Surveillance of Sexually Transmitted Infections in Primary Care

174 EDITORIALS

Sexually transmitted infections consult a general practitioner at least Sex Transm Infect: first published as 10.1136/sti.79.3.174 on 1 June 2003. Downloaded from ...... once a year, and other primary care settings, such as family planning clinics are regularly attended by young people.8 Surveillance of sexually transmitted A number of studies have provided information on the burden of STIs in infections in primary care primary care.9–11 One recent study, the Chlamydia Screening Studies (ClaSS) I Simms, A-K Hurtig, P A Rogers, G Hughes, K A Fenton project, explored C trachomatis prevalence in a general practice registered popula- ...... tion aged 16–39 between 2001 and 2002, and included the collection of a limited What do we need to do? range of variables for each patient.12 However, since these studies are unique urveillance of sexually transmitted been developed for syphilis and gonor- they cannot be used for surveillance. infections (STI) provides infor- rhoea; and the laboratory report system Infrequent panel surveys are a source Smation for public health action, a is being expanded. Although improve- of surveillance data. The Morbidity Sta- relation that was highlighted by the ments in coverage, availability, quality, tistics from General Practice (MSGP) “National Strategy for Sexual Health and timeliness, and representativeness are was undertaken every 10 years and the anticipated, lack of data from primary last study, MSGP4, was undertaken in HIV” published recently by the Depart- 8 ment of Health (England).1 Systemati- care remains.34Substantial reservoirs of 1992. The dataset was derived from cally collected, timely, accurate, detailed, predominantly asymptomatic STIs, such attendances overa1yearperiodat60 representative STI surveillance data are as Chlamydia trachomatis, genital herpes general practices in England and Wales, and represented a 1% population sample. needed to estimate the population bur- simplex virus infection (HSV), human Although not a random sample, the den of disease; monitor effectiveness of papillomavirus infection, and pelvic in- dataset is broadly representative of the STI prevention; evaluate healthcare ac- flammatory disease (PID) are known to general population in terms of age, sex, cess; and assess determinants of trans- be treated in primary care settings, marital status, socioeconomic status, mission (box 1). including general practice and family planning.5–7 Developments proposed in smoking behaviour, and burden of England has one of the world’s most 8 disease. However, although this is a comprehensive STI surveillance systems the national strategy suggest that STI potentially good source of data, it only based on data from genitourinary medi- diagnosis and management will be in- creasingly focused on primary care. The gives an insight into the prevalence and cine (GUM) clinics (the KC60 return) determinants of incidence within the and laboratory reports. Data are widely systematic collection of timely, representative data from primary care is needed if population at the time of the study. disseminated and used in strategic Nationally representative, prospective health planning at national and local we are to address future prevention 1 needs, an emerging challenge that re- data are required to produce the timely levels. A weakness in English surveil- insights into STI epidemiology that are lance is that it does not provide the quires novel approaches to surveillance. Here, we discuss a new method for esti- needed to guide health policy. information needed to interpret changes mating STI prevalence in primary care Large prospective primary care sur- in STI epidemiology. This is not unusual http://sti.bmj.com/ within the context of the available veillance datasets have become available as there are similar weaknesses in surveillance data. over the past decade. The General Prac- surveillance systems in other countries, 2 tice Research Database (GPRD) and such as Sweden. Both the KC60 and AVAILABLE EVIDENCE AND MediPlus UK Primary Care Database are laboratory report systems are being REASONS FOR OTHER STUDIES based on general practice attendances. redeveloped: patient based data collec- Population based studies provide the The GPRD covers 6.4% of the UK population is being introduced in GUM; en- best method of assessing the epidemiol- tion, is broadly similar to the Office for hanced surveillance programmes have ogy of STIs that are not generally National Statistics (ONS) census in on September 28, 2021 by guest. Protected copyright. confined to core groups, but such studies terms of age and sex, and includes data are rare. In the United Kingdom, the only on diagnosis and treatment. MediPlus Box 1 Key objectives of STI investigation of this type was the second contains clinical and prescribing data surveillance National Survey of Sexual Attitudes and from approximately 1.7 million patients Lifestyles (NATSAL 2000), which ex- who have attended 140 UK general prac- • detect trends plored the reported population experi- tices since 1991 and is representative of • provide population estimates of ence of STI infection, and the prevalence the general population in terms of age, prevalence/incidence of infection/ of C trachomatis.7 This showed that 69% of sex, and regional distribution. In addi- disease women diagnosed with C trachomatis had tion, the Royal College of General Practi- • identify risk factors associated with attended GUM services, whereas only tioners’ General Practice Research Unit infection/disease 30% diagnosed with PID had attended undertakes continuous sentinel surveil- • allow assessment of intervention GUM services. This emphasises the role lance in 72 practices covering 600 000 strategies of services other than GUM in the man- people in England and Wales and collects • provide information to inform clinical agement of STIs, and highlights the need demographic and diagnostic data. How- practice and public health action to widen the scope of STI surveillance. ever, these datasets cannot be easily • be of high sensitivity (good coverage However, the complex, expensive adapted to the specific requirements of of the target conditions) probability sampling technique used in STI surveillance because they do not • use consistent, accurate diagnostic NATSAL is not feasible for routine data capture data on reproductive history, methods collection. While not as accurate as contraceptive history, or sexual behav- • be able to detect outbreaks population studies, primary care surveil- iour. Clinical samples are not taken, and • be effective and efficient lance could provide estimates of the bur- the methodologies cannot be modified. • present and disseminate data in a den of morbidity within a group that In addition, the cost of using these data- timely and accessible manner closely corresponds to the general popu- sets can be high. Information from fam- lation. Almost 80% of the UK population ily planning clinics is only consistently

