versus dose reduction $115,870; cost per QALY gained $16,247. Genotype 2 or 3 patients: cost per additional SVR using G-CSF versus dose reduction $134,628; cost per QALY gained $18,877. Study authors’ conclusions G-CSF is cost-effective for genotype 1 patients with neutropenia. For genotype 2 or 3 patients, positive relationship between PEG IFN dose and SVR not statistically significant.
*The study also evaluated the cost-effectiveness of epoetin used in the treatment of patients with antiviral-therapy-induced anemia. For this review, we have not considered this evaluation. EVR=early virological response; G-CSF=granulocyte-colony stimulating factors; IFN=interferon; PEG IFN=pegylated interferon; QALY=quality-adjusted life year; RCT=randomized controlled trial; SVR=sustained virological response.
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 21 Systematic Review and Economic Evaluation 5.2.3 Utilization information
Brogan Inc. provided data on the concurrent utilization of filgrastim and hepatitis C antiviral therapy among treatment-naïve patients (Source: Brogan Inc., Ottawa, Ontario, Canada). There were no data for pegfilgrastim. Based on data from the Private Payer database (Source: Brogan Inc., Ottawa, Ontario, Canada), 77 (3.4%) patients had a claim for filgrastim between 2003 and 2006. The number of patients for each year ranged from 11 in 2003 to 27 in 2004 (median 24). Among the 77 patients, 14.3% made their claim for filgrastim within four weeks of the initial claim for antiviral therapy; 36.4% made the first claim within eight weeks. Based on data from the Ontario Drug Benefits plan (Source: Brogan Inc., Ottawa, Ontario, Canada), 57 (2.9%) patients had a claim for filgrastim during the four-year period. The number of patients for each year ranged from 10 in 2003 to 20 in 2004 (median 15). The data from Alberta Health and Wellness (Source: Brogan Inc., Ottawa, Ontario, Canada) did not identify any concurrent use of antiviral therapy and G-CSF products.
5.3 Canadian Economic Evaluation: Methods
The decision analytic model combines all resources and clinical outcomes from the start of antiviral treatment to death (Figure 3). The costs, probabilities, and outcomes are combined to estimate the cost differences between the G-CSF and dose reduction strategies. The analytic model includes hepatitis C patients with neutropenia delineated by viral genotype — genotype 1 and genotype 2 or 3. The primary treatment arms are G-CSF and pegylated interferon dose reduction. Cost and outcome differences are attributed to individuals whose neutropenia is controlled and those who achieve SVR. The model does not include EVR or RVR because there was insufficient clinical information for these outcomes.
5.3.1 Type of economic evaluation
Cost-effectiveness and cost-utility analyses were conducted. SVR was used as a measure of clinical-effectiveness and as an intermediate outcome measure in the cost-utility analyses. The goal of HCV therapy is to achieve SVR 24 weeks after the end of treatment. This is thought to represent clinical cure. Less than 1% of those achieving SVR have a virologic relapse in long- term follow-up.15 Although SVR has not been validated as a surrogate outcome in RCTs,56 it is the best measure available,56 and observational studies have correlated SVR with a decreased risk of hepatocellular cancer57,58 and reduced mortality.59,60 In a literature review, one economic evaluation that included both these measures was identified.53
The cost-effectiveness analysis, which is the associated measure of efficiency, is calculated by dividing the incremental costs by the incremental SVR: Cost-Effectiveness Ratio=(CostG-CSF – CostDose Reduction) / (SVRG-CSF – SVRDose Reduction)
The cost-utility analysis is also considered because of variations in the health-related quality of life profiles depending on whether the patient achieved SVR. Incremental lifetime costs and time horizon are applicable to the cost-utility analysis. We rely on an estimate derived from the literature61 to obtain an estimate of the differences in QALYs between the two treatment strategies.61 These were used to construct a cost-utility ratio: Cost-Utility Ratio=(CostG-CSF – CostDose Reduction) / (QALYG-CSF – QALYDose Reduction)
22 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation Figure 3: Decision Analytical Model: G-CSF versus Pegylated Interferon Dose Reduction Strategies for Treatment of Neutropenia in Individuals Who Are Receiving Antiviral Therapy for Hepatitis C
Note: The decision tree consists of branches and nodes. Nodes represent decisions (square), probabilities (circle), or outcomes (triangle). G-CSF=granulocyte-colony stimulating factors; PEG IFN=pegylated interferon; SVR=sustained virological response.
5.3.2 Target population
The target population is treatment-naïve adult patients with chronic hepatitis C infection who have antiviral-associated neutropenia that is defined as neutrophil counts less than 0.75×109/L.
5.3.3 Comparators
The base-case analysis compared administration of G-CSF (filgrastim 0.3 mg per week) with pegylated interferon dose reduction strategies.
5.3.4 Perspective
The costing assumption relies on estimates of medication costs, non-medication treatment costs, and lifetime consequences. Because G-CSF is not listed on any provincial or territorial formulary for the treatment of antiviral-therapy-induced neutropenia, we do not have information on the coverage of medications through employer-sponsored or private insurance plans. Therefore, it is difficult to determine the extent to which the cost of G-CSF is borne by the patient instead of by third-party payers. The lifetime costs that are attributable to treatment failure are estimated from a literature review and reported from a ministry of health perspective. Direct non-medical,
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 23 Systematic Review and Economic Evaluation indirect, and intangible costs are excluded based on an assumption that they are small relative to the included costs.
5.3.5 Resource use and costs
The resource use that is associated with the health services events is based on standard as opposed to actual practices. Standard practice refers to optimal or recommended practices in Canada. Information on event probabilities, resource use, and costs was drawn from the evidence that was identified in a systematic review of the clinical literature. Variations in practice and imprecise reporting were noted in the literature, and several limitations prevent the identification of actual practices. For example, many studies did not report treatment by genotype. Other studies did not provide dosing information and were vague when reporting dose reduction and treatment failures. Finally, small numbers and results that were not statistically significant compound the difficulties in producing reliable cost estimates.
Medication dose, timing, and duration were obtained from the literature, in particular from the Canadian consensus guidelines on the treatment of chronic hepatitis C11-13 (Table 1).
The cost-effectiveness analysis of G-CSF versus pegylated interferon dose reduction for the treatment of antiviral-therapy-induced neutropenia includes the capture of all treatment-related costs and outcomes. Medication costs are dominant during treatment. Non-medication costs during the treatment period include physician time and laboratory testing. These costs are assumed to be higher when neutropenia is uncontrolled. The results of the clinical review suggest that neutropenia will remain uncontrolled in approximately 5% of patients who have a dose reduction of antiviral therapy compared with less than 1% of patients who are treated with G- CSF. Because the differences in expected medication costs are greater than the differences in expected non-medication costs, the analysis includes only medication costs during the treatment period. Lifetime costs after the treatment period are obtained from a literature review.62
The treatment duration and costs for antiviral treatment depend on the genotype. Patients with genotype 1 infection are treated for 48 weeks. Those with genotype 2 or 3 are treated for 24 weeks. Other than this, the time horizon is identical for the two treatment arms (G-CSF versus dose reduction). It is assumed that the differences in treatment duration do not have an impact on lifetime costs and outcomes. It is assumed that the differences in discounted values of lifetime costs and QALYs are not important for this analysis.
The lifetime costs that are attributable to treatment failure are reported from a ministry of health perspective. Direct non-medical, indirect, and intangible costs are excluded based on an assumption that they are small relative to the included costs. G-CSF is not listed on any provincial or territorial formulary for the treatment of antiviral-therapy-induced neutropenia. Furthermore, we do not have information on coverage through employer-sponsored or private insurance plans.
24 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation 5.3.6 Discount rate
Discounted lifetime costs and consequences were obtained from the literature. In the base-case analysis, costs and outcomes were discounted at 5% per year. Sensitivity analyses were conducted using 0% and 3%.
5.3.7 Modelling assumptions
A costing model was developed to account for differences that were attributable to the two treatment strategies. The costs include those for medication during treatment and incremental lifetime costs after treatment failure. The base case assumes the use of filgrastim. We have used filgrastim and G-CSF synonymously in this report. Antiviral and G-CSF medication costs are dominant during treatment. Pegylated interferon-alpha-2a, ribavirin, and filgrastim costs are captured. All other costs are assumed to be equivalent between the G-CSF and dose reduction treatment arms. Differences in lifetime costs after the treatment period are observed when antiviral therapy fails. The lifetime costs are obtained from a literature review.62 The valuation of resources is mainly obtained from the literature and converted to 2008 Canadian dollars. For all items, the Canadian Consumer Price Index63 and foreign exchange indices64 were used to inflate and adjust unit costs to 2008 Canadian dollars when necessary.
a) Medication dose and unit costs Table 8 provides a standard and unit cost for pegylated interferon-alpha-2a, ribavirin, and filgrastim. Unit costs for filgrastim were obtained from the literature and the McKesson Canada online produce catalogue.65 The vial size (0.3 mg) corresponds to the weekly dosages. Therefore, wastage is not assumed to be a consideration. Volume discounting is observed. Given the uncertainty in the treatment duration, it is unknown how many individuals can take advantage of the lower price. The estimate from Chapko and Dominitz,53 adjusted for denomination and inflation, approximates an average cost and is used for the base case.
Table 8: Medication Unit Costs Medication Source Weekly Dose Price (C$) / Week (mg) Filgrastim McKesson Canada65 0.3 295.72 Filgrastim* McKesson Canada65 0.3 205.72 Filgrastim Chapko and Dominitz53 0.3 242.48 PEG IFN-alpha-2a Chapko and Dominitz53 0.18 428.50 Ribavirin (genotype 1) Chapko and Dominitz53 8,400 237.04 Ribavirin (genotype 2 or 3) Chapko and Dominitz53 5,600 158.03
Note: These drugs are manufactured and marketed directly to regional health authorities, hospitals, and pharmacies. “Average” prices are not observable. Because filgrastim is not listed for patients with antiviral-therapy-induced neutropenia, these costs are incurred through insurance (employer or private) or through direct payment by the patient. In the case of prescribed medications, manufacturers provide “price lists” to which distributor and pharmacy mark-ups and dispensing fees are added. When medications are directly marketed, prices are negotiated separately with regional health authorities, hospitals, and community pharmacies. These prices are typically not disclosed according to purchase agreements. *This price reflects volume discounting.
Pegylated interferon-alpha-2a and ribavirin doses and unit costs that are obtained from the literature are included in Table 8. Chapko and Dominitz53 assumed that the costs of pegylated
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 25 Systematic Review and Economic Evaluation interferon-alpha-2a and pegylated interferon-alpha-2b were the same. Although the difference is small, in practice the dosing varies by genotype and patient weight. Furthermore, because these products are marketed in a bundled form in Canada, only a bundled price was available.65 Weekly pegylated interferon-alpha-2a and ribavirin costs are $395. Pegylated interferon-alpha- 2b is available as vials or as premixed Redipen. Although the costs are the same, dosing is based on patient weight, and the product is bundled regardless of genotype (ribavirin may be “wasted” if the patient weighs less than 64 kg and is genotype 2 or 3, because 1,000 mg to 1,200 mg would be bundled and dispensed): $375 (40 kg to 75 kg) or $415 (more than 75 kg). Bundling Chapko and Dominitz’s53 costs would result in $665 (genotype 1) or $586 (genotype 2 or 3) per week for a typical individual (average weight not provided). These costs are different and will be examined more closely using a sensitivity analysis.
b) Dose reduction A dose reduction of pegylated interferon is assumed to occur when neutrophil counts fall below 0.75×109/L as indicated in the product monograph. A dose reduction is assumed to consist of a 25% reduction in pegylated interferon-alpha-2a or a 50% reduction in pegylated interferon- alpha-2b as indicated in the product monographs. Because the market share of these two variants is unknown, a sensitivity analysis will be used to test the two scenarios.
c) Medication duration The duration of antiviral therapy is determined by the genotype. Patients with genotype 1 are treated for 48 weeks. Those with genotype 2 or 3 are treated for 24 weeks. Based on expert opinion (KD, PT, unpublished observations, 2008) plus the utilization data from Brogan Inc. (Source: Brogan Inc., Ottawa, Ontario, Canada), which suggested that the rate of neutropenia before week 5 was less than 10%, it was assumed that treatment of neutropenia would begin in week 5 of the antiviral treatment. We took the approach that if G-CSF were publicly funded, there would be no need to reduce the dose of interferon before the administration of G-CSF. G- CSF is assumed to be provided for the duration of the antiviral treatment if neutropenia is successfully controlled. If neutropenia is not controlled by using G-CSF, antiviral treatment is assumed to end after week 8 (an additional three weeks of attempted G-CSF dose escalation).
A dose reduction of pegylated interferon is also assumed to begin at week 5. If neutropenia is successfully controlled, then dose reduction is assumed to continue for the entire treatment horizon: 48 or 24 weeks, depending on genotype. If neutropenia continues, then further dose reduction is expected to end after week 12 (an additional eight weeks). In reality, the timing, dose reduction, and duration will vary according to clinician preference and individual circumstances. These estimates are based on ideal practices and will be tested in the sensitivity analysis.
d) Non-medication costs Non-medication costs are assumed to be equivalent in the G-CSF and dose reduction treatment arms. Non-medication costs during the treatment period include physician time and laboratory testing. These costs are assumed to be higher when neutropenia is not controlled. The differences in expected medication costs are greater than the differences in expected non-medication costs. As a result, the analysis includes only medication costs during the treatment period.
26 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation e) Post-treatment costs Differences in lifetime costs after the treatment period are observed when antiviral therapy fails. The lifetime costs are obtained from a literature review.62 Expressed in 2008 Canadian dollars, this cost is $12,833. These costs, when discount rates are taken into account, are comparable to those in Brady et al.’s Canadian analysis.66
f) Probabilities The clinical probability that neutropenia was controlled and the clinical probability that SVR was achieved were obtained through a systematic review of the literature. Table 9 shows how they were examined for each branch of the decision model.
Genotype 1 is assumed to occur in 69% of the population.1 The unconditional probabilities of controlling neutropenia with G-CSF were derived from six studies32,40,41,43,52,54 that reported a total of 111 neutropenia patients. Neutropenia was not controlled in two cases. The unconditional probabilities of controlling neutropenia with interferon dose reduction were derived from three studies11,12,55 that reported a total of 304 neutropenia patients. Neutropenia was not controlled in seven cases. These probabilities did not depend on genotype. As a result, the same values were used for genotype 1 and genotype 2 or 3.
The probabilities of patients with genotype 1 attaining SVR, conditional on therapy, were taken from a trial40 that looked solely at patients with genotype 1. In this trial, 12 of 22 patients taking G-CSF achieved SVR. The rate of SVR in the dose reduction group was five of 19 patients. There was no evidence that could be used to compute these rates for patients with genotype 2 or 3, so a ratio estimate was calculated.67
The SVR rates for patients with genotype 1 range from 42% to 46%. For those with genotype 2 or 3 they range from 72% to 80%.11-13 We used the mid-point of these ranges, converted them to odds, and computed an odds ratio (OR). For patients with genotype 2 or 3, the mid-point SVR rate was 76%, which converts to an odds of 3.17 [odds=0.76/(1−0.76)]. For patients with genotype 1, the mid-point rate was 44%, which converts to an odds of 0.79. The resulting OR is 4.01 (OR=3.17/0.79). We then multiplied the odds of our estimates of SVR in patients with genotype 1 by this OR to give us an estimated odds for patients with genotype 2 or 3. For example, with patients receiving G-CSF, 12 of 22 patients with genotype 1 equals an odds of 1.2. The estimated odds for patients with genotype 2 or 3 is 4.81 (1.2×4.01). These values were converted to rates of SVR for use in our analysis. An odds of 4.81 is equivalent to 82.8% for patients who are treated with G-CSF {[4.81/(4.81+1)]×100}.
5.3.8 Valuing outcomes
a) Expected SVR Expected SVR is calculated by aggregating the probabilities of attaining SVR in the different branches.
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 27 Systematic Review and Economic Evaluation Table 9: Clinical Probabilities Branch Genotype Treatment Probability Neutropenia Probability SVR Total of (95% CI) (95% CI) (95% CI) Decision Model 1 1 G-CSF 0.982 (0.937 to Controlled 0.545 (0.347 Yes 0.535 0.995) to 0.731) (0.339 to 0.721) 2 1 G-CSF 0.982 (0.937 to Controlled 0.455 (0.269 No 0.447 0.995) to 0.653) (0.267 to 0.642) 3 1 G-CSF 0.018 (0.005 to Continues 0 Yes 0 (0 to 0) 0.063) 4 1 G-CSF 0.018 (0.005 to Continues 1 No 0.018 0.063) (0.005 to 0.063) 5 1 Dose 0.977 (0.953 to Controlled 0.263 (0.118 Yes 0.257 reduction 0.989) to 0.488) (0.116 to 0.477) 6 1 Dose 0.977 (0.953 to Controlled 0.737 (0.512 No 0.720 reduction 0.989) to 0.882) (0.499 to 0.869) 7 1 Dose 0.023 (0.011 to Continues 0 Yes 0 (0 to 0) reduction 0.047) 8 1 Dose 0.023 (0.011 to Continues 1 No 0.023 reduction 0.047) (0.011 to 0.047) 9 2 or 3 G-CSF 0.982 (0.937 to Controlled 0.828 (0.677 Yes 0.813 0.995) to 0.917) (0.660 to 0.907) 10 2 or 3 G-CSF 0.982 (0.937 to Controlled 0.172 (0.083 No 0.169 0.995) to 0.323) (0.082 to 0.317) 11 2 or 3 G-CSF 0.018 (0.005 to Continues 0 Yes 0 (0 to 0) 0.063) 12 2 or 3 G-CSF 0.018 (0.005 to Continues 1 No 0.018 0.063) (0.005 to 0.063) 13 2 or 3 Dose 0.977 (0.953 to Controlled 0.590 (0.347 Yes 0.576 reduction 0.989) to 0.795) (0.338 to 0.784) 14 2 or 3 Dose 0.977 (0.953 to Controlled 0.410 (0.205 No 0.401 reduction 0.989) to 0.653) (0.202 to 0.638) 15 2 or 3 Dose 0.023 (0.011 to Continues 0 Yes 0 (0 to 0) reduction 0.047) 16 2 or 3 Dose 0.023 (0.011 to Continues 1 No 0.023 reduction 0.047) (0.011 to 0.047)
CI=confidence interval; G-CSF=granulocyte-colony stimulating factor; SVR=sustained virological response.
28 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation b) Expected QALY Expected QALYs are calculated by aggregating the probabilities of attaining SVR in the different branches. The calculation of QALYs is based on Younossi et al.’s work,61 in which the model was based on a patient with chronic hepatitis C without cirrhosis or liver cancer. The estimates of utilities were based on actual patients’ utilities using the health utility index (Mark III) and obtained from patients with different stages of liver disease. These values were used to adjust outcomes for chronic hepatitis C, compensated liver cirrhosis, and decompensated cirrhosis.
5.3.9 Handling variability and uncertainty
One-way sensitivity analyses were conducted to test the underlying assumptions that arose from the cost and probability calculations. Wherever possible, the 95% CIs were used in the one-way sensitivity analysis.
5.4 Canadian Economic Evaluation: Results
5.4.1 Base case: Expected costs
The expected costs that correspond to our assumptions appear in Table 10. The first five columns describe the branch or path on the decision tree (Figure 3). The column labelled “Probability” provides a likelihood of experiencing an outcome that is conditional on the path taken. The sum of these conditional probabilities equals one for each genotype-treatment diad (each consecutive four branches). The incremental medication (Med) costs are derived by adding the weekly medication costs according to the assumptions. The treatment failure (NonMed) costs are assigned to the branches where SVR is not achieved.
The expected costs for the branch are obtained by summing all costs and multiplying by the conditional probabilities. EC(Tx) refers to the expected costs of each treatment arm by genotype. These are obtained by summing across the rows. ΔEC refers to the incremental costs that are obtained by subtracting the expected dose reduction costs from the expected costs that are associated with the G-CSF treatment strategy.
For example, the total cost of using G-CSF for patients with genotype 1 when neutropenia is controlled and SVR is not obtained is $55,448 and will occur 44.7% of the time (Branch #2). Multiplying these two numbers yields an expected cost of $24,785. The expected value of using G-CSF for patients with genotype 1, inclusive of all outcomes, is $47,898. Subtracting the expected cost of the dose reduction arm ($36,305) yields an incremental cost of $11,593 for the treatment of patients with genotype 1.
5.4.2 Base case: Expected outcomes
The expected outcomes that correspond to our assumptions appear in Table 11. This base case represents the most likely values. As with expected costs, the first six columns describe the 16 branches and associated conditional probabilities. The last four columns describe the calculation of the expected QALYs plus the incremental SVR and incremental QALY. For each treatment-genotype diad, one probability describes E(SVR). As a result, it does not require an intermediate calculation and separate column. For example, the expected SVR with G-
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 29 Systematic Review and Economic Evaluation CSF treatment for patients with genotype 1 equals 53.5% and so forth. Incremental or Δ(SVR) is the difference between the expected values when subtracting dose reduction from the G-CSF arm. For patients with genotype 1, treatment with G-CSF yields a 27.8% increased probability of SVR (0.535−0.257=0.278).
The calculation of expected and incremental outcomes is the same as that for expected costs. The last two columns are the result of this calculation applied to QALYs. The G-CSF arms yield 1.53 or 1.30 additional QALYs for patients with genotype 1 and genotype 2 or 3 respectively.
5.4.3 Base case: Cost-effectiveness analysis
Combining the costing and outcomes indicators results in the creation of incremental cost- effectiveness ratios. The Δ Cost/Δ SVR (cost-effectiveness) ratio provides an estimate of the additional dollars that are needed to achieve one additional SVR. An additional $42,737 is required to achieve one extra SVR in patients with genotype 1 (Table 12). The Δ Cost/Δ QALY (cost-utility) ratio reveals that an extra $7,785 is required to yield an additional QALY for patients with genotype 1 and an additional $3,124 for patients with genotype 2 or 3.
5.4.4 Sensitivity analysis
a) Clinical probabilities Table 13 examines the implications of varying clinical probabilities based on the 2.5 and 97.5 percentiles that were obtained from the clinical review. A one-way sensitivity analysis was used to examine a high and low probability for each chance node in the decision tree. A total of 16 scenarios were considered. The first five columns in the table describe the scenarios. The last four columns present the variation in incremental cost-effectiveness ratios. The last three rows provide the minimum and maximum values as a contrast to the base case. For example, scenario 1 is obtained by assuming the 95th percentile probability of controlling neutropenia in the G-CSF arm among patients with genotype 1. The incremental cost per QALY gained for patients with genotype 1 is $7,785 for the base case and ranges from $3,843 to $45,280. Although this range is large, all values fall below $100,000 per QALY gained, which is within the range that might be considered to be cost-effective68 and does not alter the findings that G- CSF compared with pegylated interferon dose reduction yields favourable incremental cost- effectiveness and cost-utility ratios.
30 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation Table 10: Expected Costs for Base Case Branch* Genotype Treatment Neutropenia SVR Probability Costs Costs EC EC(Tx) ΔEC (Med) (NonMed) (Branch) 1 1 G-CSF Controlled Yes 0.535 42,615 0 22,799 47,898 11,593 2 1 G-CSF Controlled No 0.447 42,615 12,833 24,785 3 1 G-CSF Continues Yes 0 4,602 0 0 4 1 G-CSF Continues No 0.018 4,602 12,833 314 5 1 Dose reduction Controlled Yes 0.257 27,232 0 6,999 36,305 6 1 Dose reduction Controlled No 0.720 27,232 12,833 28,847 7 1 Dose reduction Continues Yes 0 7,129 0 0 8 1 Dose reduction Continues No 0.023 7,129 12,833 459 9 2 or 3 G-CSF Controlled Yes 0.813 18,926 0 15,387 21,062 3,819 10 2 or 3 G-CSF Controlled No 0.169 18,926 12,833 5,367 11 2 or 3 G-CSF Continues Yes 0 4,286 0 0 12 2 or 3 G-CSF Continues No 0.018 4,286 12,833 308 13 2 or 3 Dose reduction Controlled Yes 0.576 11,934 0 6,874 17,243 14 2 or 3 Dose reduction Controlled No 0.401 11,934 12,833 9,932 15 2 or 3 Dose reduction Continues Yes 0 6,181 0 0 16 2 or 3 Dose reduction Continues No 0.023 6,181 12,833 437
*From Figure 3. EC=expected costs; G-CSF=granulocyte-colony stimulating factor; Med=medication; NonMed=non-medication; SVR=sustained virological response; Tx=treatment.
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 31 Systematic Review and Economic Evaluation Table 11: Expected Outcomes for Base Case Branch* Genotype Treatment Neutropenia SVR Prob Δ(SVR) +QALYs E(QALY) Δ(QALY) 1 1 G-CSF Controlled Yes 0.535 0.278 5.49 2.94 1.53 2 1 G-CSF Controlled No 0.447 0.00 5.49 4 1 G-CSF Continues No 0.018 0.00 5 1 Dose reduction Controlled Yes 0.257 5.49 1.41 6 1 Dose reduction Controlled No 0.720 0.00 7 1 Dose reduction Continues Yes 0.000 5.49 8 1 Dose reduction Continues No 0.023 0.00 9 2 or 3 G-CSF Controlled Yes 0.813 0.237 5.49 4.46 1.30 10 2 or 3 G-CSF Controlled No 0.169 0.00 11 2 or 3 G-CSF Continues Yes 0.000 5.49 12 2 or 3 G-CSF Continues No 0.018 0.00 13 2 or 3 Dose reduction Controlled Yes 0.576 5.49 3.16 14 2 or 3 Dose reduction Controlled No 0.401 0.00 15 2 or 3 Dose reduction Continues Yes 0.000 5.49 16 2 or 3 Dose reduction Continues No 0.023 0.00
*From Figure 3. E=expected; G-CSF=granulocyte-colony stimulating factor; Prob=probability; QALY=quality-adjusted life year; SVR=sustained virological response.
32 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation Table 12: Calculation of Incremental Cost-Effectiveness Ratios (base case) Cost SVR QALY ΔCost Δ Δ ΔCost / ΔCost / ($) SVR QALY ΔSVR ΔQALY Genotype 1 G-CSF 47,416 0.535 2.94 11,881 0.278 1.53 42,737 7,785 Dose reduction 35,535 0.257 1.41 Genotype 2 or 3 G-CSF 20,869 0.813 4.46 4,065 0.237 1.30 17,151 3,124 Dose reduction 16,804 0.576 3.16
G-CSF=granulocyte-colony stimulating factor; QALY=quality-adjusted life year; SVR=sustained virological response.