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available from NHS family planning Sex Transm Infect: first published as 10.1136/sti.79.3.174 on 1 June 2003. Downloaded from clinics and Brook Advisory Centres. The Table 1 Number of people required to detect differences in prevalence* data, which are not validated and con- Prevalence (%) fined to contraceptive method, age, and Difference between sex of each patient at the first contact in populations (%) 251020 the financial year, are reported to the −3 – 653 1421 2695 Department of Health on the KT31 −2 482 1604 3312 6138 − return. 1 2514 6943 13 694 24 840 +1 4023 8357 14 950 25 782 The Public Health Laboratory Service +2 1239 2311 3940 6609 (PHLS) laboratory reporting surveillance +3 653 1125 1840 3009 system managed by the Communicable Disease Surveillance Centre would be an *Calculations assumed a random sample, 5% two sided significance level. alternative method of obtaining information on STIs diagnosed in primary care. The recent Department of Health patient’s reproductive and contraceptive would allow surveillance to move to- (England) publication “Getting ahead of history, sexual behaviour, demographic wards the proactive stance required for the curve, a strategy for combatting characteristics, and health seeking be- health service planning. Diagnosis would be the main outcome infectious diseases” recommended the haviour. Points of reference should also be included to allow comparisons with measure and tests and specimen types mandatory collection of detailed data related studies. would need to be selected carefully. with all laboratory diagnoses and the Overall available primary care surveil- Molecular techniques, such as multiplex PHLS system has been redeveloped to lance data are limited because many are or microarray assays, could be used to include more information on each re- either unique studies or collected once diagnose several organisms, such as C port, such as ethnicity and source of every 10 years; prospective studies are trachomatis, N gonorrhoeae (including report.13 This will potentially provide designed for general disease surveil- antibiotic resistance) using self obtained universal laboratory surveillance data for lance; little or no behavioural, demo- vaginal and vulval swabs or non-invasive C trachomatis, Neisseria gonorrhoeae, HSV, 15 graphic, and reproductive health data are specimens, such as urine. Mycoplasma and syphilis. Soon all positive and nega- collected; and many studies do not use genitalium, genital HSV infection, and tive samples of C trachomatis will be standard diagnostic criteria. A new pri- human papillomavirus could also be reported, which will allow the diagnostic mary care STI surveillance system would included in the testing strategy but this rate to be estimated in a variety of clini- help resolve these problems and create a may raise ethical concerns as screening cal settings including primary care. Data resource to inform sexual health plan- for these infections is not generally from the roll out of the English chlamy- ning. Here we explore the attributes of recommended. dia screening programme will also pro- such a system. Potentially there are problems associ- vide measures of screening uptake, cov- ated with a panel survey, the main erage, and acceptability. However, both REPEATED PANEL SURVEYS OF concern being the comparability be- datasets are likely to be limited because PRIMARY CARE ATTENDERS: A tween the general practice age/sex regis- of the restricted ability to collect relevant WAY FORWARD? ter and the general population. Young demographic and behavioural data. Ide- The aims of the survey would be to esti- men are less likely to be registered with a ally,surveillance should collect a range of mate prevalence, and change in preva- general practitioner than young women. http://sti.bmj.com/ information on factors that influence STI lence over time. The need for the timely For patients between the ages of 15 and 44 attending general practice the median incidence (box 2), so that the diagnoses collection of detailed data, together with contact days remain relatively constant can be place within the context of the a clinical sample suggests that a method- over time at 6.4 per 100 people per week ology based on a substantial population and 9.8/100 people per week, for males sample is inappropriate. A point preva- and females respectively.16 This panel Box 2 Factors that influence STI lence sampling technique would in- survey technique is an idealised model incidence crease efficiency and would be surpris- on September 28, 2021 by guest. Protected copyright. and would have to be adapted to specific ingly small: a random sample of about situations as it may not be feasible or • sexual behaviour, such as number of 4000 for each sex would give a represen- appropriate to collect detailed data in lifetime sexual partners, frequency of tative view of disease prevalence over the some situations. In addition, the focus on sexual intercourse, and age at first range 2% to 20% (table 1). The method- general practitioners may make such a sexual intercourse ology and sample size calculations would study difficult to implement at a time of • provision and access to healthcare have to be evaluated in a pilot study and increasing demands, although primary services the sampling strategy tailored to surveil- care research networks could be used as • health service seeking behaviours lance priorities, such as young people or the framework for such an initiative. • contraceptive practice (lifetime), in geographic variation in prevalence. Pa- This system could also be used as the particular condom use, and motiva- tients could be invited to participate at basis of a harmonised surveillance sys- tion for condom use clinic visits or by post. Measuring change tem that would allow a rapid evaluation • reproductive history, such as termina- in prevalence is an important method of of STI epidemiology and sexual health tion of pregnancy, ectopic preg- evaluating intervention, but changes are within and between countries. nancy, stillbirth, miscarriage difficult to predict and may be small.14 • cigarette smoking Again, a sample of 4000 would allow year CONCLUSIONS • whether the patient has undergone on year trends to be detected accurately. The close relation between surveillance instrumentation of the cervix, such as A self administered patient question- intelligence, disease prevention, and IUD insertion, dilatation, curettage, naire that can be scanned directly into a public health policy was highlighted by hysterosalpingography computer database would be used to the Department of Health’s “Getting • consulted for subfertility reduce data entry errors and allow a ahead of the curve.” At present, STI sur- • demographic characteristics, such as database to be constructed and veillance is limited by the relative lack of age, socioeconomic status, marital “cleaned” within a few days. Infor- information from primary care: initia- status mation could thus be collected, inter- tives capable of identifying and evaluat- preted, and disseminated quickly, and ing emerging health care need to be