Table 13: Sensitivity Analyses for Variable Clinical Probabilities Genotype 1 Genotype 2 or 3 Scenario Genotype Treatment Prob Outcome ΔCost/ ΔCost/ ΔCost/ ΔCost/ ΔSVR ΔQALY ΔSVR ΔQALY S1 1 G-CSF Low Control 41,225 7,509 17,151 3,124 neutropenia S2 1 G-CSF High Control 43,079 7,847 17,151 3,124 neutropenia S3 1 Dose Low Control 43,214 7,871 17,151 3,124 reduction neutropenia S4 1 Dose High Control 42,476 7,737 17,151 3,124 reduction neutropenia S5 2 or 3 G-CSF Low Control 42,737 7,785 19,238 3,504 neutropenia S6 2 or 3 G-CSF High Control 42,737 7,785 16,651 3,033 neutropenia S7 2 or 3 Dose Low Control 42,737 7,785 16,117 2,936 reduction neutropenia S8 2 or 3 Dose High Control 42,737 7,785 17,798 3,242 reduction neutropenia S9 1 G-CSF Low SVR 169,216 30,823 17,151 3,124 S10 1 G-CSF High SVR 21,100 3,843 17,151 3,124 S11 1 Dose Low SVR 24,324 4,431 17,151 3,124 reduction S12 1 Dose High SVR 248,586 45,280 17,151 3,124 reduction S13 2 or 3 G-CSF Low SVR 42,737 7,785 65,452 11,922 S14 2 or 3 G-CSF High SVR 42,737 7,785 9,346 1,702 S15 2 or 3 Dose Low SVR 42,737 7,785 2,678 488 reduction S16 2 or 3 Dose High SVR 42,737 7,785 177,284 32,292 reduction Minimum 21,100 3,843 2,678 488 Base 42,737 7,785 17,151 3,124 Maximum 248,586 45,280 177,284 32,292
G-CSF=granulocyte-colony stimulating factor; Prob=probability; QALY=quality-adjusted life year; SVR=sustained virological response.
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 33 Systematic Review and Economic Evaluation b) Unit drug costs The costs of the medications that were available through McKesson Canada65 varied. Bundled antiviral medications were 41% less expensive than the base case. G-CSF varied from 15% less expensive to 22% more expensive. The relative costs of G-CSF compared with those of the antiviral medication drive the results. Increased G-CSF costs result in less favourable incremental cost-effectiveness ratios. Alternatively, higher antiviral medication costs may result in lower dose reduction costs, because a reduced dose results in greater savings. We chose four scenarios based on the variation (high, low) of prices of 50% for antiviral medications and 25% for G-CSF (Table 14).
Variations in the costs of these medications do not have a large impact on the incremental cost- effectiveness ratios.
Table 14: Sensitivity Analyses for Variable Drug Costs Genotype 1 Genotype 2 or 3 G-CSF Antiviral ΔCost/ ΔCost/ ΔCost/ ΔCost/ Medication ΔSVR ΔQALY ΔSVR ΔQALY Base Case 42,737 7,785 17,151 3,124 S1 High High 60,551 11,029 26,565 4,839 S2 High Low 43,829 7,983 17,858 3,253 S3 Low High 41,645 7,586 16,445 2,995 S4 Low Low 24,923 4,540 7,737 1,409
G-CSF=granulocyte-colony stimulating factor; QALY=quality-adjusted life year; SVR=sustained virological response.
c) Pegylated interferon-alpha-2a versus pegylated interferon-alpha-2b The base case was developed using pegylated interferon-alpha-2a. Although pegylated interferon-alpha-2a and pegylated interferon-alpha-2b are assumed to be equally effective in managing HCV, there are differences that include absolute versus weight-based doses, costs, and recommended dose reduction percentages (25% for pegylated interferon-alpha-2a and 50% for pegylated interferon-alpha-2b). The recommended dose reduction is the most important factor and was included in the sensitivity analysis (Table 15).
Intuitively a greater dose reduction in a conventional treatment strategy will result in poorer cost- effectiveness ratios. These ratios increase to $10,815 and $4,748 per QALY gained (genotype 1 and genotype 2 or 3 respectively) but are within the range that is considered to be cost- effective.68
Table 15: Sensitivity Analyses for Pegylated Interferon-alpha-2a versus Pegylated Interferon-alpha-2b Genotype 1 Genotype 2 or 3 ΔCost/ ΔCost/ ΔCost/ ΔCost/ ΔSVR ΔQALY ΔSVR ΔQALY Base case (PEG IFN-alpha-2a) 42,737 7,785 17,151 3,124 PEG IFN-alpha-2b 59,373 10,815 26,067 4,748
PEG IFN=pegylated interferon; QALY=quality-adjusted life year; SVR=sustained virological response.
34 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation d) Dose reduction intensity of pegylated interferon Our base case describes a standard case that is based on best evidence and practices. The variations that are observed in practice depend on several factors, including physician treatment preferences. A larger dose reduction or a shorter duration of reduction from eight weeks to four weeks (or both) may affect costs (Table 16).
Increasing the reduction from 25% to 50% yielded inconsequential increases to the cost-utility measure. Decreasing the duration of dose reduction to four weeks (from eight weeks) increases the respective incremental cost-effectiveness ratios by small amounts.
Table 16: Sensitivity Analyses for Dose Reduction Intensity Percentage Duration Genotype 1 Genotype 2 or 3 ΔCost/ ΔCost/ ΔCost/ ΔCost/ ΔSVR ΔQALY ΔSVR ΔQALY Base case 25% 8 weeks 42,737 7,785 17,151 3,124 25% 4 weeks 42,922 7,818 17,338 3,158 50% 4 weeks 59,523 10,842 26,211 4,774
QALY=quality-adjusted life year; SVR=sustained virological response. e) Intensive G-CSF dosing Our base case describes a standard case that is based on best evidence and practices. The variations in actual practice that are observed depend on several factors, including physician treatment preferences. We consider the potential that physicians may double the dose of G-CSF from one dose to two doses per week. The scenarios of a higher dose throughout the treatment trajectory appear in Table 17.
Table 17: Sensitivity Analyses for Dose Reduction Intensity G-CSF Dose Genotype 1 Genotype 2 or 3 ΔCost/ ΔCost/ ΔCost/ ΔCost/ ΔSVR ΔQALY ΔSVR ΔQALY Base case 0.3 mg/week 42,737 7,785 17,151 3,124 0.6 mg/week 80,549 14,672 37,392 6,811
QALY=quality-adjusted life year; SVR=sustained virological response.
This scenario results in an approximate doubling of the cost-utility ratios. This increase is insufficiently large to alter the conclusions that G-CSF compared with pegylated interferon dose reduction yields favourable incremental cost-effectiveness and cost-utility ratios. f) Discount Rate For the base case, future costs and consequences were discounted at 5%. Sensitivity analyses were conducted using discount rates at 3% and 0% (Tables 18 and 19).
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 35 Systematic Review and Economic Evaluation Table 18: Calculation of Incremental Cost-Effectiveness Ratios (3%) Cost SVR QALY ΔCost ΔSVR Δ ΔCost/ ΔCost/ ($) QALY ΔSVR ΔQALY Genotype 1 G-CSF 47,898 0.535 3.81 11,593 0.278 1.98 41,701 5,849 Dose reduction 36,305 0.257 1.83 Genotype 2 or 3 G-CSF 21,062 0.813 5.80 3,819 0.237 1.69 16,115 2,260 Dose reduction 17,243 0.576 4.11
G-CSF=granulocyte-colony stimulating factor; QALY=quality-adjusted life year; SVR=sustained virological response.
Table 19: Calculation of Incremental Cost-Effectiveness Ratios (0%) Cost SVR QALY ΔCost ΔSVR Δ ΔCost/ ΔCost/ ($) QALY ΔSVR ΔQALY Genotype 1 G-CSF 49,316 0.535 6.26 10,745 0.278 3.26 38,652 3,301 Dose reduction 38,571 0.257 3.01 Genotype 2 or 3 G-CSF 21,633 0.813 9.52 3,097 0.237 2.78 13,066 1,116 Dose reduction 18,536 0.576 6.74
G-CSF=granulocyte-colony stimulating factor; QALY=quality-adjusted life year; SVR=sustained virological response. g) Extremes analysis Based on the one-way sensitivity analyses, we determined that the clinical probabilities yielded the greatest variation. This finding is consistent with the clinical review, which provided an estimate of the probability of SVR based on one RCT. An analysis of the best-case scenario yields $2,434 per QALY gained for patients with genotype 1 and $77 per QALY gained for genotype 2 or 3. In the worst-case scenario for both genotypes, dose reduction dominates G-CSF where SVR for dose reduction exceeds that of the G-CSF arms. The probability of these two scenarios, however, is small — 3.2% for genotype 1 and 5% for genotype 2 or 3.
Although a probabilistic analysis (including resource use) is generally considered to be helpful, data regarding the co-variance between SVR and dosing for pegylated interferon or G-CSF do not exist. Furthermore, the sensitivity analysis on resource use did not substantially change the incremental cost-effectiveness ratio. Therefore, we decided not to conduct a probabilistic analysis.
6 HEALTH SERVICES IMPACT 6.1 Population Impact
Chronic hepatitis C places a clinical and economic burden on Canadians. It is associated with increased mortality and morbidity, including progressive liver fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma. The estimated prevalence of HCV infection in Canada in 2008 is
36 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation 0.8% to 1.0% (between 264,000 and 330,000 Canadians). It is estimated that approximately 5,000 people are infected with HCV each year and that approximately 65% of those infected are identified. Although the primary mode of HCV infection is injection drug use, as many as one- third of new infections in Canada occur in immigrants from countries where HCV infection is endemic.10
6.2 Budget Impact
Current estimates suggest that 65% of incident and prevalent cases of hepatitis C have been identified.10 Not all patients who are identified will be assessed by an expert in HCV treatment. Of those assessed, not all will receive antiviral therapy for reasons such as contraindications to therapy, medical comorbidities, lack of compliance, or a medical recommendation that therapy is not indicated. Although Health Canada maintains an Enhanced Hepatitis Strain Surveillance System,69 there is no known registry or database in Canada that describes the individuals with hepatitis C who are receiving or have previously received treatment. We have assumed that most patients with prevalent hepatitis C who were previously treated and for whom standard interferon (monotherapy or combination with ribavirin) has failed as a therapy will have been retreated with pegylated interferon and ribavirin as outlined in the Canadian consensus guidelines10 and will have achieved SVR or not. It was assumed that those who have not achieved SVR with pegylated interferon and ribavirin will not be retreated until new antiviral therapies are available.
Budgetary consequences are attributable to three groups of individuals who are eligible to receive antiviral treatment of hepatitis C. The first cohort comprises previously untreated prevalent cases. A second cohort consists of the incident cases. A third cohort includes individuals who may, influenced by innovations in the diagnosis and treatment of HCV infections, seek treatment in the future.
According to an epidemiological modelling exercise, 1% to 2% of prevalent cases have been managed.1 More recent projections suggest that up to 10% have been managed. This upward trend is partly attributable to improved outcomes as a result of advances in antiviral therapy and the uptake of the Canadian consensus guidelines.10 We assume that a lack of referral to HCV clinics, contraindications to treatment, and patient preference apply to the remaining 55% (65% of cases that have been identified minus 10% managed). Because HCV antiviral therapy is publicly funded, financial constraints are thought to play a negligible role in this cohort. This means that the increase to this cohort as a result of recommendations emanating from this report is negligible.
Ideally, the identification of incident cases (65%) will lead to a referral to HCV clinics. Of these 3,250 referrals, it is assumed that one third will be eligible for treatment.70 Of the 1,083 incident cases treated each year, neutropenia will occur in 13.0% if it is defined as neutrophil counts less than 0.75×109/L.6,7 As a result, an estimated 141 individuals who are receiving antiviral treatment are expected to be treated for neutropenia. If neutropenia is defined as neutrophil counts less than 0.5×109/L, it is estimated that 2.3% (25 patients) are expected to be treated for neutropenia.11,12,55
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 37 Systematic Review and Economic Evaluation The treatment duration depends on HCV genotype. In Canada, patients who are infected with HCV genotype 1, 4, 5, and 6 receive treatment for 48 weeks. Those infected with HCV genotype 2 or 3 are treated for 24 weeks. Patients with genotype 2 or 3 infection account for approximately 31% of cases.
Based on the data from Brogan Inc. (Source: Brogan Inc. Ottawa, Ontario, Canada), we assumed that most of the patients who are treated for hepatitis C do not have access to private drug plans that cover filgrastim. We also assume that most individuals who are receiving treatment do not have the means to pay for the increased costs that are associated with filgrastim. Therefore, in our calculations, we assume that the proportion of individuals who are receiving filgrastim is 0%. Based on base-case assumptions and defining neutropenia as neutrophil counts less than 0.75×109/L, an additional $11,881 per person is required to treat individuals with genotype 1 and an additional $4,065 per person is required to treat patients with genotype 2 or 3. An additional $1,333,584 is required to manage all cases of neutropenia in Canada. If we define neutropenia as neutrophil counts less than 0.5×109/L, an additional $236,451 is required.
Pegylated interferon plus ribavirin is expected to remain the backbone of therapy (with or without the addition of new antiviral agents) for at least the next seven to 10 years. If we assume no additional changes in diagnosis and treatment, the budgetary impact of adopting G-CSF treatment will remain constant in the short to intermediate term.
6.3 Ethical, Equity, and Psychosocial Issues
A proportion of individuals with hepatitis C represent a vulnerable and often marginalized population. Some of these individuals have comorbid conditions such as mental health issues, substance abuse issues, and HIV. Few have access to resources that would enable them to buy G- CSF.
The treatment of neutropenia using G-CSF, as opposed to pegylated interferon dose reduction, will result, on average, in an additional 1.98 QALYs in the case of genotype 1 or 1.69 QALYs for genotype 2 or 3. Because many of these patients are involved in risky behaviours, particularly injection drug use, it is unknown whether successfully managing underlying HCV infections and associated sequelae will result in socioeconomic improvements for this population.
7 DISCUSSION 7.1 Clinical Results
We identified 15 unique studies (one RCT, one CCT, two cohort, 11 case series) published between 1999 and 2007 that reported on the effectiveness and safety of G-CSF in the treatment of antiviral-therapy-induced neutropenia in treatment-naïve hepatitis C patients.
The definition of neutropenia and the trigger point for initiation of G-CSF or pegylated interferon dose reduction strategies varied across studies, ranging from neutrophil counts less than 0.5×109/L to counts less than 1.5×109/L. The dose and duration of G-CSF administration or
38 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation pegylated interferon dose reduction strategies reflected different clinical practice patterns. Although many studies did not state which G-CSF product was used, based on the administration schedules, filgrastim seems to be the only product that has been evaluated. An incomplete reporting of outcomes that were related to the virological response to antiviral treatment (EVR, RVR, SVR) was common.
The methodological quality of the two clinical trials was low. Although both cohort studies were retrospective, they were of high quality and reported the implementation of all nine bias criteria. The remaining studies were case series with no control group. They were of moderate quality. All of them reported the implementation of at least half of the 14 bias criteria. This body of work could be improved by undertaking RCTs that compare a standardized dose reduction algorithm with G-CSF for the management of antiviral-therapy-induced neutropenia; standardizing the reporting of outcomes, which would include measures of efficacy (virologic responses of RVR, EVR, and SVR) and safety (infections and adverse effects of G-CSF); and improving the quality of reporting by following guidelines such as the CONSORT statement.
7.2 Effectiveness
There is a paucity of high-quality trials that have assessed the effectiveness of G-CSF compared with interferon dose reduction to control neutropenia in patients who are receiving combination antiviral therapy. The results of a comprehensive literature search identified two small trials of low methodological quality. Different definitions of neutropenia were used in the studies. This precluded the pooling of data using meta-analysis. In the study that defined neutropenia as neutrophil counts less than 0.75×109/L, the rate of SVR for those receiving G-CSF was 54.5% (95% CI 34.7 to 73.1) compared with 26.3% (95% CI 11.8 to 48.8) for the dose reduction group. The difference was not statistically significant.
The evidence to assess the relationship between SVR and G-CSF is weak. No conclusion can be reached on the basis of this systematic review. Most researchers do not report the virologic outcomes for the patients with neutropenia. We were unable to obtain additional unpublished data from the authors who were contacted. In Van Thiel et al.’s study,71 30 consecutive patients with advanced hepatitis C were treated with interferon monotherapy plus adjuvant G-CSF or interferon monotherapy alone. In the group receiving interferon and G-CSF, 53% achieved SVR compared with 40% for the group receiving interferon alone (P=0.72).
There is evidence that patients who were treated with G-CSF did not have to discontinue antiviral therapy or were able to resume the optimal dose after taking G-CSF. The studies, however, are underpowered. Therefore, the impact on SVR is unclear. Furthermore, we were unable to examine the effectiveness of different dose reduction or dose duration strategies for G- CSF.
Research conducted among patient populations has shown the efficacy of G-CSF in controlling neutropenia.72-75 Marangolo et al.73 examined the role of chemotherapy and the maintenance of doses and schedules in the treatment of chemosensitive tumours such as breast cancer, non- Hodgkin malignant lymphomas, ovarian cancer, and small cell lung cancer. They confirmed that dose reductions were detrimental to clinical outcomes, including overall survival and time-to-
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 39 Systematic Review and Economic Evaluation treatment failure. The reason for dose reduction was hematological toxicity. The authors concluded that the standard use of G-CSF contributed to the cure of chemosensitive tumours by reducing neutropenia and maintaining dose intensity. Although an evidence base is lacking, there is no reason to believe that G-CSF will be less efficacious for the hepatitis C population.
7.3 Safety
The combination of observational and clinical trial evidence shows that the rate of adverse events associated with G-CSF is low. The most common adverse effects were bone pain, rash, body aches, headache, and splenomegaly. The studies indicated that the adverse effects were clinically insignificant, transient, required only supportive interventions, and caused no long-term consequences. This is consistent with previous research, which has shown that G-CSF is well tolerated among different patient populations with neutropenia including oncology,73 post- transplantation,72,74 and HIV.76
One observational study provided evidence to address the question of harm that is associated with the concurrent administration of G-CSF and epoetin or darbepoetin to manage antiviral- therapy-induced neutropenia and anemia respectively. The study indicated that the adverse effects were clinically insignificant, transient, and required only supportive interventions.
The combination of observational and clinical trial evidence shows that the risk of infection associated with neutropenia in patients receiving antiviral therapy for hepatitis C is low. Infections were minor, did not require hospitalization, were managed with antibiotic or antifungal agents, and were resolved without long-term consequences. These conclusions are consistent with those reported by Cooper et al.20 The authors evaluated the relationship between infectious complications and neutropenia in 192 patients who were treated with interferon monotherapy at The Ottawa Hospital Viral Hepatitis Clinic from 2000 to 2005. None of the patients received G-CSF. Overall, 67 infections occurred in 57 patients (29.7%). The risk of infection was not associated with a neutrophil count less than 1.0×109/L versus greater than 1.0×109/L (OR=1.2; 95% CI 0.6 to 2.4). Most infections were managed with oral or topical agents. Four patients had severe bacterial infections and required hospitalization. For three of these patients, the neutrophil count did not decrease to less than 1.0×109/L during therapy. In the fourth patient, the nadir neutrophil count was 0.7×109/L, but was generally greater than 1.0×109/L.
The neutrophil count threshold that was recommended for dose modification in patients with hepatitis C antiviral therapy-related neutropenia was extrapolated from data in cancer patients who developed neutropenia related to chemotherapy.77 The findings of this review suggest that neutropenia may be better tolerated by patients with hepatitis C receiving combination therapy than it is by cancer patients receiving chemotherapy.
7.4 Economic Analysis
Under base-case assumptions, the cost per additional SVR of using filgrastim instead of pegylated FN dose reduction is $42,737 per SVR for patients with genotype 1 and $17,151 for patients with genotype 2 or 3. The cost per QALY gained by using filgrastim versus pegylated
40 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation interferon dose reduction is $7,785 for patients with genotype 1 and $3,124 for patients with genotype 2 or 3. These estimates were tested under sensitivity analyses and were found to be robust for patients with genotype 1. In an extreme case analysis there was evidence that G-CSF compared with dose reduction is not cost-effective.
These results are consistent with those of Chapko and Dominitz53 who concluded that G-CSF was marginally cost-effective for patients with genotype 1 and had an unclear impact on cost- effectiveness for genotype 2 or 3. The difference between these two economic evaluations was the percentage reduction in SVR. Chapko and Dominitz tested reductions from 1% to 15% and reported them as a function of the relationship between dose reduction and SVR. This review derived estimates from the systematic review, which demonstrated a reduction of 27.8% for genotype 1 and 23.7% for genotype 2 or 3. The probability of achieving SVR for patients with genotype 1 is 27.8% greater for those receiving filgrastim than for those using pegylated interferon dose reduction strategies. These estimates are based on one RCT and should be interpreted cautiously.
Through sensitivity analyses, we examined probabilities over a range of clinical scenarios (Table 13). The worst-case scenarios based on one-way analysis are scenarios 9 and 12, which examine the upper 95% limit of filgrastim and SVR and the lower 5% limit of pegylated interferon dose reduction and SVR. In scenario 9, the difference in SVR is 8% and in scenario 12 it is 6%. Even in these two scenarios, filgrastim demonstrates an incremental cost-utility ratio threshold that falls below what might be considered to be cost-effective.
These percentage reductions in SVR in the two scenarios overlap with the range of percentage reductions that were considered by Chapko and Dominitz.53 For example, for patients with genotype 1, the authors reported a cost per QALY of $34,000 for a 6% reduction and $26,000 for an 8% reduction. These are comparable to the current estimates.
The results of the clinical review did not provide data that enabled us to conduct an economic analysis for subgroups of the hepatitis C population. Therefore, other than genotype, we were unable to examine the cost-effectiveness of G-CSF for patients with cirrhosis or by type of interferon used.
7.5 Limitations
The limitations of this review should be acknowledged. Few controlled or comparison studies were found. Therefore, our results and the strength of our conclusions are limited by the paucity of evidence. The inclusion criteria for this review specified that patients had to be receiving combination antiviral therapy (interferon and ribavirin). Research that focused on patients receiving interferon monotherapy may have contributed data to this review. It is unclear how this might have influenced our conclusions.
There was variability in the definition of neutropenia or the point at which treatment of neutropenia was started. For calculating the probabilities of controlling neutropenia and achieving SVR, we used data only from studies where treatment was started when the neutrophil count was less than 0.75×109/L. This reduced the evidence that was available to calculate
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 41 Systematic Review and Economic Evaluation probabilities. Because a neutrophil count less than 1.0×109/L is not the recommended level at which dose reduction (or administration of G-CSF) should be considered, using outcome data from the studies that used this definition of neutropenia would not reflect the current standard of care in Canada. Therefore, using outcome data from the studies that used this definition of neutropenia would not reflect the current standard of care in Canada.
Although selection bias is always possible, this was minimized, because all abstracts and primary manuscripts were screened by two independent reviewers using standard eligibility criteria.
We were unable to assess publication bias, because there was an insufficient number of controlled studies.78 Negative trials are less likely to be published and are more likely to be excluded from a review of this nature. The comprehensive search strategy, which included a hand search of recent conference proceedings to identify unpublished trials, has likely minimized such bias. Nonetheless, it is unclear how the unpublished trials may have influenced the conclusions.
There was variability in the actual dosage and duration of G-CSF. A potential for bias in the drug costs exists when standard dosages are assumed. In addition, G-CSF prices were not observable and wastage could not be quantified. The potential for bias is limited because the savings that arose from the drug costs of G-CSF were comparatively small. Furthermore, in the sensitivity analysis that varied G-CSF and antiviral medications simultaneously, the change in the incremental cost-effectiveness ratio was inconsequential.
In the decision model, G-CSF and pegylated interferon dose reduction strategies were based on algorithms that were recommended by the drug manufacturer (treat at neutrophil counts less than 0.75×109/L; discontinue at less than 0.5×109/L). No standard algorithms are in place for G-CSF or stepwise pegylated interferon dose reduction (beyond the 50% versus 25% in the product monograph). Although research has shown that dose reduction at any time may compromise outcomes,15 Davis et al.79 suggest that dose reductions during the first 12 weeks of antiviral therapy may have the largest impact on SVR. If so, administering G-CSF through week 12 followed by dose reduction may be more cost-effective than using G-CSF throughout antiviral therapy. There is a potential for improvement in the cost-effectiveness and cost-utility ratios by adopting a combination strategy. An estimate was unobtainable because no literature provided data. On the basis of the findings and the sensitivity analysis regarding the duration and shortening of the dose reduction treatment timelines, it is likely that these savings would be modest.
There are many permutations for pegylated interferon dose reduction that could have been used in our model. Small changes in dose reduction would affect the costs that are associated with antiviral therapy. Our model was not sensitive to the cost of pegylated interferon. Therefore, this would not affect our conclusions.
7.6 Generalizability of Findings
The results of the economic evaluation can be generalizable to the jurisdictions in Canada when the sensitivity analyses are taken into account. Canadian data on resource use, unit costs, and
42 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation clinical practice (based on the 2007 Canadian consensus guidelines) were used in the model, and a plausible range of parameter values that are expected to be relevant to Canada were tested in the sensitivity analyses. This analysis is relevant to the population described in the model (treatment-naïve patients who are treated with filgrastim for antiviral-therapy-induced neutropenia).
7.7 Knowledge Gaps
There are knowledge gaps regarding the treatment of neutropenia in patients with hepatitis C. Two head-to-head clinical trials of poor methodological quality examined the effectiveness of pegylated interferon dose reduction versus G-CSF. Large, well-designed clinical trials are needed to inform us about which strategy is superior to control SVR and improve health outcomes. There is a need for clinical trial data that would enable us to draw conclusions about optimal strategies for pegylated interferon dose reduction or G-CSF dose and duration. No trials have been conducted to address the impact of the treatment of neutropenia on patient subgroups, such as those with cirrhosis, recurrent hepatitis C after liver transplant, baseline neutropenia, or comorbidities such as HIV. Among these patients, not only is SVR already less likely to occur, but treatment limiting neutropenia is also common. Future research studies should provide reliable clinical and economic information to determine more clearly how these patients should be treated.
8 CONCLUSIONS
Within the limitations of existing data, the clinical review was unable to demonstrate the superiority of G-CSF versus pegylated interferon dose reduction for achieving SVR. Although the administration of G-CSF enabled patients to stay on or resume optimal antiviral therapy compared with patients using pegylated interferon dose reduction strategies, the evidence has not established that this improves outcomes. The adverse effects of G-CSF treatment are transient and mild, and they respond to simple treatments that alleviate symptoms.
Previous health economic evaluations have been limited in number and scope. This economic evaluation was undertaken from a ministry of health perspective to assess the cost-effectiveness of treating treatment-naïve hepatitis C patients with antiviral-therapy-induced neutropenia using G-CSF compared with pegylated interferon dose reduction. G-CSF compared with pegylated interferon dose reduction yields an incremental cost-effectiveness ratio of $42,737 per SVR achieved or $7,785 per QALY gained for patients with genotype 1 infection and $17,151 per SVR or $3,124 per QALY for patients with genotype 2 or 3 infection. Concluding that G-CSF compared with pegylated interferon dose reduction is cost-effective may be premature in light of the weakness of the clinical data. The economic analysis has been useful and will focus future efforts in gathering additional evidence. In the meantime, techniques such as program-budgeting marginal-analysis are available to decision makers to evaluate this evidence and set priorities.
Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: 43 Systematic Review and Economic Evaluation 9 REFERENCES
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48 Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation APPENDIX 1
Literature Search Strategy for Clinical Effectiveness Studies
OVERVIEW
*denotes databases that were updated Interface: Ovid Databases: *Medline® <1950 to March Week 3 2008> *EBM Reviews – Cochrane Central Register of Controlled Trials <1st Quarter 2008> *HealthSTAR <1966 to March 2008> Date of Search: October 29, 2007 Date of Update: March 27, 2008 Study Types: Left open Limits: None SYNTAX GUIDE / At the end of a phrase, searches the phrase as a subject heading MeSH Medical Subject Heading fs Floating subheading exp Explode a subject heading $ Truncation symbol, or wildcard: retrieves plural or variations of a word * Indicates that the marked subject heading is a primary topic adj Requires words are adjacent to each other (in any order) adj# Adjacency within # number of words (in any order) .ti Title .ab Abstract .jn. Journal .mp Title, Abstract, Subject Heading, CAS Registry/EC Number Word .pt Publication type .rn CAS registry number
A-1
MULTI-FILE STRATEGY Line # Search Results 1 Hepatitis/ 2 Hepatitis, Chronic/ 3 Hepatitis, Viral, Human/ 4 exp Hepatitis C/ 5 Hepatitis C, Chronic/ 6 Hepacivirus/ 7 (Hepatitis C or HCV$).mp. 8 or/1-7 9 exp Antiviral Agents/ 10 (((antiviral or anti-viral) adj1 therap$) and hepatitis).mp. 11 (interferon$ or IFN).mp. 12 9008-11-1.rn. 13 peginterferon$.mp. 14 (peg or peg-IFN or peg-interferon$ or ((pegylat$ or nonpegylat$ or non- pegylat$) adj3 interferon$) or (polyethylene glycol adj3 interferon$) or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex).mp. 15 (Avonex or Betaseron or Rebif or Rebetron).mp. 16 or/9-15 17 neutropen$.mp. 18 neutrophil$.mp. 19 neutrofil$.mp. 20 Agranulocytosis/ 21 agranulocytosis.mp. 22 ae.fs. 23 colony-stimulating factors/ or colony-stimulating factors, recombinant/ or exp granulocyte colony stimulating factor/ 24 G-CSF.mp. 25 "granulocyte colony stimulating factor".mp. 26 hematopoietic cell growth factors/ or colony-stimulating factors/ 27 Growth Substances/ 28 (hematopoietic growth factors or haematopoietic growth factors).mp. 29 r-metHuG-CSF.mp. 30 Filgrastim/ 31 filgrastim.mp. 32 121181-53-1.rn. 33 Neulasta.mp. 34 pegfilgrastim.mp. 35 208265-92-3.rn. 36 Neupogen.mp. 37 or/17-36 3120 38 and/8,16,37
A-2 OVERVIEW Interface: Ovid Databases: *Ovid MEDLINE® In-Process & Other Non-Indexed Citations
A-3 OVERVIEW Interface: Ovid Databases: *EMBASE <1988 to 2008 Week 12> Date of Search: October 29, 2007 Date of Update: March 27, 2008 Study Types: Left Open Limits: None STRATEGY Line # Search Results 1 HEPATITIS/ 2 Chronic Hepatitis/ 3 exp Virus Hepatitis/ 4 Hepatitis C/ 5 hepatitis c virus/ 6 (Hepatitis C or HCV$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] 7 or/1-6 8 exp Antivirus Agent/ 9 (((antiviral or anti-viral) adj1 therap$) and hepatitis).mp. 10 (interferon$ or IFN).mp. 11 9008-11-1.rn. 12 peginterferon$.mp. 13 (peg or peg-IFN or peg-interferon$ or ((pegylat$ or nonpegylat$ or non- pegylat$) adj3 interferon$) or (polyethylene glycol adj3 interferon$) or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex).mp. 14 (Avonex or Betaseron or Rebif or Rebetron).mp. 15 or/8-14 16 neutropen$.mp. 17 neutrophil$.mp. 18 neutrofil$.mp. 19 Agranulocytosis/ 20 agranulocytosis.mp. 21 ae.fs. 22 colony stimulating factor/ or granulocyte colony stimulating factor/ or recombinant granulocyte colony stimulating factor/ 23 G-CSF.mp. 24 "granulocyte colony stimulating factor".mp. 25 Hemopoietic Growth Factor/ 26 Growth Promotor/ 27 (hematopoietic growth factors or haematopoietic growth factors).mp. 28 r-metHuG-CSF.mp. 29 filgrastim.mp. 30 121181-53-1.rn. 31 Neulasta.mp. 32 pegfilgrastim.mp.
A-4 33 208265-92-3.rn. 34 Neupogen.mp. 35 or/16-34 36 and/7,15,35 8567
OVERVIEW Interface: EBSCOhost Databases: CINAHL Plus with Full Text <1937 to 2007> Date of Search: October 29, 2007 Study Types: Left Open Limits: None SYNTAX GUIDE .sh At the end of a phrase, searches the phrase as a subject heading MH Major Subject Heading + Explode a subject heading * Truncation symbol, or wildcard: retrieves plural or variations of a word TI Title SO Journal or Source STRATEGY
Line # Search Results S28 ( S27 and S14 ) 12 S27 ( S26 or S25 or S24 or S23 or S22 or S21 or S20 or S19 or S18 or S17 or S16 or S15 ) S26 Neupogen S25 pegfilgrastim S24 Neulasta S23 filgrastim S22 ( hematopoietic w1 growth w1 factors or haematopoietic w1 growth w1 factors ) S21 granulocyte w1 colony w1 stimulating w1 factor S20 G-CSF S19 ( (MH "Colony-Stimulating Factors") or (MH "Granulocyte Colony- Stimulating Factor") or (MH "Hematopoietic Cell Growth Factors") or (MH "Growth Substances") ) S18 (MH "Agranulocytosis+") S17 neutrofil* S16 neutrophil* S15 neutropen* S14 ( S6 or S5 or S4 or S3 or S2 or S1 ) and ( S12 or S11 or S10 or S9 or S8 ) S13 ( S12 or S11 or S10 or S9 or S8 ) S12 ( Avonex or Betaseron or Rebif or Rebetron ) S11 ( peg or peg-IFN* or peginterferon* or peg-interferon* or pegylat* w3 interferon* or nonpegylat* w3 interferon* or non-pegylat* w3 interferon* or
A-5 polyethylene w1 glycol w3 interferon* or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex ) S10 ( interferon* or IFN ) S9 ( Antiviral w1 therapy or anti-viral w1 therapy ) and hepatitis S8 (MH "Antiviral Agents") S7 ( S6 or S5 or S4 or S3 or S2 or S1 ) S6 Hepatitis C or HCV S5 MH "Hepatitis C, Chronic" S4 MH "Hepatitis C" S3 (MH "Hepatitis, Viral, Human") S2 (MH "Hepatitis, Chronic") S1 (MH "Hepatitis")
OVERVIEW Interface: EBSCOhost Databases: Health Source: Nursing/Academic Edition <1975 to present> Date of Search: October 29, 2007 Study Types: Left Open Limits: None STRATEGY
Line # Search Results S18 ( S17 and S6 and S1 ) 28 S17 ( S16 or S15 or S14 or S13 or S12 or S11 or S10 or S9 or S8 or S7 ) S16 Neupogen S15 Neulasta S14 filgrastim S13 ( growth w1 substances or growth w1 factors ) S12 G-CSF S11 colony w1 stimulating w1 factor S10 agranulocytosis S9 neutrophil* S8 neutrophil* S7 neutropen* S6 ( S5 or S4 or S3 or S2 ) S5 ( Avonex or Betaseron or Rebif or Rebetron ) S4 ( peg or peg-IFN* or peginterferon* or peg-interferon* or pegylat* w3 interferon* or nonpegylat* w3 interferon* or non-pegylat* w3 interferon* or polyethylene w1 glycol w3 interferon* or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex ) S3 ( interferon* or IFN ) S2 ( antiviral w1 therapy or anti-viral w1 therapy or antiviral w1 agent* or anti- viral w1 agent* ) and hepatitis S1 ( hepatitis or "Hepatitis C" or HCV )
A-6 OVERVIEW Interface: EBSCOhost Databases: Academic Search Premier <1975 to present> Date of Search: October 29, 2007 Study Types: Left Open Limits: None STRATEGY
Line # Search Results S25 ( S24 and S10 and S3 ) 60 S24 ( S23 or S22 or S21 or S20 or S19 or S18 or S17 or S16 or S15 or S14 or S13 or S12 or S11 ) S23 Neupogen S22 pegfilgrastim S21 Neulasta S20 filgrastim S19 DE "FILGRASTIM" S18 ( hematopoietic w1 growth w1 factors or haematopoietic w1 growth w1 factors ) S17 granulocyte w1 colony w1 stimulating w1 factor S16 G-CSF S15 ( DE "COLONY-stimulating factors (Physiology)" or DE "HEMATOPOIETIC growth factors" or DE "GRANULOCYTE-macrophage colony-stimulating factor" or DE "GROWTH factors" ) S14 ( (DE "AGRANULOCYTOSIS") or (DE "NEUTROPENIA") ) S13 neutrofil* S12 neutrophil* S11 neutropen* S10 ( S9 or S8 or S7 or S6 or S5 or S4 ) S9 ( Avonex or Betaseron or Rebif or Rebetron ) S8 ( peg or peg-IFN* or peginterferon* or peg-interferon* or pegylat* w3 interferon* or nonpegylat* w3 interferon* or non-pegylat* w3 interferon* or polyethylene w1 glycol w3 interferon* or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex ) S7 ( interferon* or IFN ) S6 DE "INTERFERON" S5 ( Antiviral w1 therapy or anti-viral w1 therapy ) and hepatitis S4 DE "ANTIVIRAL agents" S3 ( S2 or S1 ) S2 ( Hepatitis C or HCV ) S1 ( DE "HEPATITIS" or DE "HEPATITIS C" or DE "HEPATITIS, Viral" )
A-7 OVERVIEW Interface: Wiley Databases: Health Technology Assessment Database (HTA) via The Cochrane Library <4th Quarter 2007> Date of Search: November 1, 2007 Study Types: Not Required Limits: None SYNTAX GUIDE MeSH descriptor Medical Subject Heading Explode all trees Explode a subject heading * Truncation symbol, or wildcard: retrieves plural or variations of a word NEXT Requires words are adjacent to each other (in any order) ti Title ab Abstract kw Heading Word; usually includes subject headings and controlled vocabulary STRATEGY Line # Search Results #1 "Hepatitis OR hepatitis C and (interferon OR IFN OR peg OR ((pegylat* 1 or nonpegylat* or non-pegylat*) adj3 interferon*) or (polyethylene glycol adj3 interferon*) or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex or Avonex or Betaseron or Rebif or Rebetron) and neutropen* or "colony stimulating factor" or hematopoietic growth factors or haematopoietic growth factors or filgrastim or Neulasta or pegfilgrastim or Neupogen
A-8 OVERVIEW
Interface: ISI Thomson Research Databases: Science Citation Index Expanded® (SCI-EXPANDED)(via ISI Web of KnowledgeSM <1900-present> Social Science Citation Index® (SSCI)(via ISI Web of KnowledgeSM) <1956- present> Date of Search: October 29, 2007 Study Types: Left Open Limits: None
SYNTAX GUIDE
TS= Topic * Truncation symbol, or wildcard: retrieves plural or variations of a word SAME Finds records containing terms in the title, the same sentence in the abstract, or the same keyword phrase TI= Title of Article SO= Source
MULTI-FILE STRATEGY Line # Search Results #15 #14 AND #6 AND #1 369 #14 #13 OR #12 OR #11 OR #10 OR #9 OR #8 OR #7 #13 TS=Neupogen #12 TS=pegfilgrastim #11 TS=Neulasta #10 TS=filgrastim #9 TS=(colony SAME stimulating SAME factor* OR colony-stimulating SAME factor* OR growth SAME substances OR growth SAME factors) #8 TS=agranulocytosis #7 TS=(neutropen* OR neutrophil* OR neutrofil*) #6 #5 OR #4 OR #3 OR #2 #5 TS=(Avonex or Betaseron or Rebif or Rebetron) #4 TS=( peg or peg-IFN* or peginterferon* or peg-interferon* or pegylat* w3 interferon* or nonpegylat* w3 interferon* or non-pegylat* w3 interferon* or polyethylene w1 glycol w3 interferon* or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex ) #3 TS=(interferon* or IFN) #2 TS=((antiviral SAME therap* OR anti-viral SAME therap* OR antiviral SAME agent* OR anti-viral SAME agent*) AND TS=hepatitis) #1 TS=(hepatitis OR HCV)
A-9 OVERVIEW Interface: ISI Thomson Research Databases: BIOSIS Previews® (via ISI Web of KnowledgeSM ) <1969-present> Date of Search: October 29, 2007 Study Types: Left Open Limits: None STRATEGY Line # Search Results #16 #15 AND #6 AND #1 464 #15 #14 OR #13 OR #12 OR #11 OR #10 OR #9 OR #8 OR #7 #14 CA=(121181-53-1 OR 208265-92-3) #13 TS=Neupogen #12 TS=pegfilgrastim #11 TS=Neulasta #10 TS=filgrastim #9 TS=(colony SAME stimulating SAME factor* OR colony-stimulating SAME factor* OR growth SAME substances OR growth SAME factors) #8 TS=agranulocytosis #7 TS=(neutropen* OR neutrophil* OR neutrofil*) #6 #5 OR #4 OR #3 OR #2 #5 TS=(Avonex or Betaseron or Rebif or Rebetron) #4 TS=( peg or peg-IFN* or peginterferon* or peg-interferon* or pegylat* w3 interferon* or nonpegylat* w3 interferon* or non-pegylat* w3 interferon* or polyethylene w1 glycol w3 interferon* or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex ) #3 TS=(interferon* or IFN) #2 TS=((antiviral SAME therap* OR anti-viral SAME therap* OR antiviral SAME agent* OR anti-viral SAME agent*) AND TS=hepatitis) #1 TS=(hepatitis OR HCV)
A-10 OVERVIEW Interface: National Library of Medicine (NLM) Databases: PubMed® Date of Search: October 29, 2007 Study Types: Left Open Limits: None SYNTAX GUIDE MeSH Terms Medical Subject Heading terms SB Subset RN EC/RN Number TIAB Title/Abstract * Truncation symbol, or wildcard: retrieves plural or variations of a word STRATEGY Line # Search Results #42 Search ((#14) AND (#25)) AND (#41) 369 #41 Search ((((((((((((#26) OR (#27)) OR (#28)) OR (#29)) OR (#30)) OR (#31)) OR (#34)) OR (#35)) OR (#36)) OR (#37)) OR (#38)) OR (#39)) OR (#40) #40 Search 208265-92-3[RN] #39 Search ("pegfilgrastim"[TIAB] NOT Medline[SB]) OR "pegfilgrastim"[Substance Name] OR Neulasta[Text Word] #38 Search 121181-53-1[RN] #37 Search ("filgrastim"[TIAB] NOT Medline[SB]) OR "filgrastim"[MeSH Terms] OR r-metHuG-CSF[Text Word] OR Neupogen[Text Word] #36 Search "growth substances"[MeSH Terms] #35 Search haematopoietic cell growth factors[Text Word] OR "hematopoietic cell growth factors"[MeSH Terms] OR hematopoietic cell growth factors[Text Word] #34 Search ("granulocyte colony-stimulating factor"[TIAB] NOT Medline[SB]) OR "granulocyte colony-stimulating factor"[MeSH Terms] OR "recombinant granulocyte colony stimulating factor"[Text Word] OR "granulocyte colony stimulating factor, recombinant"[MeSH Terms] OR G-CSF[Text Word] #31 Search "colony-stimulating factors, recombinant"[MeSH Terms] OR "recombinant colony-stimulating factors"[Text Word] #30 Search "colony-stimulating factors"[MeSH Terms] OR colony-stimulating factors[Text Word] #29 Search "agranulocytosis"[MeSH Terms] OR agranulocytosis[Text Word] #28 Search neutrofil* #27 Search neutrophil* #26 Search neutropen* #25 Search (((((#16) OR (#17)) OR (#18)) OR (#20)) OR (#23)) OR (#24) #24 Search peg OR peg-IFN OR peg-interferon* OR pegylat* OR nonpegylat* OR non-pegylat* OR "polyethylene glycol interferon*" OR Pegetron OR Pegasys OR Roferon OR Intron A OR Infergen OR Avonex or Betaseron or Rebif or Rebetron
A-11 #23 Search IFN[All Fields] #20 Search ("interferons"[TIAB] NOT Medline[SB]) OR "interferons"[MeSH Terms] OR ("interferon alfa-2b"[TIAB] NOT Medline[SB]) OR "interferon alfa-2b"[MeSH Terms] OR interferon[Text Word] #18 Search antiviral therap* OR anti-viral therap* #17 Search antiviral agent* OR anti-viral agent* #16 Search "antiviral agents"[MeSH Terms] OR "antiviral agents"[Pharmacological Action] OR antiviral agents[Text Word] #14 Search (((((#2) OR (#4)) OR (#6)) OR (#8)) OR (#10)) OR (#13) #13 Search HCV[All Fields] #10 Search "chronic hepatitis c"[Text Word] OR "hepatitis c, chronic"[MeSH Terms] OR Hepatitis C, Chronic[Text Word] #8 Search "hepatitis c"[MeSH Terms] OR hepatitis c[Text Word] #6 Search "human viral hepatitis"[Text Word] OR "hepatitis, viral, human"[MeSH Terms] OR hepatitis, viral, human[Text Word] #4 Search "hepatitis, chronic"[MeSH Terms] OR "chronic hepatitis"[Text Word] #2 Search "hepatitis"[MeSH Terms] OR hepatitis[Text Word]
OTHER DATABASES
Database Search terms Date of Search ABI/INFORM (Hepatitis or Hepatitis C or HCV) AND (interferon* or IFN or peg* October Global or nonpeg* or non-peg* or "anti-viral agent*" or "antiviral agent" or 31, 2007 (ProQuest®) "anti-viral therap*" or "antiviral therap*" ) 1971 – current Results: 116 ProQuest® (Hepatitis or Hepatitis C or HCV) AND (interferon* or IFN or peg* October Dissertations & or nonpeg* or non-peg* or "anti-viral agent*" or "antiviral agent" or 31, 2007 Theses Full Text "anti-viral therap*" or "antiviral therap*" ) AND NOT (mouse or 1861 - current mice ) Results: 119 OCLC (kw: Hepatitis or kw: Hepatitis w C or kw: HCV) and (kw: October PapersFirst interferon* or kw: IFN) 29, 2007 OCLC Results: PapersFirst: 676; ProceedingsFirst: 2 ProceedingsFirst (OCLC FirstSearch)
A-12 Literature Search Strategy for Cost-Effectiveness Studies
OVERVIEW Interface: Ovid Databases: *Medline® <1950 to March Week 3 2008> *EBM Reviews – Cochrane Central Register of Controlled Trials <1st Quarter 2008> *HealthSTAR <1966 to March 2008> Date of Search: October 29, 2007 Date of Update: March 27, 2008 Study Types: Economic Filter applied (line 39-88) Limits: None SYNTAX GUIDE / At the end of a phrase, searches the phrase as a subject heading MeSH Medical Subject Heading fs Floating subheading exp Explode a subject heading $ Truncation symbol, or wildcard: retrieves plural or variations of a word * Indicates that the marked subject heading is a primary topic ADJ Requires words are adjacent to each other (in any order) ADJ# Adjacency within # number of words (in any order) .ti Title .ab Abstract .jn. Journal .mp Title, Abstract, Subject Heading, CAS Registry/EC Number Word .tw Textword: Title, Abstract and Subject Heading .pt Publication type .rn CAS registry number MULTI-FILE STRATEGY Line # Search History Results 1 Hepatitis/ 2 Hepatitis, Chronic/ 3 Hepatitis, Viral, Human/ 4 exp Hepatitis C/ 5 Hepatitis C, Chronic/ 6 Hepacivirus/ 7 (Hepatitis C or HCV$).mp. [mp=title, original title, abstract, name of substance word, subject heading word] 8 or/1-7
A-13 9 exp Antiviral Agents/ 10 (((antiviral or anti-viral) adj1 therap$) and hepatitis).mp. 11 (interferon$ or IFN).mp. 12 9008-11-1.rn. 13 peginterferon$.mp. 14 (peg or peg-IFN or peg-interferon$ or ((pegylat$ or nonpegylat$ or non- pegylat$) adj3 interferon$) or (polyethylene glycol adj3 interferon$) or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex).mp. 15 (Avonex or Betaseron or Rebif or Rebetron).mp. 16 or/9-15 17 neutropen$.mp. 18 neutrophil$.mp. 19 neutrofil$.mp. 20 Agranulocytosis/ 21 agranulocytosis.mp. 22 ae.fs. 23 colony-stimulating factors/ or colony-stimulating factors, recombinant/ or exp granulocyte colony stimulating factor/ 24 G-CSF.mp. 25 "granulocyte colony stimulating factor".mp. 26 hematopoietic cell growth factors/ 27 Growth Substances/ 28 (hematopoietic growth factors or haematopoietic growth factors).mp. 29 r-metHuG-CSF.mp. 30 Filgrastim/ 31 filgrastim.mp. 32 121181-53-1.rn. 33 Neulasta.mp. 34 pegfilgrastim.mp. 35 208265-92-3.rn. 36 Neupogen.mp. 37 or/17-36 38 and/8,16,37 39 exp economics/ 40 exp budgets/ 41 quality of life/ 42 value of life/ 43 quality-adjusted life years/ 44 models, economic/ 45 markov chains/ 46 monte carlo method/ 47 decision tree/ 48 exp "Drug Utilization"/ 49 exp "utilization review"/ 50 ec.fs. 51 ut.fs. 52 econom$.tw. 53 (cost? or costing? or costly or costed).tw. 54 (price? or pricing?).tw.
A-14 55 discount$.mp. 56 afford$.tw. 57 (pharmacoeconomic? or (pharmaco adj1 economic?)).tw. 58 (socioeconomic$ or (socio adj1 economic$)).mp. 59 budget$.tw. 60 expenditure$.tw. 61 (dollar$ or money$ or inexpensive or purchas$ or accounts or accounting or payment$ or fund$ or finance? or taxes).mp. 62 (hospital adj1 charg$).mp. 63 (value adj1 (money or monetary)).tw. 64 (rate adj1 setting).mp. 65 (fee or fees).tw. 66 quality of life.tw. 67 QOL$.tw. 68 HRQOL$.tw. 69 "quality adjusted life year$".tw. 70 QALY$.tw. 71 CBA$.tw. 72 CEA.tw. 73 CUA.tw. 74 utilit$.tw. 75 (markov$ or markow$).tw. 76 (monte carlo or montecarlo or monte-carlo).tw. 77 sensitivity analy$.mp. 78 (decision adj2 (tree$ or analys$ or model$)).tw. 79 ((clinical or critical or patient) adj1 (path? or pathway?)).tw. 80 (managed adj2 (care or network?)).tw. 81 (low adj1 cost).mp. 82 (high adj1 cost).mp. 83 (health?care adj1 cost$).mp. 84 (fiscal or funding or financial or finance).tw. 85 (cost adj1 estimate$).mp. 86 (cost adj1 variable).mp. 87 (unit adj1 cost$).mp. 88 or/39-87 89 38 and 88 220
A-15 OVERVIEW Interface: Ovid Databases: *Ovid MEDLINE® In-Process & Other Non-Indexed Citations, EBM Reviews – Cochrane Database of Systematic Reviews (CDSR) <4th Quarter 2007> EBM Reviews – Database of Abstracts and Reviews (DARE) <4th Quarter 2007> International Pharmaceutical Abstracts <1970 to October 2007> Pascal <1987 to September 2007> Date of Search: October 29, 2007 Date of Update: March 27, 2008 Study Types: Economic Filter applied (line 22-55) Limits: None MULTI-FILE STRATEGY Line # Search Results 1 (Hepatitis C or HCV$).mp. 2 (((antiviral or anti-viral) adj1 (agent$ or therap$)) and hepatitis).mp. 3 (interferon$ or IFN).mp. 4 peginterferon$.mp. 5 (peg or peg-IFN or peg-interferon$ or (pegylat$ adj3 interferon$) or (polyethylene glycol adj3 interferon$) or Pegetron or Pegasys or Roferon or Intron A or Infergen).mp. 6 (Avonex or Betaseron or Rebif or Rebetron).mp. 7 or/3-6 8 neutropen$.mp. 9 neutrophil$.mp. 10 neutrofil$.mp. 11 agranulocytosis.mp. 12 (colony-stimulating factor? or colony stimulating factor?).mp. 13 G-CSF.mp. 14 (hematopoietic growth factors or haematopoietic growth factors).mp. 15 r-metHuG-CSF.mp. 16 filgrastim.mp. 17 Neulasta.mp. 18 pegfilgrastim.mp. 19 Neupogen.mp. 20 or/8-19 21 and/1,7,20 22 (health?care adj1 (cost$ or financ$)).mp. 23 (financial adj1 management).mp. 24 utili?ation.mp. 25 econom$.tw. 26 (cost? or costing? or costly or costed).tw. 27 (price? or pricing?).tw. 28 (pharmacoeconomic? or (pharmaco adj1 economic?)).tw. 29 (socioeconomic$ or (socio adj1 economic$)).mp. 30 budget$.tw.