www.stijournal.com 176 EDITORIALS

Correspondence to: Ian Simms, PHLS, Chlamydia trachomatis infection. Lancet

developed. The method discussed here Sex Transm Infect: first published as 10.1136/sti.79.3.174 on 1 June 2003. Downloaded from could allow an efﬁcient assessment of Communicable Disease Surveillance Centre, 2001;358:1851–4. 61 Colindale Avenue, London NW9 5EQ, UK; 8 OPCS. Morbidity statistics from general STI prevalence, sexual health, and health [email protected] practice: fourth national study, 1991–1992. service access behaviour. Such develop- London: HMSO. 1995. 9 Stokes T. Screening for chlamydia in general ments will be invaluable to future REFERENCES practice: a literature review and summary of primary care STI surveillance, but no the evidence. J Public Health Med 1 Department of Health. The national strategy single method can effectively undertake 1997;19:222–32. for sexual health and HIV. London: DoH, 10 Simms I, Catchpole M, Brugha R, et al. surveillance. Other opportunities are 2001. Epidemiology of genital Chlamydia evolving such as NHS electronic health 2 Mårdh P-A, Wahren H. Klamydiainfektion— trachomatis in England and Wales. Genitourin en sexuellt överförd sjukdom i skuggan av Med 1996;73:122–6. records, a longitudinal record of patient aids. Läkartidningen 1990;87:3064–5. 11 Department of Health. Chlamydia health and health care, developments 3 Simms I, Nicoll A. Sexual health in England: trachomatis. Summary and conclusions of that have to be evaluated and assimilated a guide to national and local surveillance and CMO’s expert advisory group. London: DoH, monitoring data. London: Health Education 1998. into STI surveillance to complement Authority, 2000. 12 The ClaSS Study Group. Evidence is not existing knowledge. Creativity, innova- 4 Catchpole M, Harris J, Renton A, et al. (yet) enough for evidence based policy of tion, and vision will be needed but it is Surveillance of sexually transmitted infections: chlamydia screening. BMJ 2002;322:364–5. fit for purpose? Int J STD AIDS 13 Department of Health. Getting ahead of the only by doing this that we will be able to 1999;10:493–4. curve: a strategy for combating infectious get ahead and stay ahead of the curve. 5 Simms I, Rogers P, Charlett A. The rate of diseases. London: DoH, 2002. 14 Scholes D, Stergachis A, Heidrich F, et al. diagnosis of pelvic inflammatory disease in Prevention of pelvic inflammatory disease by Sex Transm Infect 2003;79:174–176 general practice: England and Wales. Int J screening for cervical chlamydial infection. N 10 STD AIDS 1999; :448–51. Engl J Med 1996;334:1362–6...... 6 Simms I, Hopwood J, Mallinson H, et al. 15 Black CM. Current methods of laboratory Changing screening strategies for genital diagnosis of Chlamydia trachomatis Authors’ affiliations chlamydia in family planning clinics: a good I Simms, A-K Hurtig, G Hughes, K A Fenton, infections. Clin Microbiol Rev public health strategy? Eur J Contracept 1997;10:160–84. PHLS, Communicable Disease Surveillance Reprod Health Care 2000;5:91–5. 16 Royal College of General Practitioners, Centre, 61 Colindale Avenue, London 7 Fenton KA, Korovessis C, Johnson AM, et al. Birmingham Research Unit. The weekly returns NW9 5EQ, UK Sexual behaviour in Britain: reported sexually service annual report. Birmingham: RCGP, P A Rogers, PHLS Statistics Unit transmitted infections and prevalent genital 2000.

HIV Therefore, there is an urgent require- ...... ment for new drugs with activity against such resistant species. Over the past year or so, there has been a welcome upsurge New drugs for treating drug resistant in data presented on new drugs, both within existing classes and new classes, HIV-1 with the promise of more effective thera- pies for HIV resistant viruses (see table A Isaac, D Pillay 1).

...... http://sti.bmj.com/ NUCLEOSIDE/NUCLEOTIDE Clinical management of virological failure remains an ANALOGUES important and difficult issue for HIV physicians Nucleoside analogue drugs have been the mainstay of HIV therapy since zidovudine was ﬁrst licensed in 1988,2 ne of the major barriers to a population level, more than 50% of and it is not surprising that resistance to successful treatment of HIV-1 patients who fail therapy do so with this class of drugs is most common at a on September 28, 2021 by guest. Protected copyright. infection is the emergence of viruses resistant to drugs within at least population level (Health Protection O 1 drug resistant virus. The greatest impact one class of drug, with 15–20% with Agency, unpublished data). Despite of resistance is that it limits the effective- resistance to drugs within all three some speciﬁc signature mutations for ness of subsequent antiretroviral combi- currently available classes (Health Pro- individual nucleoside analogues, there is nations following initial drug failure. At tection Agency, unpublished data). increasing evidence for cross resistance

Table 1 Some new drugs recently approved and in clinical development with possible activity against resistant viruses

Drug class Stage of development Comments

NRTIs: Tenofovir Approved Active against TAMs11 Amdoxovir (DAPD) Phase I/II Active against various NRTI associated mutations, but not necessarily multidrug resistance78 Alovudine Phase I/II Activity against TAMs and antagonism with AZT and d4T45 nNRTIs: TMC120 Phase I/II Second generation nNRTIs active against nNRTI resistant viruses13 14 TMC125 Phase I/II Capravirine Phase I/II Activity against K103N/V106/L100I mutants. Mutations at 181 codon confer high level resistance15 PIs Atazanavir Phase III Favourable resistance profile in PI naive, but unclear cross resistance pattern in PI experienced. Good side effects profiles16 Tipranavir Phase I/II Likely to be effective in patients with experience of multiple protease inhibitors19 Fusion inhibitors Enfuvirtide (T-20) Phase III Active against multidrug resistant viruses20 21