A-16 31 expenditure$.tw. 32 (dollar$ or money$ or inexpensive or purchas$ or accounts or accounting or payment$ or fund$ or finance? or taxes).mp. 33 (value adj1 (money or monetary)).tw. 34 (rate adj1 setting).mp. 35 (fee or fees).tw. 36 quality of life.tw. 37 QOL$.tw. 38 HRQOL$.tw. 39 "quality adjusted life year$".tw. 40 QALY$.tw. 41 CBA$.tw. 42 CEA.tw. 43 CUA.tw. 44 utilit$.tw. 45 (markov$ or markow$).tw. 46 (monte carlo or montecarlo or monte-carlo).tw. 47 sensitivity analy$.mp. 48 (decision adj2 (tree$ or analys$ or model$)).tw. 49 ((clinical or critical or patient) adj1 (path? or pathway?)).tw. 50 (managed adj2 (care or network?)).tw. 51 (fiscal or funding or financial or finance).tw. 52 (cost adj1 estimate$).mp. 53 (cost adj1 variable).mp. 54 (unit adj1 cost$).mp. 55 or/22-54 56 and/21,55 3
OVERVIEW Interface: Ovid Databases: *EMBASE <1988 to 2008 Week 12> Date of Search: October 29, 2007 Date of Update: March 27, 2008 Study Types: Economic Filter applied (line 36-86) Limits: None STRATEGY Line # Search Results 1 HEPATITIS/ 2 Chronic Hepatitis/ 3 exp Virus Hepatitis/ 4 Hepatitis C/ 5 hepatitis c virus/ 6 (Hepatitis C or HCV$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] or/1-6 7 exp Antivirus Agent/
A-17 8 (((antiviral or anti-viral) adj1 therap$) and hepatitis).mp. 9 (interferon$ or IFN).mp. 10 9008-11-1.rn. 11 peginterferon$.mp. 12 (peg or peg-IFN or peg-interferon$ or ((pegylat$ or nonpegylat$ or non- 13 pegylat$) adj3 interferon$) or (polyethylene glycol adj3 interferon$) or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex).mp. (Avonex or Betaseron or Rebif or Rebetron).mp. 14 or/8-14 15 neutropen$.mp. 16 neutrophil$.mp. 17 neutrofil$.mp. 18 Agranulocytosis/ 19 agranulocytosis.mp. 20 ae.fs. 21 colony stimulating factor/ or granulocyte colony stimulating factor/ or 22 recombinant granulocyte colony stimulating factor/ G-CSF.mp. 23 "granulocyte colony stimulating factor".mp. 24 Hemopoietic Growth Factor/ 25 Growth Promotor/ 26 (hematopoietic growth factors or haematopoietic growth factors).mp. 27 r-metHuG-CSF.mp. 28 filgrastim.mp. 29 121181-53-1.rn. 30 Neulasta.mp. 31 pegfilgrastim.mp. 32 208265-92-3.rn. 33 Neupogen.mp. 34 or/16-34 35 and/7,15,35 36 exp health economics/ 37 exp "health care cost"/ 38 exp "quality of life"/ 39 socioeconomics/ 40 economic aspect/ 41 financial management/ 42 health care financing/ 43 "Hospital Cost"/ 44 "cost of illness"/ 45 "Cost Benefit Analysis"/ 46 "Cost Effectiveness Analysis"/ 47 exp "Cost Minimization Analysis"/ 48 "Cost Control"/ 49 monte carlo method/ 50 "Decision Tree"/ 51 drug utilization/ 52 "Utilization Review"/ 53 pe.fs.
A-18 54 econom$.tw. 55 (cost? or costing? or costly or costed).tw. 56 (price? or pricing?).tw. 57 (pharmacoeconomic? or (pharmaco adj1 economic?)).tw. 58 (socioeconomic$ or (socio adj1 economic$)).mp. 59 budget$.tw. 60 expenditure$.tw. 61 (dollar$ or money$ or inexpensive or purchas$ or accounts or accounting or 62 payment$ or fund$ or finance? or taxes).mp. 63 (value adj1 (money or monetary)).tw. 64 (rate adj1 setting).mp. 65 (fee or fees).tw. 66 quality of life.tw. 67 QOL$.tw. 68 HRQOL$.tw. 69 "quality adjusted life year$".tw. 70 QALY$.tw. 71 CBA$.tw. 72 CEA.tw. 73 CUA.tw. 74 utilit$.tw. 75 (markov$ or markow$).tw. 76 (monte carlo or montecarlo or monte-carlo).tw. 77 sensitivity analy$.mp. 78 (decision adj2 (tree$ or analys$ or model$)).tw. 79 ((clinical or critical or patient) adj1 (path? or pathway?)).tw. 80 (managed adj2 (care or network?)).tw. 81 (health?care adj1 cost$).mp. 82 (fiscal or funding or financial or finance).tw. 83 (cost adj1 estimate$).mp. 84 (cost adj1 variable).mp. 85 (unit adj1 cost$).mp. 86 or/37-85 87 and/36,86 1245
A-19 OVERVIEW Interface: EBSCOhost Databases: CINAHL® <1937 to present> Date of Search: October 29, 2007 Study Types: Economic Filter applied (S29-S42) Limits: None Applied SYNTAX GUIDE .sh At the end of a phrase, searches the phrase as a subject heading DE Descriptor MH Major Subject Heading + Explode a subject heading * Truncation symbol, or wildcard: retrieves plural or variations of a word TI Title SO Journal or Source STRATEGY Line # Search Terms Results S43 ( S42 and S28 ) 6 S42 ( S41 or S40 or S39 or S38 or S37 or S36 or S35 or S34 or S33 or S32 or S31 or S30 or S29 ) S41 ( fiscal or funding or financial or finance ) or ( healthcare w1 cost* or health- care w1 cost* ) or ( cost w1 estimate* or cost w1 variable or unit w1 cost* ) S40 ( decision w2 tree* or decision w2 analys* or decision w2 model* ) or ( clinical w1 path* or clinical w1 pathway* or critical w1 path* or critical w1 pathway* or patient w1 path* or patient w1 pathway* ) or ( managed n2 care or managed n2 network ) S39 ( "quality of life" or QOL* or HRQOL* or "quality adjusted life year*" or QALY* or CBA* or CEA* or CUA* ) or ( utilit* or markov* or markow* or monte n1 carlo or montecarlo or monte-carlo ) or sensitivity w1 analy* S38 ( dollar* or money*or inexpensive or purchas* or accounts or accounting or payment* or fund* or finance? or taxes ) or ( hospital n1 charg* or value n1 money or value n1 monetary ) or ( rate n1 setting or fee or fees ) S37 ( pharmacoeconomic? or pharmaco-economic? ) or ( socioeconomic* or socio- economic* ) or ( budget* or expenditure* ) S36 ( cost? or costing? or costly or costed ) or ( price? or pricing? ) or ( discount* or afford* ) S35 econom* S34 ( (MH "Drug Utilization") or (MH "Health Resource Utilization") or (MH "Utilization Review") ) S33 (MH "Decision Trees") S32 (MH "Economic Value of Life") S31 (MH "Quality of Life+") S30 (MH "Budgets") S29 (MH "Economics+") S28 ( S27 and S14 )
A-20 S27 ( S26 or S25 or S24 or S23 or S22 or S21 or S20 or S19 or S18 or S17 or S16 or S15 ) S26 Neupogen S25 pegfilgrastim S24 Neulasta S23 filgrastim S22 ( hematopoietic w1 growth w1 factors or haematopoietic w1 growth w1 factors ) granulocyte w1 colony w1 stimulating w1 factor S21 G-CSF S20 ( (MH "Colony-Stimulating Factors") or (MH "Granulocyte Colony-Stimulating S19 Factor") or (MH "Hematopoietic Cell Growth Factors") or (MH "Growth Substances") ) S18 (MH "Agranulocytosis+") S17 neutrofil* S16 neutrophil* S15 neutropen* S14 ( S6 or S5 or S4 or S3 or S2 or S1 ) and ( S12 or S11 or S10 or S9 or S8 ) S13 ( S12 or S11 or S10 or S9 or S8 ) S12 ( Avonex or Betaseron or Rebif or Rebetron ) S11 ( peg or peg-IFN* or peginterferon* or peg-interferon* or pegylat* w3 interferon* or nonpegylat* w3 interferon* or non-pegylat* w3 interferon* or polyethylene w1 glycol w3 interferon* or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex ) S10 ( interferon* or IFN ) S9 ( Antiviral w1 therapy or anti-viral w1 therapy ) and hepatitis S8 (MH "Antiviral Agents") S7 ( S6 or S5 or S4 or S3 or S2 or S1 ) S6 Hepatitis C or HCV S5 MH "Hepatitis C, Chronic" S4 MH "Hepatitis C" S3 (MH "Hepatitis, Viral, Human") S2 (MH "Hepatitis, Chronic") S1 (MH "Hepatitis")
OVERVIEW Interface: EBSCOhost Databases: Health Source: Nursing/Academic Edition <1975 to present> Date of Search: October 29, 2007 Study Types: Economic Filter applied (S19-S23) Limits: None Applied STRATEGY Line # Search Terms Results S24 ( S23 and S18 ) 3 S23 ( S22 or S21 or S20 or S19 ) S22 ( fiscal or funding or financial or finance ) or ( cost w1 estimate* or cost w1 variable or unit w1 cost* )
A-21 S21 ( sensitivity w1 analy* or decision w2 tree* or decision w2 analys* or decision w2 model* ) or ( clinical w1 path* or clinical w1 pathway* or critical w1 path* or critical w1 pathway* or patient w1 path* or patient w1 pathway* ) or ( managed w2 care or managed w2 network* ) S20 ( value w1 money or value w1 monetary or rate w1 setting or fee or fees ) or ( "quality of life" or QOL* or HRQOL* or "quality adjusted life year*" or QALY or CBA* or CEA* or CUA* ) or ( utilit* or markov* or markow* or monte w1 carlo or montecarlo or monte-carlo ) S19 ( health-care w1 cost* or health?care w1 financ* or financial w1 management ) or ( econom* or cost? or costing? or costly or costed or price? or pricing? or pharmacoeconomic? or pharmaco-economic? or socioeconomic* or socio- economic* ) or ( budget* or expenditure* or dollar* or money* or inexpensive or purchas* or accounts or accounting or payment* or fund* or finance? or taxes ) S18 ( S17 and S6 and S1 ) S17 ( S16 or S15 or S14 or S13 or S12 or S11 or S10 or S9 or S8 or S7 ) S16 Neupogen S15 Neulasta S14 filgrastim S13 ( growth w1 substances or growth w1 factors ) S12 G-CSF S11 colony w1 stimulating w1 factor S10 agranulocytosis S9 neutrophil* S8 neutrophil* S7 neutropen* S6 ( S5 or S4 or S3 or S2 ) S5 ( Avonex or Betaseron or Rebif or Rebetron ) S4 ( peg or peg-IFN* or peginterferon* or peg-interferon* or pegylat* w3 interferon* or nonpegylat* w3 interferon* or non-pegylat* w3 interferon* or polyethylene w1 glycol w3 interferon* or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex ) S3 ( interferon* or IFN ) S2 ( antiviral w1 therapy or anti-viral w1 therapy or antiviral w1 agent* or anti- viral w1 agent* ) and hepatitis S1 ( hepatitis or "Hepatitis C" or HCV )
OVERVIEW Interface: EBSCOhost Databases: Academic Search Premier <1975 to present> Date of Search: October 29, 2007 Study Types: Economic Filter applied (S19-S26) Limits: None Applied STRATEGY Line # Search Terms Results S27 ( (S26 and S18) ) 7
A-22 S26 ( S25 or S24 or S23 or S22 or S21 or S20 or S19 ) S25 ( fiscal or funding or financial or finance or healthcare w1 cost* or health-care w1 cost* or cost w1 estimate* or cost w1 variable or unit w1 cost* ) S24 ( hospital n1 charg* or value n1 money or value n1 monetary or rate n1 setting or fee or fees ) or ( "quality of life" or QOL* or HRQOL* or "quality adjusted life year*" or QALY* or CBA* or CEA* or CUA* or utilit* or markov* or markow* or monte n1 carlo or montecarlo or monte-carlo or sensitivity w1 analy* ) or ( decision w2 tree* or decision w2 analys* or decision w2 model* or clinical w1 path* or clinical w1 pathway* or critical w1 path* or critical w1 pathway* or patient w1 path* or patient w1 pathway* or managed n2 care or managed n2 network ) S23 ( econom* or cost? or costing? or costly or costed or price? or pricing? or discount* or afford* ) or ( pharmacoeconomic? or pharmaco-economic? or socioeconomic* or socio-economic* or budget* or expenditure* ) or ( dollar* or money*or inexpensive or purchas* or accounts or accounting or payment* or fund* or finance? or taxes ) S22 ( (DE "DRUG utilization" ) and (DE "MEDICAL care, Cost of" or DE "MEDICAL economics" or DE "MEDICAL care -- Cost control") ) S21 DE "DECISION trees" S20 DE "BUDGET" S19 ( DE "ECONOMICS" or DE "MEDICAL economics" or DE "QUALITY of life" or DE "VALUE" ) S18 ( S17 and S6 and S1 ) S17 ( S16 or S15 or S14 or S13 or S12 or S11 or S10 or S9 or S8 or S7 ) S16 Neupogen S15 Neulasta S14 filgrastim S13 ( growth w1 substances or growth w1 factors ) S12 G-CSF S11 colony w1 stimulating w1 factor S10 agranulocytosis S9 neutrophil* S8 neutrophil* S7 neutropen* S6 ( S5 or S4 or S3 or S2 ) S5 ( Avonex or Betaseron or Rebif or Rebetron ) S4 ( peg or peg-IFN* or peginterferon* or peg-interferon* or pegylat* w3 interferon* or nonpegylat* w3 interferon* or non-pegylat* w3 interferon* or polyethylene w1 glycol w3 interferon* or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex ) S3 ( interferon* or IFN ) S2 ( antiviral w1 therapy or anti-viral w1 therapy or antiviral w1 agent* or anti- viral w1 agent* ) and hepatitis S1 ( hepatitis or "Hepatitis C" or HCV )
A-23 OVERVIEW Interface: EBSCOhost Databases: EconLit <1969 to present> Date of Search: October 30, 2007 Study Types: Economic Filter applied Limits: None Applied MULTI-FILE STRATEGY Line # Search Terms Results S1 (hepatitis or "Hepatitis C" or HCV) and (health-care w1 cost* or health?care w1 22 financ* or financial w1 management or econom* or cost? or costing? or costly or costed or price? or pricing? or pharmacoeconomic? or pharmaco-economic? or socioeconomic* or socio-economic* or budget* or expenditure* or dollar* or money* or inexpensive or purchas* or accounts or accounting or payment* or fund* or finance? or taxes or value w1 money or value w1 monetary or rate w1 setting or fee or fees or "quality of life" or QOL* or HRQOL* or "quality adjusted life year*" or QALY or CBA* or CEA* or CUA* or utilit* or markov* or markow* or monte w1 carlo or montecarlo or monte-carlo or sensitivity w1 analy* or decision w2 tree* or decision w2 analys* or decision w2 model* or clinical w1 path* or clinical w1 pathway* or critical w1 path* or critical w1 pathway* or patient w1 path* or patient w1 pathway* or managed w2 care or managed w2 network* or fiscal or funding or financial or finance or cost w1 estimate* or cost w1 variable or unit w1 cost*)
OVERVIEW Interface: Wiley Databases: Health Technology Assessment Database (HTA) via The Cochrane Library; NHS Economic Evaluation Database via The Cochrane Library (NHS EED) Date of Search: November 1, 2007 Study Types: Left Open Limits: None Applied SYNTAX GUIDE * Truncation symbol, or wildcard: retrieves plural or variations of a word NEXT Requires words are adjacent to each other (in any order) MULTI-FILE STRATEGY Line # Search Results "Hepatitis OR hepatitis C and (interferon OR IFN OR peg OR ((pegylat* or 3 nonpegylat* or non-pegylat*) adj3 interferon*) or (polyethylene glycol adj3 interferon*) or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex or Avonex or Betaseron or Rebif or Rebetron) and neutropen* or "colony stimulating factor" or hematopoietic growth factors or haematopoietic growth factors or filgrastim or Neulasta or pegfilgrastim or Neupogen
A-24 OVERVIEW Interface: ISI Thomson Research Databases: Science Citation Index Expanded® (SCI-EXPANDED)(via ISI Web of KnowledgeSM) <1900-present>; Social Science Citation Index® (SSCI)(via ISI Web of KnowledgeSM) <1956- present> Date of Search: October 29, 2007 Study Types: Economic Filter applied (#16 - #19) Limits: None SYNTAX GUIDE TS= Topic * Truncation symbol, or wildcard: retrieves plural or variations of a word SAME Finds records containing terms in the title, the same sentence in the abstract, or the same keyword phrase. TI= Title of Article SO= Source MULTI-FILE STRATEGY
Line Search Results #20 #19 AND #15 54 #19 #18 OR #17 OR #16 #18 TS=(decision SAME tree* or decision SAME analys* or decision SAME model* or clinical SAME path* or clinical SAME pathway* or critical SAME path* or critical SAME pathway* or patient SAME path* or patient SAME pathway* or managed SAME care or managed SAME network* or fiscal or funding or financial or finance or cost SAME estimate* or cost SAME variable or unit SAME cost*) #17 TS=(fund* or finance* or taxes or value SAME money or value SAME monetary or rate SAME setting or fee or fees or "quality of life" or QOL* or HRQOL* or "quality adjusted life year*" or QALY or CBA* or CEA* or CUA* or utilit* or markov* or markow* or monte SAME carlo or montecarlo or monte-carlo or sensitivity SAME analy*) #16 TS=(health-care SAME cost* or health*care SAME financ* or financial SAME management or econom* or cost* or costing* or costly or costed or price* or pricing* or pharmacoeconomic* or pharmaco-economic* or socioeconomic* or socio-economic* or budget* or expenditure* or dollar* or money* or inexpensive or purchas* or accounts or accounting or payment*) #15 #14 AND #6 AND #1 #14 #13 OR #12 OR #11 OR #10 OR #9 OR #8 OR #7 #13 TS=Neupogen #12 TS=pegfilgrastim #11 TS=Neulasta #10 TS=filgrastim #9 TS=(colony SAME stimulating SAME factor* OR colony-stimulating SAME factor* OR growth SAME substances OR growth SAME factors)
A-25 #8 TS=agranulocytosis #7 TS=(neutropen* OR neutrophil* OR neutrofil*) #6 #5 OR #4 OR #3 OR #2 #5 TS=(Avonex or Betaseron or Rebif or Rebetron) #4 TS=( peg or peg-IFN* or peginterferon* or peg-interferon* or pegylat* w3 interferon* or nonpegylat* w3 interferon* or non-pegylat* w3 interferon* or polyethylene w1 glycol w3 interferon* or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex ) #3 TS=(interferon* or IFN) #2 TS=((antiviral SAME therap* OR anti-viral SAME therap* OR antiviral SAME agent* OR anti-viral SAME agent*) AND TS=hepatitis) #1 TS=(hepatitis OR HCV)
OVERVIEW Interface: ISI Thomson Research Databases: BIOSIS Previews® (via ISI Web of KnowledgeSM) <1969-present> Date of Search: October 29, 2007 Study Types: Economic Filter applied (#17-#20) Limits: None
STRATEGY
Line Search Results #21 #20 AND #1 4 #20 #19 OR #18 OR #17 #19 TS=(decision SAME tree* or decision SAME analys* or decision SAME model* or clinical SAME path* or clinical SAME pathway* or critical SAME path* or critical SAME pathway* or patient SAME path* or patient SAME pathway* or managed SAME care or managed SAME network* or fiscal or funding or financial or finance or cost SAME estimate* or cost SAME variable or unit SAME cost*) #18 TS=(fund* or finance* or taxes or value SAME money or value SAME monetary or rate SAME setting or fee or fees or "quality of life" or QOL* or HRQOL* or "quality adjusted life year*" or QALY or CBA* or CEA* or CUA* or utilit* or markov* or markow* or monte SAME carlo or montecarlo or monte-carlo or sensitivity SAME analy*) #17 TS=(health-care SAME cost* or health*care SAME financ* or financial SAME management or econom* or cost* or costing* or costly or costed or price* or pricing* or pharmacoeconomic* or pharmaco-economic* or socioeconomic* or socio-economic* or budget* or expenditure* or dollar* or money* or inexpensive or purchas* or accounts or accounting or payment*) #16 #15 AND #6 AND #1 #15 #14 OR #13 OR #12 OR #11 OR #10 OR #9 OR #8 OR #7 #14 CA=(121181-53-1 OR 208265-92-3) #13 TS=Neupogen #12 TS=pegfilgrastim #11 TS=Neulasta
A-26 #10 TS=filgrastim #9 TS=(colony SAME stimulating SAME factor* OR colony-stimulating SAME factor* OR growth SAME substances OR growth SAME factors) #8 TS=agranulocytosis #7 TS=(neutropen* OR neutrophil* OR neutrofil*) #6 #5 OR #4 OR #3 OR #2 #5 TS=(Avonex or Betaseron or Rebif or Rebetron) #4 TS=( peg or peg-IFN* or peginterferon* or peg-interferon* or pegylat* w3 interferon* or nonpegylat* w3 interferon* or non-pegylat* w3 interferon* or polyethylene w1 glycol w3 interferon* or Pegetron or Pegasys or Roferon or Intron A or Infergen or Wellferon or Berlex or PegIntron or Reiferon Etard or Cinnovex ) #3 TS=(interferon* or IFN) #2 TS=((antiviral SAME therap* OR anti-viral SAME therap* OR antiviral SAME agent* OR anti-viral SAME agent*) AND TS=hepatitis) #1 TS=(hepatitis OR HCV)
OTHER DATABASES
Database Search terms Date of Search ProQuest® (Hepatitis or Hepatitis C or HCV) AND (interferon* or IFN October 29, 2007 Dissertations & or peg* or nonpeg* or non-peg* or "anti-viral agent*" or Theses Full Text "antiviral agent" or "anti-viral therap*" or "antiviral 1861 - current therap*" ) AND NOT (mouse or mice ) Results: 119 OCLC PapersFirst (kw: Hepatitis or kw: Hepatitis w C or kw: HCV) and (kw: OCLC First Search interferon* or kw: IFN) Results:
A-27 Grey Literature and Hand Searches for Clinical Effectiveness and Cost-effectiveness
Dates for Search: October 31 – November 5, 2007 Keywords: hepatitis C, interferon, filgrastim, pegfilgrastim Limits: Publication years: 2002-2007
Meetings and Conference Abstracts
American Association for the Study of Liver Disease (AASLD) www.aasld.org
American Society of Virology www.asv.org
BioMed Central http://www.biomedcentral.com/meetings/
Canadian Association for the Study of the Liver (CASL) http://hepatology.ca/cm
European Viral Hepatitis Educational Initiative (EVHEI) http://www.evhei.com/home/home.cfm#
European Association for the Study of the Liver (EASL) www.easl.ch
Microbiology and Virology Meetings http://www.tulane.edu/~dmsander/garryfavwebmeet.html
NLM Gateway http://gateway.nlm.nih.gov
Trial Registers
CenterWatch Drugs in Clinical Trials Database http://www.centerwatch.com/professional/cwpipeline/
ClinicalTrials.gov http://clinicaltrials.gov/
Cost Effectiveness Analysis (CEA) Registry https://research.tufts-nemc.org/cear/default.aspx
A-28 CRISP http://crisp.cit.nih.gov/
Current Controlled Trials http://www.controlled-trials.com
EVHEI (European Viral Hepatitis Educational Initiative) http://www.evhei.com/home/home.cfm
National Research Register 2007 Issue 4 www.update-software.com/National
ReFER (Research Findings Register) http://liinwww.ira.uka.de/bibliography/Misc/refer.nhs.uk.html
TRIP Database http://www.tripdatabase.com/index.html
Adverse Events and Safety
Aggressive Research Intelligence Facility (ARIF) http://www.arif.bham.ac.uk/NICE/h-nice-a-z/h-nice.htm
Canada’s Adverse Drug Reaction Database http://www.hc-sc.gc.ca/dhp-mps/medeff/databasdon/agreement_accord_e.html
Canadian Agency for Drugs and Technologies in Health http://cadth.ca/
Therapeutic Goods and Adverse Drug Reactions Unit (Australia) http://www.tga.gov.au/adr/adrac.htm
TOXLINE® (U.S. National Library of Medicine) http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?TOXLINE
US FDA http://www.fda.gov/
Hand Searches—last 5 years for abstracts, posters, conferences
Canadian Journal of Gastroenterology
Hepatology: official journal of the American Association for the Study of Liver Diseases
Journal of Viral Hepatitis
A-29 Journal of Viral Hepatology
Journal of Hepatology
Search Engines
Google http://www.google.ca/
A-30 APPENDIX 2: EXCLUDED STUDIES
Clinical Review (N = 240)
Study Design (N = 58) The following studies were uncontrolled or were not primary research in evaluating the use of G-CSF for antiviral therapy induced neutropenia in patients with hepatitis C.
1. Pegasys (peginterferon alfa-2a) drug description. RxList: The Internet Drug Index. 2008 [cited 17 June 2008]. Available from: www.rxlist.com/cgi/generic/pegasys.htm
2. Abdala E, Gotardo DRM, Bonazzi PR, Bacchella T. Hepatitis C treatment before and after liver transplant. Braz J Infect Dis 2007;11(Suppl 1):61-5.
3. Adis International Limited. First reports of serious adverse drug reactions in recent weeks. Drugs Ther Perspect 2006;22(11):21.
4. Alcantar RM. Treatment of hepatitis C before and after liver transplantation. Ann Hepatol 2006;5(Suppl 1):S63-6.
5. Almasio PL, Cottone C, D'Angelo F. Pegylated interferon therapy in chronic hepatitis C: lights and shadows of an innovative treatment. Dig Liver Dis 2007;39(Suppl 1):S88-S95.
6. Annicchiarico BE, Siciliano M, Di Srasi C, Bombardieri G. Proximal splenic artery embolization allows pegylated interferon and ribavirin combination therapy in chronic hepatitis C virus-infected patients with severe cytopenia. Eur J Gastroenterol Hepatol 2006;18(1):119-21.
7. Asselah T, Bouton V, Boyer N, Marcellin P. Treatment of chronic hepatitis C. J Pharmacie Clinique 2006;25(1):57-65. (French).
8. Bacon BR, McHutchison JG. Into the light: strategies for battling hepatitis C. Am J Manag Care 2007;13(Suppl 12):S319-26.
9. Ballerga GE, Fernandez N, Losso M. Management of adverse effects of hepatitis C treatment. Acta Gastroenterol Latinoam 2006;36(Suppl 1):S61-4. (Spanish).
10. Brady B, Siebert U, Sroczynski G, Murphy G, Husereau D, Sherman M, et al. Clinical and cost-effectiveness of interferon-based therapies for chronic hepatitis C virus infection. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2007 Mar. Report No.: Technology Overview no 27.
11. Brau N. Chronic hepatitis C in patients with HIV/AIDS: a new challenge in antiviral therapy. J Antimicrob Chemother 2005;56(6):991-5.
A-31 12. Carreno V. Present treatment expectations and risks of chronic hepatitis C. Clin Microbiol Infect 2002;8(2):74-9.
13. Chapko MK, Dominitz JA. Cost-effectiveness of growth factors during hepatitis C anti-viral therapy. Aliment Pharmacol Ther 2006;24(7):1067-77.
14. Ciesla A, Mach T, Zejc-Bajsarowicz M, Sobczyk-Krupiarz I, Warunek W, Janas- Skulina U, et al. Haematological side effects in patients with chronic viral hepatitis C during treatment with alpha interferon and ribavirin. Przeglad Gastroenterol 2007;2:74-8. (Polish).
15. Collantes RS, Younossi ZM. The use of growth factors to manage the hematological side effects of PEG-interferon alfa and ribavirin. J Clin Gastroenterol 2005;39(Suppl 1):S9-S13.
16. Contreras Jorge MS. Treatment of hepatitis C virus infection and hemophilia. Ann Hepatol 2006;5(Suppl 1):S56-7.
17. Dar Santos AE, Partovi N, Ford JA, Yoshida EM. Use of hematopoietic growth factors as adjuvant therapy for anemia and neutropenia in the treatment of hepatitis C. Ann Pharmacother 2007;41(2):268-75.
18. Dieterich DT, Spivak JL. Hematologic disorders associated with hepatitis C virus infection and their management. Clin Infect Dis 2003;37(4):533-41.
19. Everson GT. Treatment of chronic hepatitis C in patients with decompensated cirrhosis. Rev Gastroenterol Disord 2004;4(Suppl 1):S31-8.
20. Fredrick RT, Hassanein TI. Role of growth factors in the treatment of patients with HIV/HCV coinfection and patients with recurrent hepatitis C following liver transplantation. J Clin Gastroenterol 2005;39(Suppl 1):S14-S22.
21. Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002;36(5 Suppl 1):S237-44.
22. Gournay J, Richou C. Treatment of chronic hepatitis C: side effects, tolerability and quality of life. Gastroenterol Clin Biol 2002;26(Spec No 2):B60-75. (French).
23. Guay DR. Evaluation of interferon in the treatment of hepatitis C virus infection. Formulary 1999;34:137-40,143.
24. Hauschild A, Hinrichsen H, Christophers E. Side effects of interferon therapy and their management. Hautarzt 2000;51(10):793-803. (German).
25. Heathcote J. Do we know how to achieve optimal response to pegylated interferon alpha and ribavirin? J Hepatol 2003;39(1):136-8.
A-32 26. Jansen PLM, Reesink HW. Antiviral effect of peginterferon alfa-2b and alfa-2a compared. J Hepatol 2006;45(2):172-3.
27. Keating GM, Plosker GL. Peginterferon alpha-2a (40KD) plus ribavirin: a review of its use in the management of patients with chronic hepatitis C and persistently 'normal' ALT levels. Drugs 2005;65(4):521-36.
28. Lima MA, Auriel E, Wuthrich C, Borenstein NM, Koralnik IJ. Progressive multifocal leukoencephalopathy as a complication of hepatitis C virus treatment in an HIV- negative patient. Clin Infect Dis 2005;41(3):417-9.
29. LoBuono C. Guidelines for treating HCV-HIV patients undergo update. Drug Topics 2004;148(6):HSE15.
30. Maddrey WC. Safety of combination interferon alfa-2b/ribavirin therapy in chronic hepatitis C-relapsed and treatment-naive patients. Semin Liv Dis 1999;19(suppl 1):67- 75.
31. McHutchison JG, Bacon BR, Owens GS. Making it happen: managed care considerations in vanquishing hepatitis C. Am J Managed Care 2007;13(suppl 12):S327-36.
32. Muir AJ, McHutchison JG. Growth factors during HCV therapy may be "cost- effective", but are they "effective"? Hepatology 2006;44(6):1400-3.
33. Mulhall BP, Younossi Z. Impact of adherence on the outcome of antiviral therapy for chronic hepatitis C. J Clin Gastroenterol 2005;39(Suppl 1):S23-7.
34. Murphy MJ. HIV/HCV co-infection has treatment implications. HIV Clin 2005;12(2):1.
35. Ong JP, Younossi ZM. Managing the hematologic side effects of antiviral therapy for chronic hepatitis C: anemia, neutropenia, and thrombocytopenia. Cleve Clin J Med 2004;71(Suppl 3):S17-21.
36. Parker SD. Evaluation and treatment of hepatitis C in patients with coexisting HIV infection. Med Gen Med 2006;8(3).
37. Pawlotsky JM. Therapy of hepatitis C: from empiricism to eradication. Hepatology 2006;43(2 Suppl 1):S207-20.
38. Poniachik J. Management of adverse reactions to chronic hepatitis C treatment. Ann Hepatol 2006;5(Suppl 1):S67-8.
39. Roget M. Secondary effects of treatment with interferon and ribavirin. Enfermedades Emergentes 2003;5(3):181-9. (Spanish).
A-33 40. Russo MW, Fried MW. Side effects of therapy for chronic hepatitis C. Gastroenterology 2003;124(6):1711-9.
41. Sadovsky R. Ribavirin and interferon alfa is chronic hepatitis C. Am Fam Physician 1997;55(4):1369.
42. Saracco G, Verme G. Interferon in the treatment of chronic virus hepatitis. Argomenti di Gastroenterologia Clinica 1990;3(5):269-76. (Italian).
43. Shepherd J, Jones J, Hartwell D, Davidson P, Price A, Waugh N. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C: a systematic review and economic evaluation. Health Technol Assess 2007;11(11):iii-106.
44. Sherman M, Shafran S, Burak K, Doucette K, Wong W, Girgrah N, et al. Management of chronic hepatitis C: consensus guidelines. Can J Gastroenterol 2007;21(Suppl C):25C-34C.
45. Shiffman ML. Side effects of medical therapy for chronic hepatitis C. Ann Hepatol 2004;3(1):5-10.
46. Shiffman ML. Treating chronic hepatitis C virus after liver transplantation: balancing the risks against the chance for success. Liver Transpl 2007;13(8):1088-91.
47. Shobokshi OA, Tantawe AO, Al-Kayyal BM. Chronic hepatitis C treatment. Side effects and their management. Saudi Med J 2003;24(Suppl 2):S76-8.
48. Sulkowski MS. Management of the hematologic complications of hepatitis C therapy. Clin Liver Dis 2005;9(4):601-16.
49. Thevenot T, Di Martino V, Lunel-Fabiani F, Vanlemmens C, Becker MC, Bronowicki JP, et al. Complementary treatments of chronic viral hepatitis C. Gastroenterol Clin Biol 2006;30(2):197-214. (French).
50. Thevenot T, Cadranel JF, Di Martino V, Pariente A, Causse X, Renou C, et al. A national French survey on the use of growth factors as adjuvant treatment of chronic hepatitis C. Hepatology 2007;45(2):377-83.
51. Thevenot T, Di Martino V, Mathurin P, Cervoni JP, Richou C, Lunel-Fabiani F. Benefit of hematopoietic growth factors in the treatment of chronic hepatitis C. Hepato-Gastro 2007;14(5):339-46. (French).
52. Thevenot T, Di Martino V, Lunel-Fabiani F. Re-evaluating the use of growth factors as adjuvant treatment of chronic hepatitis C: reply. Hepatology 2007;46(4):1308-9.
53. Trautwein C, Tacke F. Treatment of hepatitis B and C virus infection. Dtsch Med Wochensch 2003;128(Suppl 2):S87-9. (German).
A-34 54. Vigani AG. Adverse event management. Braz J Infect Dis 2007;11(Suppl 1):66-70.
55. Weis NM, Krarup HB, Skinhoj P. Pegylated interferon-alpha for the treatment of chronic hepatitis C. Ugeskr Laeger 2003;165(44):4211-5. (Danish).
56. Worman HJ. Re-evaluating the use of growth factors as adjuvant treatment of chronic hepatitis C. Hepatology 2007;46(4):1307-8.
57. Zein NN. Managing side effects related to treatment for chronic hepatitis C. Gastroenterol Hepatol 2007;3(6 Suppl 20):12-21.
58. Zeuzem S. Diagnosis and selective therapy in hepatitis C virus infections with interferon alpha. Therapie und Erfolg Dermatologie 1998;28(5):200-5. (German).
Population (N = 122) The following studies were excluded because they did not include treatment naïve adult (>18 yr.) hepatitis C patients with antiviral therapy-induced neutropenia.
1. Side effects. Safety and effectiveness of interferon and ribavirin in HIV+ people co- infected with hepatitis C virus. Treatment Update 2001;12(8):4-5.
2. Update on the use of alternative interferon formulations in difficult-to-treat hepatitis C patients. Gastroenterol Hepatol 2006;21(12 Suppl 18):6-10.
3. Abdelmalek MF, Firpi RJ, Soldevila-Pico C, Reed AI, Hemming AW, Liu C, et al. Sustained viral response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C. Liver Transpl 2004;10(2):199-207.
4. Ahmad J, Dodson SF, Demetris AJ, Fung JJ, Shakil AO. Recurrent hepatitis C after liver transplantation: a nonrandomized trial of interferon alfa alone versus interferon alfa and ribavirin. Liver Transpl 2001;7(10):863-9.
5. Arase Y, Suzuki F, Suzuki Y, Akuta N, Kawamura Y, Kobayashi M, et al. Side effects of combination therapy of peginterferon and ribavirin for chronic hepatitis C. Intern Med 2007;46(22):1827-32.
6. Ascione A, De Luca M, Di Costanzo GG, Picciotto FP, Lanza AG, Canestrini C, et al. Incidence of side effects during therapy with different types of alpha interferon: a randomised controlled trial comparing recombinant alpha 2b versus leukocyte interferon in the therapy of naive patients with chronic hepatitis C. Curr Pharm Des 2002;8(11):977-80. Erratum in: Curr Pharm Des 2002;8(28):2581.
7. Barnes E, Harcourt G, Brown D, Lucas M, Phillips R, Dusheiko G, et al. The dynamics of T-lymphocyte responses during combination therapy for chronic hepatitis C virus infection. Hepatology 2002;36(3):743-54.
A-35 8. Ben-Ari Z, Mor E, Shaharabani E, Bar-Nathan N, Shapira Z, Tur-Kaspa R. Combination of interferon-alpha and ribavirin therapy for recurrent hepatitis C virus infection after liver transplantation. Transplant Proc 2000;32(4):714-6.
9. Bernstein D, Kleinman L, Barker CM, Revicki DA, Green J. Relationship of health- related quality of life to treatment adherence and sustained response in chronic hepatitis C patients. Hepatology 2002;35(3):704-8.
10. Bizollon T, Palazzo U, Ducerf C, Chevallier M, Elliott M, Baulieux J, et al. Pilot study of the combination of interferon alfa and ribavirin as therapy of recurrent hepatitis C after liver transplantation. Hepatology 1997;26(2):500-4.
11. Brady B, Siebert U, Sroczynski G, Murphy G, Husereau D, Sherman M, et al. Pegylated interferon combined with ribavirin for chronic hepatitis C virus infection: an economic evaluation. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2007 Mar. Report No.: Technology report no. 82.
12. Brok J, Gluud LL, Gluud C. Effects of adding ribavirin to interferon to treat chronic hepatitis C infection: a systematic review and meta-analysis of randomized trials. Arch Intern Med 2005;165(19):2206-12.
13. Brown RSJ. Review article: a pharmacoeconomic analysis of thrombocytopenia in chronic liver disease. Aliment Pharmacol Ther 2007;26(Suppl 1):41-8.
14. Carreno V, Quiroga JA. Biologic response modifiers in chronic hepatitis C. J Hepatol 1995;22(Suppl 1):122-6.
15. Carreno V, Parra A, Navas S, Quiroga JA. Granulocyte-macrophage colony- stimulating factor as adjuvant therapy for factor as adjuvant therapy for interferon alpha treatment of chronic hepatitis C. Cytokine 1996;8(4):318-22.
16. Castedal M, Siewert-Delle A, Olausson M, Friman S. Combination therapy of interferon alpha-2b and ribavirin for recurrent hepatitis C after liver transplantation. Transplant Proc 2003;35(2):820-1.
17. Chan TM, Ho SK, Tang CS, Tse KC, Lam MF, Lai KN, et al. Pilot study of pegylated interferon-alpha 2a in dialysis patients with chronic hepatitis C virus infection. Nephrology 2007;12(1):11-7.
18. Choudhury M, Mann H, Goddard NJ, Lee C. An outline of the current orthopaedic management of haemophilic disease of the upper limb. Haemophilia 2007;13(5):599- 605.
19. Cindoruk M, Karakan T, Selahattin U. Therapy for treatment-refractory chronic hepatitis C virus genotype 1b infection: a retrospective analysis. Curr Ther Res 2005;66(5).
A-36 20. Cooper CL, Al-Bedwawi S, Lee C, Garber G. Rate of infectious complications during interferon-based therapy for hepatitis C is not related to neutropenia. Clin Infect Dis 2006;42(12):1674-8.
21. Cooper CL, Al-Bedwawi S. Infection rates in HIV-HCV patients treated with interferon are similar to those in HCV mono-infection and not related to neutropenia. HIV Clin Trials 2006;7(5):251-4.
22. de Oliveira AC. Treatment options in the management of thrombocytopenia in patients infected with HCV. Braz J Infect Dis 2007;11(Suppl 1):71-2.
23. de Vera M, Eghtesad B, Jain A, Fung J. Progression and treatment of recurrent hepatitis C after liver transplantation in patients co-infected with HIV. Hepatology 2003;38(4 Suppl 1):161A
24. Del Corso L, Bresci G, Romanelli AM, Borelli A, Pentimone F. Recombinant interferon alpha-2b in the treatment of chronic hepatitis C in the elderly. Giornale di Gerontologia 1993;41(7):273-5. (Italian).
25. Desmond CP, Roberts SK, Dudley F, Mitchell J, Day C, Nguyen S, et al. Sustained virological response rates and durability of the response to interferon-based therapies in hepatitis C patients treated in the clinical setting. J Viral Hepat 2006;13(5):311-5.
26. Di Marco V, Almasio PL, Ferraro D, Calvaruso V, Alaimo G, Peralta S, et al. Peg- interferon alone or combined with ribavirin in HCV cirrhosis with portal hypertension: a randomized controlled trial. J Hepatol 2007;47(4):484-91.
27. Domen RE, Horowitz S. Vancomycin-induced neutropenia associated with anti- granulocyte antibodies. Immunohematology 1990;6(2):41-3.
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Intervention (N = 26) The following studies were excluded because study participants did not receive GCSF or did not experience a reduction or discontinuation of their antiviral therapy in response to antiviral-induced neutropenia.
1. The impact of growth factors on PEG-intron and rebetol dose reduction in patients treated for genotype 1 chronic hepatitis C. Gastroenterology 2006;130(4 Suppl 2):A783-4.
2. Brau N, Bini EJ, Currie S, Shen H, Schmidt WN, King PD, et al. Black patients with chronic hepatitis C have a lower sustained viral response rate than non-Blacks with genotype 1, but the same with genotypes 2/3, and this is not explained by more frequent dose reductions of interferon and ribavirin. J Viral Hepat 2006;13(4):242-9.
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5. Cinelli R, Di GG, Nasti G, Tedeschi R, Dal ML, Canzonieri V, et al. Efficacy and safety of combined treatment with pegylated-IFN-alpha2b plus ribavirin in HIV- hepatitis C virus-co-infected patients. AIDS 2004;18(7):1079-80.
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9. Foruny JR, Blazquez J, Moreno A, Barcena R, Gil-Grande L, Quereda C, et al. Safe use of pegylated interferon/ribavirin in hepatitis C virus cirrhotic patients with hypersplenism after partial splenic embolization. Eur J Gastroenterol Hepatol 2005;17(11):1157-64.
10. Fukuda A, Kobayashi H, Teramura K, Yoshimoto S, Ohsawa N. Effects of interferon- alpha on peripheral neutrophil counts and serum granulocyte colony-stimulating factor levels in chronic hepatitis C patients. Cytokines Cell Mol Ther 2000;6(3):149- 54.
11. Gaeta GB, Precone DF, Felaco FM, Bruno R, Spadaro A, Stornaiuolo G, et al. Premature discontinuation of interferon plus ribavirin for adverse effects: a multicentre survey in 'real world' patients with chronic hepatitis C. Aliment Pharmacol Ther 2002;16(9):1633-9.
12. Iacobellis A, Siciliano M, Perri F, Annicchiarico BE, Leandro G, Caruso N, et al. Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: a controlled study. J Hepatol 2007;46(2):206-12.
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14. Kim JH, Han KH, Lee KS, Park YN, Ahn SH, Chon CY, et al. Efficacy and long- term follow up of combination therapy with interferon alpha and ribavirin for chronic hepatitis C in Korea. Yonsei Med J 2006;47(6):793-8.
15. Koliouskas D, Sidiropoulos I, Masmanidou M, Dokas S, Ziakas A. Comparative analysis and effect of GM-CSF on neutropenia in peg-interferon alpha-2b and ribavirin-treated chronic hepatitis C patients. J Hepatol 2002;36(Suppl 1):238.
16. Koliouskas D, Sidiropoulos I, Masmanidou M, Mandraveli K, Lazaraki G, Dokas S, et al. Comparative analysis and effect of GM-CSF on neutropenia in peg-interferon alpha-2b and ribavirin-treated chronic hepatitis C patients. Hepatology 2002;36(4 Part 2):587A.
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18. Kugelmas M, Ryan O, Spiegelman GA, Mah'moud M. Do growth factors improve EVR in chronic HCV-genotype 1 patients treated with PEG-Intron and ribavirin? Gastroenterology 2007;132(4):A780.
19. Lai MY, Kao JH, Yang PM, Wang JT, Chen PJ, Chan KW, et al. Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. Gastroenterology 1996;111(5):1307-12.
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21. Rotman Y, Ben-Ari Z, Braun M, Cohen M, Cohen-Ezra O, Manhaim V, et al. Low body weight predicts PEG-interferon alfa-2a (PEGASYS) induced neutropenia in chronic hepatitis C patients. Hepatology 2005;42(4 Suppl 1):664A-5A.
22. Sarin SK, Goyal A, Kumar S, Guptan RC, Hashmi AZ, Sakhuja P, et al. A randomized trial of a 4- vs 12-week daily interferon dose regimen combined with ribavirin in treatment of patients with chronic hepatitis C. Hepatobiliary Pancreat Dis Int 2004;3(1):42-8.
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24. Shiffman ML. Chronic hepatitis C and granulocyte macrophage stimulating factor. CRISP. 1996. [cited 11 Mar 2008]. Available from: http://crisp.cit.nih.gov
25. Smith AD, Rockey DC, Mascitelli L, Pezzetta F. Viral hepatitis C. Lancet 2004;363(9409):661.
26. Soza A, Everhart J, Ghany M, Doo E, Heller T, Promrat K, et al. Neutropenia associated with alpha interferon therapy of chronic hepatitis C. Gastroenterology 2002;123(Suppl 1):75-6.
Outcomes (N = 13) The following studies were excluded because they did not report data on at least one outcome of interest.
1. Beckebaum S, Cicinnati VR, Zhang X, Malago M, Dirsch O, Erim Y, et al. Combination therapy with peginterferon alpha-2B and ribavirin in liver transplant
A-47 recipients with recurrent HCV infection: preliminary results of an open prospective study. Transplant Proc 2004;36(7):2207.
2. Cacoub P, Rosenthal E, Halfon P, Sene D, Perronne C, Pol S. Treatment of hepatitis C virus and human immunodeficiency virus coinfection: from large trials to real life. J Viral Hepat 2006;13(10):678-82.
3. Castells L, Vargas V, Allende H, Bilbao I, Luis LJ, Margarit C, et al. Combined treatment with pegylated interferon (alpha-2b) and ribavirin in the acute phase of hepatitis C virus recurrence after liver transplantation. J Hepatol 2005;43(1):53-9.
4. Di Bisceglie AM, Ghalib RH, Hamzeh FM, Rustgi VK. Early virologic response after peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin treatment in patients with chronic hepatitis C. J Viral Hepat 2007;14(10):721-9.
5. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr. et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. New Engl J Med 2002;347(13):975-82.
6. Golia P, Talal AH, Jacobson IM, Flynn S, Golia P. A preliminary study of growth factors versus dose reduction for peg interferon alfa-2b and ribavirin associated neutropenia and anemia in HIV/HCV co-infected patients. Gastroenterology 2003;124(4, Suppl 1):A766.
7. Hanouneh IA, Miller C, Aucejo FN, Lopez R, Quinn MK, Zein NN. Recurrent hepatitis C after liver transplantation: ON-treatment prediction of response to peginterferon/ribavirin therapy. Liver Transpl 2008;14(1):53-8.
8. Horoldt B, Haydon G, O'Donnell K, Dudley T, Nightingale P, Mutimer D. Results of combination treatment with pegylated interferon and ribavirin in cirrhotic patients with hepatitis C infection. Liver Int 2006;26(6):650-9.
9. Liu CJ, Chen PJ, Lai MY, Kao JH, Jeng YM, Chen DS. Ribavirin and interferon is effective for hepatitis C virus clearance in hepatitis B and C dually infected patients. Hepatology 2003;37(3):568-76.
10. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001:352(9286):958-65.
11. Pau AK, McLaughlin MM, Hu Z, Agyemang AF, Polis MA, Kottilil S. Predictors for hematopoietic growth factors use in HIV/HCV-coinfected patients treated with peginterferon alfa 2b and ribavirin. AIDS Patient Care STDs 2006;20(9):612-9.
12. Talal A. Treatment of anemia and neutropenia in HIV/HCV coinfected patients treated with pegylated interferon and ribavirin. ClinicalTrials. 2002. [cited 10 Mar 2008]. Available from: http://clinicaltrials.gov
A-48 13. Witthoft T, Moller B, Wiedmann KH, Mauss S, Link R, Lohmeyer J, et al. Safety, tolerability and efficacy of peginterferon alpha-2a and ribavirin in chronic hepatitis C in clinical practice: the German Open Safety Trial. J Viral Hepat 2007;14(11):788- 96.
Insufficient Data (N = 12) The following studies met inclusion criteria, but did not provide enough data to be included in the review.
1. Bahra M, Neumann UP, Jacob D, Langrehr JM, Neuhaus R, Neuhaus P. Long term results after therapy with pegylated interferon alpha 2A in HCV positive liver transplant recipients. Hepatology 2005;42(4 Suppl 1):488A-9A.
2. Berenguer M, Palau A, Fernandez A, Benlloch S, Aguilera V, Prieto M, et al. Efficacy, predictors of response, and potential risks associated with antiviral therapy in liver transplant recipients with recurrent hepatitis C. Liver Transpl 2006;12(7):1067-76.
3. Carey E, Rosati M, Anderson M, Khatib M, Vargas H, Harrison M, et al. Use of G- CSF allows for optimal PEG-INF dosing during therapy for hepatitis C virus with pegylated interferon and ribavirin. Hepatology 2002;36(4 Part 2):604A
4. Carrion JA, Navasa M, Garcia-Retortillo M, Garcia-Pagan JC, Crespo G, Brugera M, et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study. Gastroenterology 2007;132:1746-56.
5. Cash W, Patterson K, Callender M, McDougall NI. Does adjuvant therapy with erythropoietin and GCSF improve sustained virological response in patients receiving combination therapy with pegylated interferon and ribavirin for chronic hepatitis C? J Hepatol 2007;46(Suppl 1):S219-20.
6. Gotardo DRM, Abdala E, Bonazzi PR, Campos SV, Silva LS, Estela R, et al. Safety of reccurent hepatitis C treatment after liver transplantation with use of adjuvants. Liver Transpl 2007:13(Suppl 1):S152-3
7. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140(5):346-55.
8. Neff GW, Montalbano M, O'Brien CB, Nishida S, Safdar K, Bejarano PA, et al. Treatment of established recurrent hepatitis C in liver-transplant recipients with pegylated interferon-alfa-2b and ribavirin therapy. Transplantation 2004;78(9):1303- 7.
A-49 9. Nudo CG, Wong P, Hilzenrat N, Deschenes M. Elderly patients are at greater risk of cytopenia during antiviral therapy for hepatitis C. Can J Gastroenterol 2006;20(9):589-92.
10. Shehab TM, Fontana RJ, Oberhelman K, Marrero JA, Su GL, Lok ASF. Effectiveness of interferon alpha-2b and ribavirin combination therapy in the treatment of naive chronic hepatitis C patients in clinical practice. Clin Gastroenterol Hepatol 2004;2(5):425-31.
11. Tran TT, Patel Y, Benner JS, Petrilla AA, Poordad F. Neutropenia associated with pegylated interferon treatment for chronic hepatitis C: a single center experience. Am J Gastroenterol 2005;100(9 Suppl S):S127.
12. Turbide C, Soulellis C, Deschenes M, Hilzenrat N. Does a rapid decline in the hematological and biochemical parameters induced by interferon and ribavirin combination therapy for the hepatitis C virus predict a sustained viral response? Can J Gastroenterol 2008;22(2):149-52.
Unavailable (N = 9) The following articles could not be retrieved or were pending translation and could not be assessed by the deadline for the review.
1. Interferons and hepatitis C. Prescrire Int 1996;5(24):98-100.
2. Arase Y. Side effects of interferon therapy for chronic hepatitis C. Nippon Rinsho 2006;64(7):1363-7. (Japanese).
3. Charuworn P, Ahmed AM, Ahmed A. The role of recombinant human granulocyte colony-stimulating factor (G-CSF, filgrastim) in the management of pegylated interferon alfa-2b (PEG-IFN) induced neutropenia in patients with chronic hepatitis C (CHC). Am J Gastroenterol 2003;98(9 Suppl):S88.
4. Cromie S, Roberts S, Jenkins P, Dudley F. Interferon and ribavirin treatment of chronic hepatitis C: a systematic review of randomised controlled trials. Proceedings of the 48th American Association for the Study of Liver Diseases; 1997 Chicago; IL; 1997.
5. Hwang SY, Lee HJ, Park KT, Kim KY, Lee SM, Park CW, et al. Effectiveness and complications of combination therapy with interferon alpha and ribavirin in patients with chronic hepatitis C. Korean J Gastroenterol 2007;49(3):166-72. (Korean).
6. Rhine LA, Pruemer JM. Innovative guidelines for cost conscious times: evaluating G- CSF use. 30th Annual ASHP Midyear Clinical Meeting 1995;30:PMCS-49.
7. Schmid M, Homoncik M, Jessner W, Formann E, Ferenci P, Gangl A, et al. Suppression of hematopoiesis during therapy with different IFN-alpha mono- and combination therapy regimes. Proceedings of Digestive Disease; 2003, May 17-22, 2003 Orlando; FL; 2003.
A-50 8. Vashakidze ET, Gegeshidze TN, Zhamutashvili MT, Svanidze MB. Side effects of the combined antiviral therapy in patients with chronic hepatitis C. Georgian Med News 2007;7-8(148-149):28. (Russian).
9. Zarski JP, Leroy V, Maynard-Muet M. Treatment of viral hepatitis C. Revue du Praticien-Medecine Generale 1997;11(384):11-5. (French).
A-51 APPENDIX 3: EXCLUDED STUDIES
Economic Review (N = 237)
Study Design (N = 56) The following studies were uncontrolled or were not primary research in evaluating the use of G-CSF for antiviral therapy induced neutropenia in patients with hepatitis C.
1. Pegasys (peginterferon alfa-2a) drug description. RxList: The Internet Drug Index. 2008 [cited 17 June 2008]. Available from: www.rxlist.com/cgi/generic/pegasys.htm
2. Abdala E, Gotardo DRM, Bonazzi PR, Bacchella T. Hepatitis C treatment before and after liver transplant. Braz J Infect Dis 2007;11(Suppl 1):61-5.
3. Adis International Limited. First reports of serious adverse drug reactions in recent weeks. Drugs Ther Perspect 2006;22(11):21.
4. Alcantar RM. Treatment of hepatitis C before and after liver transplantation. Ann Hepatol 2006;5(Suppl 1):S63-6.
5. Almasio PL, Cottone C, D'Angelo F. Pegylated interferon therapy in chronic hepatitis C: lights and shadows of an innovative treatment. Dig Liver Dis 2007;39(Suppl 1):S88-S95.
6. Annicchiarico BE, Siciliano M, Di Srasi C, Bombardieri G. Proximal splenic artery embolization allows pegylated interferon and ribavirin combination therapy in chronic hepatitis C virus-infected patients with severe cytopenia. Eur J Gastroenterol Hepatol 2006;18(1):119-21.
7. Asselah T, Bouton V, Boyer N, Marcellin P. Treatment of chronic hepatitis C. Journal de Pharmacie Clinique 2006;25(1):57-65. (French).
8. Bacon BR, McHutchison JG. Into the light: strategies for battling hepatitis C. Am J Manag Care 2007;13(Suppl 12):S319-26.
9. Ballerga GE, Fernandez N, Losso M. Management of adverse effects of hepatitis C treatment. Acta Gastroenterol Latinoam 2006;36(Suppl 1):S61-4. (Spanish).
10. Brady B, Siebert U, Sroczynski G, Murphy G, Husereau D, Sherman M, et al. Clinical and cost-effectiveness of interferon-based therapies for chronic hepatitis C virus infection. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2007 Mar. Report No.: Technology Overview no 27.
11. Brau N. Chronic hepatitis C in patients with HIV/AIDS: a new challenge in antiviral therapy. J Antimicrob Chemother 2005;56(6):991-5.
A-52 12. Carreno V. Present treatment expectations and risks of chronic hepatitis C. Clin Microbiol Infect 2002;8(2):74-9.
13. Ciesla A, Mach T, Zejc-Bajsarowicz M, Sobczyk-Krupiarz I, Warunek W, Janas- Skulina U, et al. Haematological side effects in patients with chronic viral hepatitis C during treatment with alpha interferon and ribavirin. Przeglad Gastroenterol 2007;2:74-8. (Polish).
14. Collantes RS, Younossi ZM. The use of growth factors to manage the hematological side effects of PEG-interferon alfa and ribavirin. J Clin Gastroenterol 2005;39(Suppl 1):S9-S13.
15. Contreras Jorge MS. Treatment of hepatitis C virus infection and hemophilia. Ann Hepatol 2006;5(Suppl 1):S56-7.
16. Dar Santos AE, Partovi N, Ford JA, Yoshida EM. Use of hematopoietic growth factors as adjuvant therapy for anemia and neutropenia in the treatment of hepatitis C. Ann Pharmacother 2007;41(2):268-75.
17. Dieterich DT, Spivak JL. Hematologic disorders associated with hepatitis C virus infection and their management. Clin Infect Dis 2003;37(4):533-41.
18. Everson GT. Treatment of chronic hepatitis C in patients with decompensated cirrhosis. Rev Gastroenterol Disord 2004;4(Suppl 1):S31-8.
19. Fredrick RT, Hassanein TI. Role of growth factors in the treatment of patients with HIV/HCV coinfection and patients with recurrent hepatitis C following liver transplantation. J Clin Gastroenterol 2005;39(Suppl 1):S14-S22.
20. Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002;36(5 Suppl 1):S237-44.
21. Gournay J, Richou C. Treatment of chronic hepatitis C: side effects, tolerability and quality of life. Gastroenterol Clin Biol 2002;26(Spec No 2):B60-75. (French).
22. Guay DR. Evaluation of interferon in the treatment of hepatitis C virus infection. Formulary 1999;34:137-40,143.
23. Hauschild A, Hinrichsen H, Christophers E. Side effects of interferon therapy and their management. Hautarzt 2000;51(10):793-803. (German).
24. Heathcote J. Do we know how to achieve optimal response to pegylated interferon alpha and ribavirin? J Hepatol 2003;39(1):136-8.
25. Jansen PLM, Reesink HW. Antiviral effect of peginterferon alfa-2b and alfa-2a compared. J Hepatol 2006;45(2):172-3.
A-53 26. Keating GM, Plosker GL. Peginterferon alpha-2a (40KD) plus ribavirin: a review of its use in the management of patients with chronic hepatitis C and persistently 'normal' ALT levels. Drugs 2005;65(4):521-36.
27. Lima MA, Auriel E, Wuthrich C, Borenstein NM, Koralnik IJ. Progressive multifocal leukoencephalopathy as a complication of hepatitis C virus treatment in an HIV- negative patient. Clin Infect Dis 2005;41(3):417-9.
28. LoBuono C. Guidelines for treating HCV-HIV patients undergo update. Drug Topics 2004;148(6):HSE15.
29. McHutchison JG, Bacon BR, Owens GS. Making it happen: managed care considerations in vanquishing hepatitis C. Am J Managed Care 2007;13(suppl 12):S327-36
30. Muir AJ, McHutchison JG. Growth factors during HCV therapy may be "cost- effective", but are they "effective"? Hepatology 2006;44(6):1400-3.
31. Mulhall BP, Younossi Z. Impact of adherence on the outcome of antiviral therapy for chronic hepatitis C. J Clin Gastroenterol 2005;39(Suppl 1):S23-7.
32. Murphy MJ. HIV/HCV co-infection has treatment implications. HIV Clin 2005;12(2):1.
33. Ong JP, Younossi ZM. Managing the hematologic side effects of antiviral therapy for chronic hepatitis C: anemia, neutropenia, and thrombocytopenia. Cleve Clin J Med 2004;71(Suppl 3):S17-21.
34. Parker SD. Evaluation and treatment of hepatitis C in patients with coexisting HIV infection. Med Gen Med 2006;8(3).
35. Pawlotsky JM. Therapy of hepatitis C: from empiricism to eradication. Hepatology 2006;43(2 Suppl 1):S207-20.
36. Poniachik J. Management of adverse reactions to chronic hepatitis C treatment. Ann Hepatol 2006;5(Suppl 1):S67-8.
37. Roget M. Secondary effects of treatment with interferon and ribavirin. Enfermedades Emergentes 2003;5(3):181-9. (Spanish).
38. Russo MW, Fried MW. Side effects of therapy for chronic hepatitis C. Gastroenterology 2003;124(6):1711-9.
39. Sadovsky R. Ribavirin and interferon alfa is chronic hepatitis C. Am Fam Physician 1997;55(4):1369.
40. Saracco G, Verme G. Interferon in the treatment of chronic virus hepatitis. Argomenti di Gastroenterologia Clinica 1990;3(5):269-76. (Italian).
A-54 41. Shepherd J, Jones J, Hartwell D, Davidson P, Price A, Waugh N. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C: a systematic review and economic evaluation. Health Technol Assess 2007;11(11):iii-106.
42. Sherman M, Shafran S, Burak K, Doucette K, Wong W, Girgrah N, et al. Management of chronic hepatitis C: consensus guidelines. Can J Gastroenterol 2007;21(Suppl C):25C-34C.
43. Shiffman ML. Side effects of medical therapy for chronic hepatitis C. Ann Hepatol 2004 Jan;3(1):5-10.
44. Shiffman ML. Treating chronic hepatitis C virus after liver transplantation: balancing the risks against the chance for success. Liver Transpl 2007;13(8):1088-91.
45. Shobokshi OA, Tantawe AO, Al-Kayyal BM. Chronic hepatitis C treatment. Side effects and their management. Saudi Med J 2003;24(Suppl 2):S76-8.
46. Sulkowski MS. Management of the hematologic complications of hepatitis C therapy. Clin Liver Dis 2005;9(4):601-16.
47. Thevenot T, Di Martino V, Lunel-Fabiani F, Vanlemmens C, Becker MC, Bronowicki JP, et al. Complementary treatments of chronic viral hepatitis C. Gastroenterol Clin Biol 2006;30(2):197-214. (French).
48. Thevenot T, Cadranel JF, Di Martino V, Pariente A, Causse X, Renou C, et al. A national French survey on the use of growth factors as adjuvant treatment of chronic hepatitis C. Hepatology 2007;45(2):377-83.
49. Thevenot T, Di Martino V, Mathurin P, Cervoni JP, Richou C, Lunel-Fabiani F. Benefit of hematopoietic growth factors in the treatment of chronic hepatitis C. Hepato-Gastro 2007;14(5):339-46. (French).
50. Thevenot T, Di Martino V, Lunel-Fabiani F. Re-evaluating the use of growth factors as adjuvant treatment of chronic hepatitis C: Reply. Hepatology 2007;46(4):1308-9.
51. Trautwein C, Tacke F. Treatment of hepatitis B and C virus infection. Dtsch Med Wochensch 2003;128(Suppl 2):S87-9. (German).
52. Vigani AG. Adverse event management. Braz J Infect Dis 2007;11(Suppl 1):66-70.
53. Weis NM, Krarup HB, Skinhoj P. Pegylated interferon-alpha for the treatment of chronic hepatitis C. Ugeskr Laeger 2003;165(44):4211-5. (Danish).
54. Worman HJ. Re-evaluating the use of growth factors as adjuvant treatment of chronic hepatitis C. Hepatology 2007;46(4):1307-8.
A-55 55. Zein NN. Managing side effects related to treatment for chronic hepatitis C. Gastroenterol Hepatol 2007;3(6 Suppl 20):12-21.
56. Zeuzem S. Diagnosis and selective therapy in hepatitis C virus infections with interferon alpha. Therapie und Erfolg Dermatologie 1998;28(5):200-5. (German).
Population (N = 122) The following studies were excluded because they did not include treatment naïve adult (>18 yr.) hepatitis C patients with antiviral therapy-induced neutropenia.
1. Side effects. Safety and effectiveness of interferon and ribavirin in HIV+ people co- infected with hepatitis C virus. Treatment Update 2001;12(8):4-5.
2. Update on the use of alternative interferon formulations in difficult-to-treat hepatitis C patients. Gastroenterol Hepatol 2006;21(12 Suppl 18):6-10.
3. Abdelmalek MF, Firpi RJ, Soldevila-Pico C, Reed AI, Hemming AW, Liu C, et al. Sustained viral response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C. Liver Transpl 2004;10(2):199-207.
4. Ahmad J, Dodson SF, Demetris AJ, Fung JJ, Shakil AO. Recurrent hepatitis C after liver transplantation: a nonrandomized trial of interferon alfa alone versus interferon alfa and ribavirin. Liver Transpl 2001;7(10):863-9.
5. Arase Y, Suzuki F, Suzuki Y, Akuta N, Kawamura Y, Kobayashi M, et al. Side effects of combination therapy of peginterferon and ribavirin for chronic hepatitis-C. Intern Med 2007;46(22):1827-32.
6. Ascione A, De Luca M, Di Costanzo GG, Picciotto FP, Lanza AG, Canestrini C, et al. Incidence of side effects during therapy with different types of alpha interferon: a randomised controlled trial comparing recombinant alpha 2b versus leukocyte interferon in the therapy of naive patients with chronic hepatitis C. Curr Pharm Des 2002;8(11):977-80. Erratum in: Curr Pharm Des 2002;8(28) 2581.
7. Barnes E, Harcourt G, Brown D, Lucas M, Phillips R, Dusheiko G, et al. The dynamics of T-lymphocyte responses during combination therapy for chronic hepatitis C virus infection. Hepatology 2002;36(3):743-54.
8. Ben-Ari Z, Mor E, Shaharabani E, Bar-Nathan N, Shapira Z, Tur-Kaspa R. Combination of interferon-alpha and ribavirin therapy for recurrent hepatitis C virus infection after liver transplantation. Transplant Proc 2000;32(4):714-6.
9. Bernstein D, Kleinman L, Barker CM, Revicki DA, Green J. Relationship of health- related quality of life to treatment adherence and sustained response in chronic hepatitis C patients. Hepatology 2002;35(3):704-8.
A-56 10. Bizollon T, Palazzo U, Ducerf C, Chevallier M, Elliott M, Baulieux J, et al. Pilot study of the combination of interferon alfa and ribavirin as therapy of recurrent hepatitis C after liver transplantation. Hepatology 1997;26(2):500-4.
11. Brady B, Siebert U, Sroczynski G, Murphy G, Husereau D, Sherman M, et al. Pegylated interferon combined with ribavirin for chronic hepatitis C virus infection: an economic evaluation. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2007 Mar. Report No.: Technology report no. 82.
12. Brok J, Gluud LL, Gluud C. Effects of adding ribavirin to interferon to treat chronic hepatitis C infection: a systematic review and meta-analysis of randomized trials. Arch Intern Med 2005;165(19):2206-12.
13. Brown RSJ. Review article: a pharmacoeconomic analysis of thrombocytopenia in chronic liver disease. Aliment Pharmacol Ther 2007;26(Suppl 1):41-8.
14. Carreno V, Quiroga JA. Biologic response modifiers in chronic hepatitis C. J Hepatol 1995;22(Suppl 1):122-6.
15. Carreno V, Parra A, Navas S, Quiroga JA. Granulocyte-macrophage colony- stimulating factor as adjuvant therapy for factor as adjuvant therapy for interferon alpha treatment of chronic hepatitis C. Cytokine 1996;8(4):318-22.
16. Castedal M, Siewert-Delle A, Olausson M, Friman S. Combination therapy of interferon alpha-2B and ribavirin for recurrent hepatitis C after liver transplantation. Transplant Proc 2003;35(2):820-1.
17. Chan TM, Ho SK, Tang CS, Tse KC, Lam MF, Lai KN, et al. Pilot study of pegylated interferon-alpha 2a in dialysis patients with chronic hepatitis C virus infection. Nephrology 2007;12(1):11-7.
18. Choudhury M, Mann H, Goddard NJ, Lee C. An outline of the current orthopaedic management of haemophilic disease of the upper limb. Haemophilia 2007;13(5):599- 605.
19. Cindoruk M, Karakan T, Selahattin U. Therapy for treatment-refractory chronic hepatitis C virus genotype 1b infection: a retrospective analysis. Curr Ther Res 2005;66(5).
20. Cooper CL, Al-Bedwawi S, Lee C, Garber G. Rate of infectious complications during interferon-based therapy for hepatitis C is not related to neutropenia. Clin Infect Dis 2006;42(12):1674-8.
21. Cooper CL, Al-Bedwawi S. Infection rates in HIV-HCV patients treated with interferon are similar to those in HCV mono-infection and not related to neutropenia. HIV Clin Trials 2006;7(5):251-4.
A-57 22. de Oliveira AC. Treatment options in the management of thrombocytopenia in patients infected with HCV. Braz J Infect Dis 2007;11(Suppl 1):71-2.
23. de Vera M, Eghtesad B, Jain A, Fung J. Progression and treatment of recurrent hepatitis C after liver transplantation in patients co-infected with HIV. Hepatology 2003;38(4 Suppl 1):161A
24. Del Corso L, Bresci G, Romanelli AM, Borelli A, Pentimone F. Recombinant interferon alpha-2b in the treatment of chronic hepatitis C in the elderly. Giornale di Gerontologia 1993;41(7):273-5. (Italian).
25. Desmond CP, Roberts SK, Dudley F, Mitchell J, Day C, Nguyen S, et al. Sustained virological response rates and durability of the response to interferon-based therapies in hepatitis C patients treated in the clinical setting. J Viral Hepat 2006;13(5):311-5.
26. Di Marco V, Almasio PL, Ferraro D, Calvaruso V, Alaimo G, Peralta S, et al. Peg- interferon alone or combined with ribavirin in HCV cirrhosis with portal hypertension: a randomized controlled trial. J Hepatol 2007;47(4):484-91.
27. Domen RE, Horowitz S. Vancomycin-induced neutropenia associated with anti- granulocyte antibodies. Immunohematology 1990;6(2):41-3.
28. Duche A, Decocq G, Capron-Chivrac D, Andrejak M. Evaluation of side effects of interferon-alpha in 72 patients treated for chronic active hepatitis C. Therapie 1995;50(5):419-23. (French).
29. Durante-Mangoni E, Iardino P, Utili R, Adinolfi LE, Ruggiero G. Defective synthesis of granulocyte-colony stimulating factor in pegylated interferon-alpha treated chronic hepatitis C patients with declining leukocyte counts. Antivir Ther 2006;11(5):637-40.
30. Dusheiko GM, Roberts JA. Treatment of chronic type B and C hepatitis with alpha interferon. An economic appraisal. Hepatology 1995;22(6):1863-73.
31. Farrell G, Cooksley WG, Dudley FJ, Watson K. Efficacy and tolerance of a 6-month treatment course of daily interferon-alpha 2a for chronic hepatitis C with cirrhosis. The Australian Hepatitis C Study Group. J Viral Hepat 1997;4(5):317-23.
32. Feliu A, Carrion JA, Massaguer A, Martinez-Bauer E, Garcia-Retortillo M, Gonzalez P, et al. Sensitivity to antiviral therapy may change after liver transplantation in patients with chronic hepatitis C virus infection. J Viral Hepat 2006;13(8):544-51.
33. Fernandez AB. An unusual case of autoimmune hemolytic anemia in treatment naive hepatitis C virus infection. Hematology 2006;11(5-6):385-7.
34. Ferreira MS. Treatment of chronic hepatitis C in treatment-naive patients. Braz J Infect Dis 2007;11(Suppl 1):45-9.
A-58 35. Fontanges T, Beorchia S, Douvin C, Delassalle P, Combis JM, Hanslik B, et al. Safety and efficacy of combination therapy with peginterferon alfa-2a (40kD) and ribavirin in the outpatient setting: prospective analysis of 197 patients with chronic hepatitis C viral infection. Gastroenterol Clin Biol 2007;31(6-7):566-72.
36. Fukuda A, Kobayashi H, Teramura K, Yoshimoto S, Ohsawa N. Effects of interferon- alpha on peripheral neutrophil counts and serum granulocyte colony-stimulating factor levels in chronic hepatitis C patients. Cytokines Cell Mol Ther 2000;6(3):149- 54.
37. Groenbaek K. Interferon alpha-2b alone or combined with recombinant granulocyte- macrophage colony-stimulating factor as treatment of chronic hepatitis C [abstract]. J Hepatol 2002;36(Suppl 1):109-10.
38. Gupta R, Ramakrishna CH, Lakhtakia S, Tandan M, Banerjee R, Reddy DN. Efficacy of low dose peginterferon alpha-2b with ribavirin on chronic hepatitis C. World J Gastroenterol 2006;12(34):5554-6.
39. Heathcote EJ, Shiffman ML, Cooksley WG, Dusheiko GM, Lee SS, Balart L, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000;343(23):1673-80.
40. Hofer H, Gurguta C, Bergholz U, Steindl-Munda P, Ferenci P. Standard interferon- alpha in combination with ribavirin for hepatitis C patients with advanced liver disease and thrombocytopenia. Wien Klin Wochenschr 2006;118(19-20):595-600.
41. Homoncik M, Sieghart W, Formann E, Schmid M, Ferenci P, Gangl A, et al. Erythropoietin treatment is associated with more severe thrombocytopenia in patients with chronic hepatitis C undergoing antiviral therapy. Am J Gastroenterol 2006;101(10):2275-82.
42. Horban A, Wasilewski M, Berak H, Staczak JJ, Bardadin K, Paprocka H. Study of the efficacy of combined therapy with interferon alfacon-1 and ribavirin for chronic hepatitis C. Przegl Epidemiol 2006;60(3):563-9. (Polish).
43. Itoh H, Okada M, Yanaoka K, Arii K, Tamai H, Oka H, et al. Efficacy and side effects of interferon-beta twice administration a day for chronic active hepatitis C. Ther Res 1999;20(4):389-94.
44. Jones JS. A phase 3, randomized, multi-center study to evaluate the efficacy and safety of albumin interferon alfa-2b (alb-IFN) in combination with ribavirin compared with peginterferon alfa-2a (PEGASYS or PEG-IFN alfa-2a) in combination with ribavirin in interferon alfa naive subjects with chronic hepatitis c genotype 1. CenterWatch. 2008 [cited 11 Mar 2008]. Available from: http://www.centerwatch.com
A-59 45. Kallinowski B, Hofmann WJ, Otto HF, Gmelin K, Tox U, Kommerell B, et al. Therapy of chronic hepatitis C and non-A, non-B with alpha-interferon. Innere Medizin 1991;18(4):80-3. (German).
46. Kamal SM, El Kamary SS, Shardell MD, Hashem M, Ahmed IN, Muhammadi M, et al. Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response. Hepatology 2007;46(6):1732-40.
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48. Karaaslan Y, Haznedaroglu S, Ozilkan E, Kaftan O. Granulocytopenia due to nifuroxazide followed by a G-CSF induced leukemoid reaction. Ann Pharmacother 1999;33:1229-30.
49. Kasahara A. How to avoid discontinuation of ribavirin in combination with interferon to maintain efficacy of treatment for chronic hepatitis C patients. J Gastroenterol 2004;39(11):1125-6.
50. Kevans D, Farrell G, Hopkins S, Mahmud N, White B, Norris S, et al. Haematological support during peg-interferon therapy for HCV-infected haemophiliacs improves virological outcomes. Haemophilia 2007;13(5):593-8.
51. Khalili M, Hoffman-Terry M, Fisher E, Bernstein D, Lentz E, Barylski C, et al. Efficacy and safety of peginterferon alfa-2a (40 KD) treatment of patients with HIV/HCV: results of a multicenter trial. Abstr Intersci Conf Antimicrob Agents Chemother 2003;43:503.
52. Kim WR, Poterucha JJ, Hermans JE, Therneau TM, Dickson ER, Evans RW, et al. Cost-effectiveness of 6 and 12 months of interferon-alpha therapy for chronic hepatitis C. Ann Intern Med 1997;127(10):866-74.
53. Kishi Y, Sugawara Y, Akamatsu N, Kaneko J, Tamura S, Kokudo N, et al. Splenectomy and preemptive interferon therapy for hepatitis C patients after living- donor liver transplantation. Clin Transplant 2005;19(6):769-72.
54. Kitis G, Papagianni E, Tzilves D, Kordits F, Kokozidis G. Co-administration of granulocyte colony-stimulating factor allows completion of interferon therapy in chronic viral hepatitis with neutropenia. Hepatology 1994;20(4 part 2):171A.
55. Kitis G, Papagianni E, Tzilves D, Kordits F, Kokozidis G. Granulocyte colony- stimulating factor (G-CSF) and interferon A-2a in chronic viral hepatitis with neutropenia. J Hepatol 1994;21(Suppl 1):S111.
56. Kumar D, Wallington-Beddoe C, George J, Lin R, Samarasinghe D, Liddle C, et al. Effectiveness of interferon alfa-2b/ribavirin combination therapy for chronic hepatitis C in a clinic setting. Med J Aust 2003;178(6):267-71.
A-60 57. Lebray P, Pichard AV, Broissand C, Nalpas B, Sobesky R, Fontaine H, et al. Usefulness of erythropoietin and G-CSF during treatment for chronic hepatitis C with pegylated interferon: a clinical descriptive analysis. Hepatology 2002;36(4 Part 2):574A.
58. Lebray P, Nalpas B, Vallet-Pichard A, Broissand C, Sobesky R, Serpaggi J, et al. The impact of haematopoietic growth factors on the management and efficacy of antiviral treatment in patients with hepatitis C virus. Antivir Ther 2005;10(6):769-76.
59. Luetkemeyer A, Hare CB, Stansell J, Tien PC, Charlesbois E, Paula L, et al. Clinical presentation and course of acute hepatitis C infection in HIV-infected patients. JAIDS 2006;41(1):31-6.
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61. Marrache F, Consigny Y, Ripault MP, Cazals-Hatem D, Martinot M, Boyer N, et al. Safety and efficacy of peginterferon plus ribavirin in patients with chronic hepatitis C and bridging fibrosis or cirrhosis. J Viral Hepat 2005;12(4):421-8.
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71. Oze T, Hiramatsu N, Kurashige N, Tsuda N, Yakushijin T, Kanto T, et al. Early decline of hemoglobin correlates with progression of ribavirin-induced hemolytic anemia during interferon plus ribavirin combination therapy in patients with chronic hepatitis C. J Gastroenterol 2006;41(9):862-72.
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73. Pearlman BL, Ehleben C, Saifee S. Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis C genotype 1-infected slow responders. Hepatology 2007;46(6):1688-94.
74. Peck-Radosavljevic M, Wichlas M, Homoncik-Kramil M, Kreil A, Hofer H, Jessner W, et al. Rapid suppression of hematopoiesis by standard or pegylated interferon- alpha. Gastroenterology 2002;123(1):141-51.
75. Perez R, Jimenez M, Crespo J, Diago M, Enriquez J, Vaquero P, et al. Comparative study of the efficacy of an induction dose of interferon-alpha2b with ribavirin compared with standard combined treatment in naive patients with chronic hepatitis C. J Viral Hepat 2003;10(6):437-45.
76. Perkins JB. Update on hematopoietic growth factors. P & T 1994;Jun:577-86.
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78. Ramos-Casals M, Garcia-Carrasco M, Lopez-Medrano F, Trejo O, Forns X, Lopez- Guillermo A, et al. Severe autoimmune cytopenias in treatment-naive hepatitis C virus infection: clinical description of 35 cases. Medicine (Baltimore) 2003;82(2):87- 96.
79. Raptopoulou M, Tsantoulas D, Vafiadi I, Ketikoglou I, Paraskevas E, Vassiliadis T, et al. The effect of adherence to therapy on sustained response in daily or three times a week interferon alpha-2b plus ribavirin treatment of naive and nonresponder chronic hepatitis C patients. J Viral Hepat 2005;12(1):91-5.
80. Renou C, Germain S, Harafa A, Martin S, Larroque O, Muller P, et al. Interstitial pneumonia recurrence during chronic hepatitis C treatment. Am J Gastroenterol 2005;100(7):1625-6.
A-62 81. Rosina F, Saracco G, Lattore V, Bona P. Alpha 2 recombinant interferon in the treatment of chronic hepatitis delta virus (HDV) hepatitis. In: Rizzetto M, Gerin JL, Purcell RH, editors. Treatment of chronic delta hepatitis with alpha-2 recombinant interferon. New York; Alan R. Liss; 1987 p. 299-303.
82. Rostaing L, Izopet J, Baron E, Duffaut M, Puel J, Durand D, et al. Preliminary results of treatment of chronic hepatitis C with recombinant interferon alpha in renal transplant patients. Nephrol Dial Transplant 1995;10(Suppl 6):93-6.
83. Russo F, Bacosi M, Miglioresi L, Ricci GL. Leucopenia is a side effect of combination therapy for hepatitis C infection. Am J Gastroenterol 2000;95(4):1100-1.
84. Saadoun D, Cacoub P, Pozzato G. Treatment with Peg-interferon alfa-2b and ribavirin of hepatitis C virus-associated mixed cryoglobulinemia. J Hepatol 2005;43(4):737-9.
85. Sagmeister M, Wong JB, Mullhaupt B, Renner EL. A pragmatic and cost-effective strategy of a combination therapy of interferon alpha-2b and ribavirin for the treatment of chronic hepatitis C. Eur J Gastroenterol Hepatol 2001;13(5):483-8.
86. Saito H, Tada S, Ebinuma H, Ishii H, Kashiwazaki K, Takahashi M, et al. Role of erythrocytes as a reservoir for ribavirin and relationship with adverse reactions in the early phase of interferon combination therapy for chronic hepatitis C virus infections. J Clin Microbiol 2006;44(10):3562-8.
87. Saito T, Shinzawa H, Kuboki M, Ishibashi M, Toda H, Okuyama Y, et al. A randomized, controlled trial of human lymphoblastoid interferon in patients with compensated type C cirrhosis. Am J Gastroenterol 1994;89(5):681-6.
88. Samuel D, Forns X, Berenguer M, Trautwein C, Burroughs A, Rizzetto M, et al. Report of the monothematic EASL conference on liver transplantation for viral hepatitis (Paris, France, January 12-14, 2006). J Hepatol 2006;45(1):127-43.
89. Schmitz V, Kiessling A, Bahra M, Puhl G, Kahl A, Berg T, et al. Peginterferon alfa- 2b plus ribavirin for the treatment of hepatitis C recurrence following combined liver and kidney transplantation. Ann Transplant 2007;12(3):22-7.
90. Seal KH, Currie SL, Shen H, Anand BS, Bini EJ, Brau N, et al. Hepatitis C treatment candidacy and outcomes among 4318 US veterans with chronic hepatitis C virus infection: does a history of injection drug use matter? J Clin Gastroenterol 2007;41(2):199-205.
91. Sennfalt K, Reichard O, Hultkrantz R, Wong JB, Jonsson D. Cost-effectiveness of interferon alfa-2b with and without ribavirin as therapy for chronic hepatitis C in Sweden. Scand J Gastroenterol 2001;36(8):870-6.
92. Shiell A, Brown S, Farrell GC. Hepatitis C: an economic evaluation of extended treatment with interferon. Med J Aust 1999;171(4):189-93.
A-63 93. Shiffman ML. Evaluation of GM-CSF for treatment of chronic HCV. CRISP. 1999. [cited 11 Mar 2008]. Available from: http://crisp.cit.nih.gov
94. Shiffman ML, Hofmann CM, Luketic VA, Thompson EB, Sanyal AJ. Randomized controlled trial comparing interferon-alpha-2b alone to a combination of interferon (INF) plus granulocyte-macrophage colony stimulating factor (GMCSF) for treatment of chronic hepatitis C virus (HCV). Hepatology 1996;24(4):1104.
95. Shiffman ML. Combination therapy of interferon A2B with GMCSF for chronic hepatitis C. CRISP. 1997 [cited 11 Mar 2008]. Available from: http://crisp.cit.nih.gov
96. Shiffman ML. Evaluation of granulocyte macrophage. CRISP. 1997. [cited 18 June 2008]. Available from: http://crisp.cit.nih.gov
97. Shiffman ML, Hofmann CM, Luketic VA, Sanyal AJ. Use of granulocyte macrophage colony stimulating factor alone or in combination with interferon-alpha- 2b for treatment of chronic hepatitis C. J Hepatol 1998;28(3):382-9.
98. Shiffman ML. Evaluation of GM-CSF for treatment of chronic HCV. CRISP. 1998 [cited 11 Mar 2008]. Available from: http://crisp.cit.nih.gov
99. Shiffman ML. Evaluation of GM-CSF for treatment of chronic HCV. CRISP. 2000 [cited 11 Mar 2008]. Available from: http://crisp.cit.nih.gov
100. Shiffman ML. Evaluation of GM-CSF for treatment of chronic HCV. CRISP. 2001 [cited 11 Mar 2008]. Available from: http://crisp.cit.nih.gov
101. Shiffman ML. Evaluation of GM-CSF for treatment of chronic HCV. CRISP. 2004. [cited 18 June 2008]. Available from: http://crisp.cit.nih.gov
102. Shiffman ML. Evaluation of GM-CSF for treatment of chronic HCV. CRISP. 2008 [cited 11 Mar 2008]. Available from: http://crisp.cit.nih.gov
103. Shiffman ML. Randomized controlled trial to determine efficacy of combination therapy. CRISP. 2008 [cited 11 Mar 2008]. Available from: http://crisp.cit.nih.gov
104. Sjogren MH, Sjogren R Jr, Lyons MF, Ryan M, Santoro J, Reddy KR, et al. Antiviral response of HCV genotype-1 to consensus interferon and ribavirin compared with pegylated interferon and ribavirin. A preliminary report. Hepatology 2004;4(S4):396A.
105. Soza A, Hoofnagle JH. Mortality rate during interferon alfa-ribavirin combination therapy of chronic hepatitis C. Hepatology 2003;38(1):267.
106. Steinberg J. Benefit vs. harm of treatment of chronic hepatitis C. Am Fam Physician 2005;71(8):1489-90.
A-64 107. Sulkowski M, Reindollar R, Thomas DL, Brinkley-Laughton S, Hudson M, Yu J. Peginterferon-alpha-2a (40kD) and ribavirin in patients with chronic hepatitis C: a phase II open-label study. Biodrugs 2002;16(2):105-9.
108. Suzuki H, Ichida F, Fujisawa K, Takino T. Double-blind controlled study of the antiviral effect of human interferon on chronic active hepatitis. 6th Triennial International Symposium on Viral Hepatitis and Liver Disease; London, May 26- 28, 1987; p. 864-7.
109. Thomas WL Jr, Ramos F, Hospenthal DR. Adverse response to pegylated interferon therapy in two patients with chronic hepatitis C. Hawaii Med J 2003;62(8):163-4.
110. Tigue CC, Trifilio SM, Tallman MS, Goldman JM, Bennett CL. Long-term safety of filgrastim (rhG-CSF) administration: response to Confer & Miller and Bacher & Zander. Br J Haematol 2007;137(1):79-80.
111. Toccaceli F, Rosati S, Scuderi M, Iacomi F, Picconi R, Laghi V. Leukocyte and platelet lowering by some interferon types during viral hepatitis treatment. Hepatogastroenterology 1998;45(23):1748-52.
112. Tzilves D, Patsanas T, Rapti E, Kokozidis G, Kitis G. Co-administration of granulocyte colony-stimulation factor allows completion of interferon therapy in chronic viral hepatitis with neutropenia. Ann Gastroenterol 2002;15(1):62-6.
113. Van Thiel DH, Faruki H, Friedlander L, Fagiuoli S, Caraceni P, Molloy PJ, et al. Combination treatment of advanced HCV associated liver disease with interferon and G-CSF. Hepatogastroenterology 1995;42(6):907-12.
114. Vigano P, Gubertini G, Isabella L, Valsecchi L, Magnani C, Dedivitiis G, et al. Chronic C hepatitis in HIV seropositive patients: treatment with interferon and zidovudine. G Mal Infett Parassit 1993;45(7-8):875-8. (Italian).
115. Voigt E, Schulz C, Klausen G, Goelz J, Mauss S, Schmutz G, et al. Pegylated interferon alpha-2b plus ribavirin for the treatment of chronic hepatitis C in HIV- coinfected patients. J Infect 2006;53(1):36-42.
116. Wirth S, Lang T, Gehring S, Gerner P. Recombinant alfa-interferon plus ribavirin therapy in children and adolescents with chronic hepatitis C. Hepatology 2002;36(5):1280-4.
117. Wong DK, Heathcote J. The role of interferon in the treatment of viral hepatitis. Pharmacol Ther 1994;63(2):177-86.
118. Wong JB, Poynard T, Ling MH, Albrecht JK, Pauker SG. Cost-effectiveness of 24 or 48 weeks of interferon alpha-2b alone or with ribavirin as initial treatment of chronic hepatitis C. International Hepatitis Interventional Therapy Group. Am J Gastroenterol 2000;95(6):1524-30.
A-65 119. Wright HI, Gavaler JS, Baddour N, Van Thiel DH. Granulocyte colony stimulating factor (G-CSF) combined with alpha-interferon for the treatment of liver allograft recipients with viral hepatitis. J Hepatol 1994;21(5):915-6.
120. Younossi ZM, Singer ME, McHutchison JG, Shermock KM. Cost effectiveness of interferon alpha2b combined with ribavirin for the treatment of chronic hepatitis C. Hepatology 1999;30(5):1318-24.
121. Yu ML, Dai CY, Lee LP, Hsieh MY, Hou NJ, Huang JF, et al. Outcome of chronic hepatitis C patients who required early termination of pegylated interferon-alpha plus ribavirin combination therapy. Antivir Ther 2006;11(8):1015-9.
122. Zeuzem S, Hultcrantz R, Bourliere M, Goeser T, Marcellin P, Sanchez-Tapias J, et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004;40(6):993-9. Erratum in: J Hepatol 2005 Mar;42(3):434.
Intervention (N = 26) The following studies were excluded because study participants did not receive GCSF or did not experience a reduction or discontinuation of their antiviral therapy in response to antiviral-induced neutropenia.
1. The impact of growth factors on PEG-intron and rebetol dose reduction in patients treated for genotype 1 chronic hepatitis C. Gastroenterology 2006;130(4 Suppl 2):A783-4.
2. Brau N, Bini EJ, Currie S, Shen H, Schmidt WN, King PD, et al. Black patients with chronic hepatitis C have a lower sustained viral response rate than non-Blacks with genotype 1, but the same with genotypes 2/3, and this is not explained by more frequent dose reductions of interferon and ribavirin. J Viral Hepat 2006;13(4):242-9.
3. Carreno V, Parra A, Navas S, Quiroga J. Granulocyte-macrophage colony-stimulating factor as adjuvant therapy for interferon-alpha treatment of chronic hepatitis C. J Hepatol 1995;23(Suppl 1):106.
4. Carreno V, Martin J, Pardo M, Brotons A, Anchia P, Navas S, et al. Randomized controlled trial of recombinant human granulocyte-macrophage colony-stimulating factor for the treatment of chronic hepatitis C. Cytokine 2000;12(2):165-70.
5. Cinelli R, Di GG, Nasti G, Tedeschi R, Dal ML, Canzonieri V, et al. Efficacy and safety of combined treatment with pegylated-IFN-alpha2b plus ribavirin in HIV- hepatitis C virus-co-infected patients. AIDS 2004;18(7):1079-80.
6. de Vera ME, Dvorchik I, Tom K, Eghtesad B, Thai N, Shakil O, et al. Survival of liver transplant patients coinfected with HIV and HCV is adversely impacted by recurrent hepatitis C. Am J Transplant 2006;6(12):2983-93.
A-66 7. Economou MS, Filis S, Vienna H, Christodoulou D, Christou L, Tsianos EV. Treatment and retreatment in patients with chronic hepatitis C: 10 years clinical practice in a single centre. Liver Int 2007;27(3):340-6.
8. Farmer D, Collantes R, Makay S, Ong JP, Gujral H, Farquhar L, et al. Filgrastim for the neutropenia associated with combination therapy in chronic hepatitis C. Gastroenterology 2005;128(4 Suppl 2):A725.
9. Foruny JR, Blazquez J, Moreno A, Barcena R, Gil-Grande L, Quereda C, et al. Safe use of pegylated interferon/ribavirin in hepatitis C virus cirrhotic patients with hypersplenism after partial splenic embolization. Eur J Gastroenterol Hepatol 2005;17(11):1157-64.
10. Fukuda A, Kobayashi H, Teramura K, Yoshimoto S, Ohsawa N. Effects of interferon- alpha on peripheral neutrophil counts and serum granulocyte colony-stimulating factor levels in chronic hepatitis C patients. Cytokines Cell Mol Ther 2000;6(3):149- 54.
11. Gaeta GB, Precone DF, Felaco FM, Bruno R, Spadaro A, Stornaiuolo G, et al. Premature discontinuation of interferon plus ribavirin for adverse effects: a multicentre survey in 'real world' patients with chronic hepatitis C. Aliment Pharmacol Ther 2002;16(9):1633-9.
12. Iacobellis A, Siciliano M, Perri F, Annicchiarico BE, Leandro G, Caruso N, et al. Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: a controlled study. J Hepatol 2007;46(2):206-12.
13. Khakoo S, Glue P, Grellier L, Wells B, Bell A, Dash C, et al. Ribavirin and interferon alfa-2b in chronic hepatitis C: assessment of possible pharmacokinetic and pharmacodynamic interactions. Br J Clin Pharmacol 1998;46(6):563-70.
14. Kim JH, Han KH, Lee KS, Park YN, Ahn SH, Chon CY, et al. Efficacy and long- term follow up of combination therapy with interferon alpha and ribavirin for chronic hepatitis C in Korea. Yonsei Med J 2006;47(6):793-8.
15. Koliouskas D, Sidiropoulos I, Masmanidou M, Dokas S, Ziakas A. Comparative analysis and effect of GM-CSF on neutropenia in peg-interferon alpha-2b and ribavirin-treated chronic hepatitis C patients. J Hepatol 2002;36(Suppl 1):238.
16. Koliouskas D, Sidiropoulos I, Masmanidou M, Mandraveli K, Lazaraki G, Dokas S, et al. Comparative analysis and effect of GM-CSF on neutropenia in peg-interferon alpha-2b and ribavirin-treated chronic hepatitis C patients. Hepatology 2002;36(4 Part 2):587A.
17. Kuboki M, Iino S, Okuno T, Omata M, Kiyosawa K, Kumada H, et al. Peginterferon alpha-2a (40 KD) plus ribavirin for the treatment of chronic hepatitis C in Japanese patients. J Gastroenterol Hepatol 2007;22(5):645-52. Erratum in: J Gastroenterol Hepatol 2007;22(5):768.
A-67 18. Kugelmas M, Ryan O, Spiegelman GA, Mah'moud M. Do growth factors improve EVR in chronic HCV-genotype 1 patients treated with PEG-Intron and ribavirin? Gastroenterology 2007;132(4):A780.
19. Lai MY, Kao JH, Yang PM, Wang JT, Chen PJ, Chan KW, et al. Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. Gastroenterology 1996;111(5):1307-12.
20. Posthouwer D, Fischer K, De Heusden N, Mauser-Bunschoten EP. Pegylated interferon and ribavirin combination therapy for chronic hepatitis C in patients with congenital bleeding disorders: a single-centre experience. Haemophilia 2007;13(1):98-103.
21. Rotman Y, Ben-Ari Z, Braun M, Cohen M, Cohen-Ezra O, Manhaim V, et al. Low body weight predicts PEG-interferon alfa-2a (PEGASYS) induced neutropenia in chronic hepatitis C patients. Hepatology 2005;42(4 Suppl 1):664A-5A.
22. Sarin SK, Goyal A, Kumar S, Guptan RC, Hashmi AZ, Sakhuja P, et al. A randomized trial of a 4- vs 12-week daily interferon dose regimen combined with ribavirin in treatment of patients with chronic hepatitis C. Hepatobiliary Pancreat Dis Int 2004;3(1):42-8.
23. Schmid M, Kreil A, Jessner W, Homoncik M, Datz C, Gangl A, et al. Suppression of haematopoiesis during therapy of chronic hepatitis C with different interferon-alpha mono and combination therapy regimens. Gut 2005;54:1014-20.
24. Shiffman ML. Chronic hepatitis C and granulocyte macrophage stimulating factor. CRISP. 1996. [cited 11 Mar 2008]. Available from: http://crisp.cit.nih.gov
25. Smith AD, Rockey DC, Mascitelli L, Pezzetta F. Viral hepatitis C. Lancet 2004;363(9409):661.
26. Soza A, Everhart J, Ghany M, Doo E, Heller T, Promrat K, et al. Neutropenia associated with alpha interferon therapy of chronic hepatitis C. Gastroenterology 2002;123(Suppl 1):75-6.
Outcomes (N = 11) The following studies were excluded because they did not report data on at least one outcome of interest.
1. Beckebaum S, Cicinnati VR, Zhang X, Malago M, Dirsch O, Erim Y, et al. Combination therapy with peginterferon alpha-2B and ribavirin in liver transplant recipients with recurrent HCV infection: preliminary results of an open prospective study. Transplant Proc 2004;36(7):2207.
2. Cacoub P, Rosenthal E, Halfon P, Sene D, Perronne C, Pol S. Treatment of hepatitis C virus and human immunodeficiency virus coinfection: from large trials to real life. J Viral Hepat 2006;13(10):678-82.
A-68 3. Castells L, Vargas V, Allende H, Bilbao I, Luis LJ, Margarit C, et al. Combined treatment with pegylated interferon (alpha-2b) and ribavirin in the acute phase of hepatitis C virus recurrence after liver transplantation. J Hepatol 2005;43(1):53-9.
4. Di Bisceglie AM, Ghalib RH, Hamzeh FM, Rustgi VK. Early virologic response after peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin treatment in patients with chronic hepatitis C. J Viral Hepat 2007;14(10):721-9.
5. Golia P, Talal AH, Jacobson IM, Flynn S, Golia P. A preliminary study of growth factors versus dose reduction for peg interferon alfa-2b and ribavirin associated neutropenia and anemia in HIV/HCV co-infected patients. Gastroenterology 2003;124(4, Suppl 1):A766.
6. Hanouneh IA, Miller C, Aucejo FN, Lopez R, Quinn MK, Zein NN. Recurrent hepatitis C after liver transplantation: ON-treatment prediction of response to peginterferon/ribavirin therapy. Liver Transpl 2008;14(1):53-8.
7. Horoldt B, Haydon G, O'Donnell K, Dudley T, Nightingale P, Mutimer D. Results of combination treatment with pegylated interferon and ribavirin in cirrhotic patients with hepatitis C infection. Liver Int 2006;26(6):650-9.
8. Liu CJ, Chen PJ, Lai MY, Kao JH, Jeng YM, Chen DS. Ribavirin and interferon is effective for hepatitis C virus clearance in hepatitis B and C dually infected patients. Hepatology 2003;37(3):568-76.
9. Pau AK, McLaughlin MM, Hu Z, Agyemang AF, Polis MA, Kottilil S. Predictors for hematopoietic growth factors use in HIV/HCV-coinfected patients treated with peginterferon alfa 2b and ribavirin. AIDS Patient Care STDs 2006;20(9):612-9.
10. Talal A. Treatment of anemia and neutropenia in HIV/HCV coinfected patients treated with pegylated interferon and ribavirin. ClinicalTrials. 2002. [cited 10 Mar 2008]. Available from: http://clinicaltrials.gov
11. Witthoft T, Moller B, Wiedmann KH, Mauss S, Link R, Lohmeyer J, et al. Safety, tolerability and efficacy of peginterferon alpha-2a and ribavirin in chronic hepatitis C in clinical practice: the German Open Safety Trial. J Viral Hepat 2007;14(11):788- 96.
Insufficient Data (N = 13) The following studies met inclusion criteria, but did not provide enough data to be included in the review.
1. Bahra M, Neumann UP, Jacob D, Langrehr JM, Neuhaus R, Neuhaus P. Long term results after therapy with pegylated interferon alpha 2A in HCV positive liver transplant recipients. Hepatology 2005;42(4 Suppl 1):488A-9A.
A-69 2. Berenguer M, Palau A, Fernandez A, Benlloch S, Aguilera V, Prieto M, et al. Efficacy, predictors of response, and potential risks associated with antiviral therapy in liver transplant recipients with recurrent hepatitis C. Liver Transpl 2006;12(7):1067-76.
3. Carrion JA, Navasa M, Garcia-Retortillo M, Garcia-Pagan JC, Crespo G, Brugera M, et al. Efficacy of antiviral therapy on hepatits C recurrence after liver transplantation: a randomized controlled study. Gastroenterology 2007;132:1746-56.
4. Cash W, Patterson K, Callender M, McDougall NI. Does adjuvant therapy with erythropoietin and GCSF improve sustained virological response in patients receiving combination therapy with pegylated interferon and ribavirin for chronic hepatitis C? J Hepatol 2007;46(Suppl 1):S219-20.
5. Gopal DV, Rabkin JM, Berk BS, Corless CL, Chou S, Olyaei A, et al. Treatment of progressive hepatitis C recurrence after liver transplantation with combination interferon plus ribavirin. Liver Transpl 2001;7(3):181-90.
6. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140(5):346-55.
7. Neff GW, Montalbano M, O'Brien CB, Nishida S, Safdar K, Bejarano PA, et al. Treatment of established recurrent hepatitis C in liver-transplant recipients with pegylated interferon-alfa-2b and ribavirin therapy. Transplantation 2004;78(9):1303- 7.
8. Neumann U, Puhl G, Bahra M, BergT, Langrehr JM, NeuhausR, et al. Treatment of patients with recurrent hepatitis C after liver transplantation with peginterferon alfa- 2B plus ribavirin. Transplantation 2006;82(1):43-7.
9. Nudo CG, Wong P, Hilzenrat N, Deschenes M. Elderly patients are at greater risk of cytopenia during antiviral therapy for hepatitis C. Can J Gastroenterol 2006;20(9):589-92.
10. Sharma S, Marrer JA, Fontana RJ, Greenson JK, Conjeevaram H, Su GL et al. Sustained virologic response to therapy of recurrent hepatitis C after liver transplantation is related to early virologic response and dose adherence. Liver Transpl 2007;13:1100-8.
11. Shehab TM, Fontana RJ, Oberhelman K, Marrero JA, Su GL, Lok ASF. Effectiveness of interferon alpha-2b and ribavirin combination therapy in the treatment of naive chronic hepatitis C patients in clinical practice. Clin Gastroenterol Hepatol 2004;2(5):425-31.
A-70 12. Tran TT, Patel Y, Benner JS, Petrilla AA, Poordad F. Neutropenia associated with pegylated interferon treatment for chronic hepatitis C: a single center experience. Am J Gastroenterol 2005;100(9 Suppl S):S127.
13. Turbide C, Soulellis C, Deschenes M, Hilzenrat N. Does a rapid decline in the hematological and biochemical parameters induced by interferon and ribavirin combination therapy for the hepatitis C virus predict a sustained viral response? Can J Gastroenterol 2008;22(2):149-52.
Unavailable (N = 9) The following articles could not be retrieved or were pending tanslation and could not be assessed by the deadline for the review.
1. Interferons and hepatitis C. Prescrire Int 1996;5(24):98-100.
2. Arase Y. Side effects of interferon therapy for chronic hepatitis C. Nippon Rinsho 2006;64(7):1363-7. (Japanese).
3. Charuworn P, Ahmed AM, Ahmed A. The role of recombinant human granulocyte colony-stimulating factor (G-CSF, filgrastim) in the management of pegylated interferon alfa-2b (PEG-IFN) induced neutropenia in patients with chronic hepatitis C (CHC). Am J Gastroenterol 2003;98(9 Suppl):S88.
4. Cromie S, Roberts S, Jenkins P, Dudley F. Interferon and ribavirin treatment of chronic hepatitis C: a systematic review of randomised controlled trials. Proceedings of the 48th American Association for the Study of Liver Diseases; 1997 Chicago; IL; 1997.
5. Hwang SY, Lee HJ, Park KT, Kim KY, Lee SM, Park CW, et al. Effectiveness and complications of combination therapy with interferon alpha and ribavirin in patients with chronic hepatitis C. Korean J Gastroenterol 2007;49(3):166-72. (Korean).
6. Rhine LA, Pruemer JM. Innovative guidelines for cost conscious times: evaluating G- CSF use. 30th Annual ASHP Midyear Clinical Meeting 1995;30:PMCS-49.
7. Schmid M, Homoncik M, Jessner W, Formann E, Ferenci P, Gangl A, et al. Suppression of hematopoiesis during therapy with different IFN-alpha mono- and combination therapy regimes. Proceedings of Digestive Disease; 2003, May 17-22, 2003 Orlando; FL; 2003.
8. Vashakidze ET, Gegeshidze TN, Zhamutashvili MT, Svanidze MB. Side effects of the combined antiviral therapy in patients with chronic hepatitis C. Georgian Med News 2007;7-8(148-149):28. (Russian).
9. Zarski JP, Leroy V, Maynard-Muet M. Treatment of viral hepatitis C. Revue du Praticien-Medecine Generale 1997;11(384):11-5. (French).
A-71 APPENDIX 4: Forms
Inclusion/Exclusion Criteria: Clinical and Economic Review
Reviewer: Date: ______Record ID: ______Yes No Unclear/Comments Population: Treatment naïve adult hepatitis C patients with antiviral Yes No therapy-induced neutropenia Study design: RCT or CCT or prospective or retrospective Yes No observational studies (cohort or case control) or case series (for assessing safety)
Exclude secondary research, other uncontrolled studies (clinical studies). Do not exclude on the basis of study design (economic studies) Intervention: Granulocyte colony stimulating factor (G-CSF): Yes No filgrastim (trade name: Neupogen) or pegfilgrastim (trade name: Neulesta) OR Control: Dose reduction or discontinuation of combination antiviral Yes No therapy (PEG IFN and ribavirin) Outcomes: One or more of the following Efficacy/effectiveness and Safety Primary outcome: Other outcomes of interest: [ ] Neutrophil count [ ] Quality of life [ ] Early virological response [ ] Complications (e.g. infection) [ ] Sustained virological response [ ] Hospitalization [ ] ED admission Safety Outcomes: [ ] Bone pain [ ] Splenic rupture [ ] Local skin reactions [ ] Other (specify): *Death and disability are uncommon. Additional safety outcomes will be considered. Cost-effectiveness Primary outcome: Other outcomes of interest: [ ] Event probability [ ] Complications (e.g. bacterial [ ] Resource measurement (utilization) infections, hospitalization, ED [ ] Valuation (cost) admission) [ ] HRQoL (disease specific, generic and preference-based utility Study addresses question 2 (efficacy/effectiveness/safety) Yes No Unclear Study addresses questions 3 & 4 (cost-effectiveness) Yes No Unclear Final decision: Should this study be included? Yes No Unclear Results of discussion:
A-72 DATA EXTRACTION: Clinical and Economic Studies
Manuscript ID ______Extractor ______
Principal investigator’s name: Publication date:
Country(ies) in Start date: which study took (data collection or place: patient recruitment)
Study setting: tertiary care Completion date: academic centre (data collection or community hospital patient recruitment) other Specify: Single centre Multi-centred
Specify source of funding: (Check all that apply) Internal Industry (other than Government agency Pharmaceutical industry funds pharmaceutical)
Not Specified Foundation/charity Professional organization Other Specify:
Role of Funding Organization (authorship, data analysis, etc): Not Specified Not applicable Study Objective:
Contact with Authors: (specify if required) Relevant to Q1. Efficacy Q2. Effectiveness Question(s): Q3. Safety Q4. Economic
Study Description Type of trial Type of Observational Study / Data RCT parallel CCT Case-control Retrospective Prospective Before/After RCT cross-over cohort cohort
ITT analysis: yes Quasi- experimental Survey Administrative ITT analysis: no data ITT analysis: unclear
A-73 Inclusion criteria:
Exclusion criteria:
N of Population Total ‘n’ Total ‘n’ Total ‘n’ excluded after Total number of Total ‘n’ completed: eligible: enrolled: meeting inclusion criteria withdrawals/ or being included: dropouts:
Number of ‘n’ Group 1 Excluded Group 1______W/D Group 1 Completed Group 1 groups: ______Excluded Group 2______W/D Group 2 ‘n’ Group 2 Completed Group 2 ______Excluded Group 3______W/D Group 3 ______
‘n’ Group 3 Completed Group 3 ______
Reasons for exclusion (all): Reasons for W/D (all):
Reasons Group 1 Reasons for W/D Group 1
Reasons Group 2 Reasons for W/D Group 2
Reasons Group 3 Reasons for W/D Group 3
A-74 Population Characteristics (circle measure used) Characteristic All (Total Neutropenia Neutropenia Neutropenia population treated with treated with dose treated with with or GCSF reduction discontinuation of without (specify) antiviral therapy neutropenia, as appropriate) Age -median (IQR) -mean SD -range NR Sex, male (n, %)
Weight -median (IQR) -mean SD -range NR Body mass index -median (IQR) -mean SD -range NR Race (n, %) White Black Asian Hispanic Other HVC Genotype (n, %) Genotype 1 Genotype 2 Genotype 3 Other Duration or time since diagnosis of Hep C (mean, range in years) Source of infection (n, %) Transfusion Injection drug use Medical procedures Sexual contact Other
A-75 Baseline Physiologic Measures (circle measure used or specify if other) Measure All (Total Neutropenia Neutropenia Neutropenia population with treated with treated with dose treated with or without GCSF reduction discontinuation of neutropenia, as (specify) antiviral therapy appropriate) Platelets x103 cells/μl, -median (IQR) -mean SD -range in cells NR Hemoglobin mg/dl, -median (IQR) -mean SD -range NR White blood cell count x103 cells/μl, -median (IQR) -mean SD -range NR Neutrophil count (cells/μl) (actual numbers, if given plus the range) >1500 <1500 <750 <500 HCV viral load
A-76 Other baseline data All (Total Neutropenia Neutropenia Neutropenia population with treated with treated with treated with or without GCSF dose reduction discontinuation of neutropenia, as (specify) antiviral therapy appropriate) Treatment naïve patients (n, %) Patients on monotherapy (n, %) (for studies that compare mono to multi- therapy, take multi- therapy arm only) Patients on combination therapy (n, %) Patients who develop neutropenia out of the total number included (n, %) Patients with HIV co- infection (n, %) Patients with haemophilia (n, %) Patients with cirrhosis (n, %) Record stages of fibrosis if given (F1-F4 where F4 is cirrhosis, F3 bridging fibrosis) Patients with HBV co- infection (n, %) Patients with other forms of Hepatitis (n, %) (Specify) Post-transplantation patients (n, %) Patients on with anemia and receiving erythropoietin [specify dose & frequency] (n, %).
A-77 Antiviral therapy (combination interferon and ribavirin) Pegasys (n, %) Dose: Timing/frequency of treatment: Duration of (i.e., number per week) treatment: (at outset of therapy) Pegatron (n, %) Dose: Timing/frequency of treatment: Duration of (i.e., number per week) treatment: (at outset of therapy) Non-pegylated (n, %) Dose: Timing/frequency of treatment: Duration of (i.e., number per week) treatment: (at outset of therapy) Ribavirin therapy Dose n, % Timing/frequency Weight cut-off points 800 mg/day 1000 mg/day 1200 mg/day 1400 mg/day Additional adjuvant therapies:
Neutropenia Definition of neutropenia:
Definition of severe neutropenia:
Interventions Patients with n, % Dose Duration Therapy neutropenia (see Cut-off Time until Time until Time until table below for points (i.e., dose treatment is administration severe or other when is decrease stopped of G-CSF levels of therapy neutropenia) d/c) Patients on G-CSF (specify type: Neupogen or Neulesta Patients who discontinued antiviral therapy (which one, when, what triggered it)
A-78 Patients with n, % Dose Duration Therapy neutropenia (see Cut-off Time until Time until Time until table below for points (i.e., dose treatment is administration severe or other when is decrease stopped of G-CSF levels of therapy neutropenia) d/c) Patients who had antiviral therapy dose reductions (which one, how much, how long, what triggered it) Notes:
Patients with n, Dose Duration Therapy severe % Cut-off Time until Time until Time until neutropenia points (i.e., dose treatment is administration when is decrease stopped of G-CSF therapy d/c) Patients on G-CSF (specify type: Neupogen or Neulesta Patients who discontinued antiviral therapy (which one, when, what triggered it) Patients who had antiviral therapy dose reductions (which one, how much, how long, what triggered it) Notes:
A-79 Outcomes for patients with neutropenia (record information for each subgroup if available) Outcome All (Total Neutropenia Neutropenia Neutropenia population with or treated with treated with dose treated with without GCSF reduction discontinuation of neutropenia, as (specify) antiviral therapy appropriate) Length of follow up
SVR (n, %)
Time SVR is achieved
EVR (n, %)
RVR if given (4 week PCR)
Serum HCV-RNA at end point
Other: specify
Other: specify
Adverse events from GCSF or from infections AE All (Total Neutropenia Neutropenia Neutropenia population with or treated with treated with dose treated with without GCSF reduction discontinuation of neutropenia, as (specify) antiviral therapy appropriate) Bacterial infections (n, %) Cause of infection (specify if neurtropenia related or other) Hospitalizations for infections (n, %)
Other infection- related adverse events (n, %)
Biochemical response
A-80 AE All (Total Neutropenia Neutropenia Neutropenia population with or treated with treated with dose treated with without GCSF reduction discontinuation of neutropenia, as (specify) antiviral therapy appropriate) (normalization of ALT values)
Changes in liver histology
Author’s conclusions (as they relate to neutropenia patients)
Completion rates for antiviral therapy All (Total Neutropenia Neutropenia Neutropenia population with treated with treated with dose treated with or without GCSF reduction discontinuation of neutropenia, as (specify) antiviral therapy appropriate) Patients who completed therapy (n, %) Average percentage of prescribed dosage taken Notes:
Quality of life
What measure?
Specify outcomes reported
Cost-effectiveness
A-81 Page number
Specify outcomes and measures
Resources
Additional information/comments
A-82 QUALITY ASSESSMENT FORMS
Reviewer: Date: / /2008 Record ID:
QUALITY ASSESSMENT FOR RCTs/CCTs
Jadad scale
YES NO 1. Was the study described as randomized (this includes the use of 1 0 words such as randomly, random and randomization)? 2. Was the study described as double-blind? 1 0 3. Was there a description of withdrawals and drop-outs? 1 0 4. Method to generate the sequence of randomization was described 1 0 and was appropriate (e.g. table of random numbers, computer generated, coin tossing, etc.). 5. Method of double-blinding described and appropriate (identical 1 0 placebo, active placebo, dummy). 6. Method of randomization described and it was inappropriate -1 0 (allocated alternately, according to date of birth, hospital number, etc.). 7. Method of double-blinding described but it was inappropriate -1 0 (comparison of tablet vs. injection with no double dummy). OVERALL SCORE (Maximum 5)
Concealment of treatment allocation – Schulz
Concealment of treatment allocation Adequate Inadequate Unclear Adequate: e.g. central randomization; numbered/coded containers; drugs prepared by pharmacy; serially numbered, opaque, sealed envelopes Inadequate: e.g. alternation, use of case record numbers, dates of birth or day of week; open lists Unclear: Allocation concealment approach not reported or fits neither above category
A-83 Reviewer: Date: / /2008 Record ID:
NEW CASTLE-OTTAWA FOR COHORT STUDIES A study can be awarded a maximum of one star for each numbered item in the Selection and Outcome categories. A maximum of two stars can be given for Comparability
Selection 1) Representativeness of the exposed cohort a) truly representative of the average ______(describe) in the community * (1) b) somewhat representative of the average ______in the community * (1) c) selected group of users e.g. nurses, volunteers d) no description of the derivation of the cohort 2) Selection of the non exposed cohort a) drawn from the same community as the exposed cohort * (1) b) drawn from a different source c) no description of the derivation of the non exposed cohort 3) Ascertainment of exposure a) secure record (eg surgical records) * (1) b) structured interview c) written self report d) no description 4) Demonstration that outcome of interest was not present at start of study a) yes * (1) b) no Comparability 5) Comparability of cohorts on the basis of the design or analysis a) study controls for ______(select the most important factor) * (1) b) study controls for any additional factor * (This criteria could be modified to indicate specific control for a second important factor) (1) Outcome 6) Assessment of outcome a) independent blind assessment * (1) b) record linkage * (1) c) self report d) no description 7) Was follow-up long enough for outcomes to occur a) yes (select an adequate follow up period for outcome of interest) * (1) b) no 8) Adequacy of follow up of cohorts a) complete follow up - all subjects accounted for * (1) b) subjects lost to follow up unlikely to introduce bias - small number lost - > ____ % (select an adequate %) follow up, or description provided of those lost) * (1) c) follow up rate < ____% (select an adequate %) and no description of those lost d) no statement
A-84 CHECKLIST FOR METHODOLOGICAL QUALITY OF CASE SERIES:
Reviewer: Date: / /2008 Record ID:
Source of potential bias Yes No Not stated Selection bias • Source of case series (patients) is reported (e.g. database,
charts, hospitals/clinics involved) • Results are from a consecutive series of patients • Clear indications of patient characteristics: Genotype Age (mean, SD or by category) Inclusion criteria specified Proportion of patients who are treatment naive Attrition bias • Losses to follow-up with respect to outcomes of interest
were <10% Detection bias • Trigger point for treating neutropenia is described • Treatment protocol for neutropenia is clearly described (drug/doses/route/administration times, dose reduction, discontinuation) • Adverse events of GCSF are reported • Infections due to neutropenia are reported Assessment bias • Primary outcome of the study is stated • Measurement of the primary outcome is described • The impact of neutropenia on the course of AVT is described (e.g., not changed, dose reduction, discontinuation)
A-85 APPENDIX 5: GENERAL CHARACTERISTICS OF EFFECTIVENESS AND SAFETY STUDIES
Author, Year Study design Site No. participants Mean age (SD) Country Publication status No. centres Co-morbidity No. males (%) No. genotype 1 (%) Ball32 1999 Case series Unclear 8 Median: 53 yr. United States Abstract 4 (50) NR Jeffers33 2004 Case series NR 106 Black pt: 46.3 yr. (6.2); United States Peer reviewed journal Multicentre White pt: 44.7 yr. (7.4) 73 (68.8) 106 (100) Juarez-Navarro34 2005 Case series Community hospital 209 46 yr. (17.9) Mexico Peer reviewed journal Single centre 106 (50.7) 169 (80.9) Koirala35 2007 Retrospective cohort Academic centre 60 GCSF: 51 yr.; Control: 48 United States Peer reviewed journal Single centre yr. 28 (46.6) 42 (70) Koskinas36 2006 CCT Academic centre 39 GCSF: 53 yr. (9); d/r: 47 yr. Greece Abstract Multicentre (7) 21 (53.8) 39 (100) Puoti37 2004 Retrospective cohort Academic centre 255 Median: 40 yr.; IQR: 34–58 Italy Peer reviewed journal Multicentre 179 (70) NR Renou38 2002 Retrospective cohort; Academic centre; 14 46 yr. (7) France Abstract Single centre 10 (71.4) 7 (50)
A-86 Author, Year Study design Site No. participants Mean age (SD) Country Publication status No. centres Co-morbidity No. males (%) No. genotype 1 (%) Senkbeil39 2003 Case series Centre (not specified) 50 NR United States Abstract Single centre NR NR Sharvadze40 2007 RCT (parallel) Academic centre 47 Range: 23–64 yr. Georgia Peer reviewed journal Single centre 38 (81) 47 (100) Sood41 2001 Case series Academic centre 12 NR United States Abstract Single centre NR NR Soza42 2002 Case series Outpatient clinic 119 47 yr., range: 27–63 United States Peer reviewed journal Single centre 75 (63.0) 88 (73.9) Younossi43 2008 Case series Academic centre 101 47.8 yr. (7.7) United States Peer reviewed journal Multicentre 60 (59.4) 65 (64.3) Liver transplant recipents Gopal44 2001 Case series Academic centre 12 Median: 46 yr., range: 34– United States Peer reviewed journal Single centre Recurrent HCV after 64 liver transplant 10 (83.3) 9 (75) Neumann45 2006 Case series Academic centre 25 Median: 49.2 yr., range: 26– Germany Peer reviewed journal Single centre Recurrent HCV after 68 liver transplant 20 (80) 20 (80) Sharma46 2007 Case series Academic centre 35 Median: 48.5 yr., range: 36– United States Peer reviewed journal single centre Recurrent HCV after 62 liver transplant 27 (77) 27 (77) CCT = clinical controlled trial; IQR = interquartile range; NR = not reported; RCT = randomized controlled trial; pt. = patient
A-87 APPENDIX 6: PARTICIPANTS, ANTIVIRAL THERAPY, NEUTROPENIA THERAPY AND OUTCOMES
Author, Antiviral Neutropenia Dose reduce G-CSF only Both dose Discontinue Discontinue SVR at 6 Year Therapy n/N (%) IFN only reduction + IFN AVT months post GCSF treatment Ball32 1999 RBV daily + 8/8 1 2 5 (2 resumed 0 0 NR IFN 3MU TIW full IFN) or IFN 3MU/day Jeffers33 RBV 1,000– Black pt.: Black pt.: All: Black: 3/78 Unclear Black pt.: 18 (2 Anemia: Black pt.: 2004 1,200 mg/d + 29/78 (37) 36/78 (40) (4) (may neutropenia, 2 Black pt.: 78 20/78 (25.6) Peg-IFNα2a White pt.: Neutropenia:29 have had d/r infection, 14 (24) White pt: 180 µg/wk. for 5/28 (18) /78 (37.2) IFN) others) White pt.: 11/28 (39.2) 48 wk. White pt.: All: White: 2/28 White pt.: 11 (1 9/28 (32) If 48 wk. of 8/28 (29); (7) thrombocytopeni AVT: Neutropenia: a, 1 abnormal Black pt.: 5/28 (17.9) liver test, 20/62 (32.2) infections; 6 White pt.: other) 11/22 (50) Juarez- RBV 800/d 95/209 (46) 3/95 (32) 0 0 0 due to NR SVR: 0/3; Navarro34 (non-T1); neutropenia EVR 1/3 2005 1,000–1,200 (33.3) [d/r mg/d (T1) + IFN] Peg-IFNα2a 180 µg/wk. for 24 wk. (non- T1) or 48 wk. (T1)
A-88 Author, Antiviral Neutropenia Dose reduce G-CSF only Both dose Discontinue Discontinue SVR at 6 Year Therapy n/N (%) IFN only reduction + IFN AVT months post GCSF treatment Koirala35 RBV 800– 30/60 (50) 0 30/60 (50) 0 0 due to 0 G-CSF: 2007 1,200 mg/d + neutropenia 13/21 (61); Peg-IFN α2a no G-CSF: 180 µg/wk. 13/17 (76) RBV 800– EVR: G- 1,200 mg/d + CSF: 23/30 Peg-IFN α2b (77); no G- 1.5µg/wk. CSF: 27/30 (90) Koskinas36 RBV 800– 39/39 (100) Grp B: 4/19 20/39 (51.3) 0 Grp B: 3/19 NR SVR: All: 2006 1,400 mg/d (21.1) (15.8) 10/39 (25.6); WB + Peg- G-CSF: 6/20 IFNα2b (30); Grp B: 1.5µg/kg/wk. 4/19 (21) EVR: 12/20 (60) Grp B: 9/19 (47) Puoti37 2004 Grp 1:RBV All: 61/255 All: 22/255 (9); NR NR All: 2/255 (0.8); NR NR 1,000–1,200/d (24); Grp 1: 18/152 Grp 1: 1/152 + Peg-IFNα2b Grp 1: (12); (0.7); (n=120) or α2a 48/152 (48); Grp 2: 4/103 Grp 2: 1/103 (n=32) 1.5 Grp 2: (4) (1.0) µg/kg/wk.; 13/103 (9) Grp 2: RBV 1,000–1,200/d + IFN α2b 3MU 3x/wk.
A-89 Author, Antiviral Neutropenia Dose reduce G-CSF only Both dose Discontinue Discontinue SVR at 6 Year Therapy n/N (%) IFN only reduction + IFN AVT months post GCSF treatment Renou38 RBV 1,000– 4/11 (36.4); 0 0 0 3/11 (27.3) NR 5/11 (45.5) 2002 1,200 mg/d + (1/14 (7.1) at IFN α2b 3 MU baseline) 3/wk. for 6 mo. (T3) or 12 mo. (T1) Senkbeil39 RBV 800 mg/d 10/50 (20) 1/10 (10) 9/10 (90) 0 0 2/8 (25) 2003 or weight (8 resumed based 800– full dose 1,400 mg/d + IFN) Peg-IFN 1.5 µg/kg/wk. for 48 wk. Sharvadze40 RBV 1,000– 41/47 (87.2) 19/41 (46.3) 22/41 (53.7) 0 0 for G-CSF NR 12/22 (55) 2007 1200 mg/d + group (G-CSF); Peg-IFNα2a (26.3) (d/r or 180µkg or α2b d/c) 1.5 µg/kg Sood41 2001 RBV/IFN 12/12 (100) 0 6/12 (50) 6/12 (50) 0 due to 4/12 NR (n=5); neutropenia (unrelated to RBV/Peg-IFN neutropenia (n=7) Soza42 2002 RBV 1,000– 32/119 (27) 0 for 0 0 0 for neutropenia NR 50/119 (42) 1,200/d + IFNα (13 pt. severe neutropenia; 16 3 MIU 3x/wk neutropenia) (13%) other
A-90 Author, Antiviral Neutropenia Dose reduce G-CSF only Both dose Discontinue Discontinue SVR at 6 Year Therapy n/N (%) IFN only reduction + IFN AVT months post GCSF treatment Younossi43 RBV 800– 38/101 (38); NA All: 38/101 NA All:14/101 (14) 9/101 (9) All: 46/101 2007 1,400 mg/d + NR for tx (38). G-CSF: (1 for anemia; (45); 21/38 Peg-IFN α2b naïve patients 12/101 (12); neutropenia, 13 8/101 (8) (55) (G- 1.5 µg/kg/wk G-CSF + other); other; CSF); for 24 wk. (T2 EPO 26/101 NR for tx naïve NR for tx 31/64 (48.4) and 3); 48 wk. (26) patients naïve (TX naïve); (T1 and 4, NR for tx patients EVR: 41/64 negative at 24 naïve patients (64.1) wk.) Liver transplant recipients Gopal44 RBV 600– 9/12 (75) 3/9 (33) 2/9 (22) 4/9 (44) 1/12 (8) 11/12 (92) 1/12 (8) 2001 1,200 mg/d + (G-CSF) IFNα2b 1-3 MU or consensus IFN 5 or 15µg/kg x3/wk.
Neumann45 RBV 400– 15/25 (60) 4/15 (26.7); 0 11/15 (73.3) 1/12 (not for NR All: 9/25 2006 1,000 mg/d + 9/25 (36) (RBV neutropenia) (36); Peg-IFN α2b d/r) 1/4 (25) 1.0mg/kg /BW (GCSG + d/r for 48 wk. Peg-IFN); 5/11 (45) (d/r Peg-IFN); 6/15 (40) (neutropenia)
A-91 Author, Antiviral Neutropenia Dose reduce G-CSF only Both dose Discontinue Discontinue SVR at 6 Year Therapy n/N (%) IFN only reduction + IFN AVT months post GCSF treatment Sharma46 RBV 800/d in 21/35 (60) 10/21 (48) d/r; 0 6/21 (29) 1/21 (5) (severe 15/35 (43) All: 13/35 2007 2 doses + Peg- 4/21 (19) neutropenia and (37); IFNα2a received d/r as myalgias) 9/21 (42.9) 180µg/wk. or only Tx (neutropenia) α2b ; 1.5µg/kg/wk. 3/6 (50) (G- for 48 wk. CSF) AVT = antiviral therapy; d/c = discontinued; d/r = dose reduction; Grp = group; NA = Not Applicable; NR = Not Reported; TIW = three times a week; Tx = treatment
A-92 APPENDIX 7: SAFETY OUTCOMES FOR PATIENTS WITH NEUTROPENIA
Author, Year Patients with Treatment group Comparison group Outcomes for Adverse effects of neutropenia, N (%) (G-CSF), N (IFN DR or no patients with G-CSF Definition of treatment) neutropenia, N neutropenia Type of G-CSF (%) Infections Dose Ball32 1999 8 (100%) 7 NA d/c AVT: 0/8 (0) 0/7 Neutrophil count Filgrastim <0.75x109/L NR NR Jeffers33 2004 34 (32.1%) 5/34 34/34 d/r d/c AVT: 2/34 (5.9) NR Neutrophil count NR <0.75x109/L NR 0/34 Juarez-Navarro34 92/209 (44.0%) with NA NR NR NA 2005 neutrophil count 16/95 (16.8) mild 0.75x109/L to infections (no 1.5x109/L; hospitalization) in patients 3/209 (1.4%) with with neutrophil count neutrophil count <1.5x109/L vs. 17/114 0.5x109/L to (14.9) with no neutropenia; 0.75x109/L; 1 pt with neutrophil count 0/209 with neutrophil <0.75x109/L had a mild count <0.5x109/L infection Koskinas36 2006 39 (100%) 20 19 EVR: 12/20 (60.0) 0/20 (G-CSF) vs. 9/19 Neutrophil count NR Escalating d/r for 2 (47.4) (d/r/d/c) NR <1.0x109/L 150–300 µg s/c 2x wk or d/c for 1-2 wk SVR: 6/20 (30) vs. per wk in unresolved cases 4/19 (21.0)
A-93 Puoti37 2004 61/255 with neutrophil NA NA NR NA count <1.0x109/L; 22/255 with neutrophil 8/85 (9.4) respiratory count <0.75x109/L; infections 2/255 with neutrophil count <0.5x109/L Renou38 2002 4/11 (36.4%) NA 0/4 d/r SVR: 2/4 (50) NA Neutrophil count <0.75x109/L 0/4 Sharvadze40 41 (100%) 22 19 SVR: 12/22 (54.4) 0/22 2007 PEG IFN d/r when (G-CSF) vs. 5/19 Neutrophil count Filgrastim neutrophil count (26.3) (d/r/d/c) NR <0.75x109/L 300 µg sc 1x/wk <0.75x109/L; d/c d/c AVT: 0/22 (0) when neutrophil count <0.5x109/L; until neutrophil count >1.0x109/L Sood41 2001 12 (100%) 12 NA d/c AVT: 1/12 (8.3) 1/12 d/c G-CSF due to Filgrastim severe headache Neutrophil count 300–480 µg 1x/wk <1.0x109/L for (6) 2x/wk for NR (2), 3x/wk for (4); 6 d/r when neutrophil count <0.75x109/L but resumed normal dose after G-CSF and neutrophil count >1.0x109/L
A-94 Soza42 2002 32/119 (26.9%) with NA NA NR NA neutrophil count <1.5x109/L; 0/13 with neutrophil count 11/119 (9.2%) with <0.75x109/L neutrophil count <0.75x109/L; 2/119 (1.7%) with neutrophil count <0.5x109/L Younossi43 2007 38 (37.6%) NR NA DC AVT: 1/38 (2.6) 13/38 (34.2) (bone pain, Filgrastim body aches, enlarged Neutrophil count 150 µg qw to 200 spleen [no significant <0.75x109/L µg 3x per wk until clinical sequelae]) neutrophil count NR >1.0x109/L AVT = antiviral therapy; d/c = discontinued; d/r = dose reduction; NA = not applicable; NR = not reported; qw = every week; sc = subcutaneous
A-95 APPENDIX 8: METHODOLOGICAL QUALITY OF STUDIES INCLUDED FOR CLINICAL REVIEW
Table 1: Methodological quality of randomized controlled trial
Quality Components
Author, Year Randomized (0, +1) Double-blind (0, +1) Description of withdrawals/dropouts (0, +1) Method of randomization appropriate (0, +1) Method of double-blinding appropriate (0, +1) Method of randomization (0, -1) inappropriate Method of double-blinding (0, -1) inappropriate Overall (0-5) Concealment of allocation Sharvadze40 2007 1 0 1 0 0 0 0 2 Unclear
A-96 Table 2: Methodological quality of clinical controlled trial Quality Components
Author, Year Randomized (0, +1) Double-blind (0, +1) Description of +1) withdrawals/dropouts (0, Method of randomization appropriate (0, +1) Method of double-blinding appropriate (0, +1) Method of randomization (0, -1) inappropriate Method of double-blinding (0, -1) inappropriate Overall (0-3) Concealment of allocation Koskinas36 2006 NA 0 1 NA 0 NA 0 1/3 Unclear
A-97 Table 3: Methodological quality of cohort studies Quality Components Selection Comparability Outcomes
) *1 (
y resent at the start of the stud Author, p Truly representative of the average in the Truly representative of the community (*1) Somewhat representative of the average in the community (*1) Selected group of users e.g., nurses, volunteers No description Drawn from the same community as the (*1) exposed cohort Drawn from a different source non- derivation of the No description of the exposed cohort Secure record (*1) (e.g., surgical record) Structured interview Written self-report No description Demonstration that outcome of interest was not Year HIV co- 1; 2) for: 1) genotype Study controls infection *1 factors (*1) for any addition Study controls blind assessment (*1) Independent Record linkage (*1) Self -report No description Was follow-up long enough for outcome to occur (*1) accounted Complete follow-up, all subjects for (*1) unlikely to Subjects lost to follow-up number lost (*1) introduce bias—small <90 % and not description of Follow-up Rate those lost No statement Total number of components filled Koirala35 Y Y Y Y Y Y Y Y Y 9 2007 Puoti37 2004 Y Y Y Y Y Y Y Y Y 9
A-98 Table 4: Methodological quality of case series with no control group Source of Potential Bias Selection Attrition Detection Assessment orted p Total number of components filled Source of case series (patients) is reported (e.g., database, charts, hospitals/clinics involved) Results are from a consecutive series of patients patient Clear indication of characteristics: Genotype patient Clear indication of characteristics: Age (mean, SD or by category) Inclusion criteria specified are treatment patients who of Proportion naïve Losses to follow-up with respect to outcomes of interest were < 10% is for treating neutropenia Trigger point described neutropenia is Treatment protocol for clearly described (drug/doses/route/administration times, dose reduction, discontinuation) Adverse events of GCSF are reported are to neutropenia Infections due re Author, Year Primary outcome of the study is stated Measurement of the primary outcome is described on the course The impact of neutropenia of AVT is described (e.g., not changed, dose reduction, discontinuation) Ball32 1999 N N N Y N N Y Y Y Y N Y Y Y 8 Gopal44 2001 Y N Y Y Y N Y Y Y Y N Y Y Y 11 Jeffers33 2004 Y N Y Y Y Y Y Y Y Y Y Y Y Y 13 Juarez-Navarro34 Y N Y Y Y N Y Y Y N Y Y Y Y 11 2005 Neumann45 2006 Y N Y Y Y Y Y Y Y N N Y Y Y 11 Renou38 2002 Y Y Y Y N N Y Y N N Y Y N Y 9 Senkbeil39 2003 Y N N N N Y Y Y N N N Y Y Y 7 Sharma46 2007 Y Y Y Y Y N Y Y N N N Y Y Y 10 Sood41 2001 Y Y N N N N Y Y Y Y N Y Y Y 9 Soza42 2002 Y Y Y Y Y N Y Y N N Y Y Y Y 11 Younossi43 2008 Y N Y Y Y Y Y Y Y Y Y Y Y Y 13
A-99