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between certain drugs, such as ZDV and mutations in this regard are K103N, activity. More work is required to Sex Transm Infect: first published as 10.1136/sti.79.3.174 on 1 June 2003. Downloaded from d4T, as well as the emergence of muta- T181C, and G190A/E, all of which com- further clarify such “clinical cut offs” tions conferring broad cross resistance, promise nevirapine, efavirenz, and dela- whereby clinicians can be guided on the such as the 69 insertions, and the virdine responses, and this cross resist- likely effect of this new drug in a patient Q151M constellation of mutations ance represents a major limitation of the with existing PI resistant virus. within reverse transcriptase. Interesting class as a whole. However, two new com- data have been presented for alovudine, pounds, TMC 125 and TMC120, appear FUSION INHIBITORS to have activity against such resistance a thymidine analogue previously shown Data are now emerging from the trials of viruses, both in vitro and in vivo.12 13 to have considerable toxicity in the clinic. T-20(enfuvirtide), the first fusion inhibi- Another compound (capravirine) dem- Now reassessed at lower doses, activity is tor to enter the clinic. Since the phase III onstrated activity against a virus bearing observed in patients with ZDV/d4T re- trials were undertaken in heavily pre- the K103N or V106A or L100I single sistance (up to five thymidine analogue treated patients it is not surprising that mutation, although high level resistance resistance associated mutations, TAMS) failure rates (lack of full suppression) although antagonism between these to this drug was reported in the presence of mutations at codon 181.14 It appears were relatively high overall; however, this thymidine analogues is observed when affords the opportunity to characterise 34 not so much that different patterns of used in combination. More data are the emergence of resistance.19 20 Data awaited for this rejuvenated compound. resistance mutations are observed with these new nNRTI drugs, but rather that from phase II studies demonstrate that Amdoxovir (DAPD) is a new nucleoside the majority of such failure patients had analogue prodrug whose oral adminis- emergence of resistance is much slower than existing nNRTIs—note that single mutations in the gp41 region targeted by tration leads to a rapid in vivo conversion the drug—namely, between amino acids − α dose nevirapine in pregnancy is suffi- to ( )- -D-dioxalane guanosine (DXG). 36–45, which indeed confirms that activ- Resistance to this drug in the laboratory cient to select for resistant mutants— and that the well recognised nNRTI ity of the drug is mediated through the appears to involve the K65R and L74V 21 mutations have a marginal, and possibly proposed mechanism. Since variation mutations, similar to those observed for in this region is very rare in T-20 naive abacavir (although ABC failure is rarely clinically irrelevant, impact on fold susceptibility. It is argued that these proper- patients, including those infected with associated with these mutations in the non-subtype B viruses, it can be assumed 5 ties are a function of the unique struc- clinic). Phase I/II studies demonstrate a tures of these second generation nNRTIs, that previous RT inhibitor and PI therapy reasonable activity of this drug against 22 in the context of binding to the RT will not compromise T-20 activity itself. nucleoside analogue resistant viruses, enzyme. We look forward to more exten- The key issue with use of T-20 in salvage although more data are needed before sive clinical trial data for both these therapy will therefore be the choice of clarifying its potential role. However, drugs. other active drugs to combine with it. Of activity in vitro is compromised by the interest, the second generation fusion multinucleoside resistance mutation PROTEASE INHIBITORS inhibitor T-1249 appears to be active Q151M together with changes at amino Issues of resistance and cross resistance against most T-20 resistance mutants, acid 69 of reverse transcriptase, which are particularly pertinent to the protease although this is based on in vitro may limit its role in higher nucleoside evidence alone.23 67 inhibitor class of drugs. Many claims analogue experienced patients. The have been made on the apparent unique- drug attracting most excitement at ness of resistance patterns for specific CONCLUSION present is the recently approved nucle- http://sti.bmj.com/ drugs, based on in vitro data, which do Despite the undoubted success of anti- otide analogue tenofovir, which appears not then translate into clinical benefit for to be unencumbered by the toxicity retroviral therapy clinical management that drug in PI experienced patients. Two of virological failure remains an impor- problems of its cousin, adefovir. As for new PIs have now undergone initial many other drugs, the HIV mutations in tant and difficult issue for HIV physi- clinical evaluation. Atazanavir (ATZ), cians. Since such patients often have reverse transcriptase associated with soon to be available within an expanded reduced activity in the clinic are not nec- drug resistant virus, the choice of new access programme, demonstrated differ- combinations is often based, at least to

essarily those selected by tenofovir in the on September 28, 2021 by guest. Protected copyright. ent resistance profiles when used in PI some extent, on our knowledge of resist- laboratory (K65R). This is because the naive or PI experienced patients. In the drug has been most widely tested in drug ance characteristics of available drugs. former group, resistance emerges with We have summarised the data on a experienced patients in whom resistant 15 the I50L and A71V mutations. This is a whole series of new drugs within exist- virus already exists and predictors of unique combination since amprenavir poor response can be identified. Thus, ing and new classes. After some years of resistance mutations include a different promising in vitro data, these drugs have common nucleoside analogue resistance amino acid change at position 50 mutations such as M41L, L210W (possi- demonstrated promise in clinical trials, (namely, I50V), although the A71V mu- with particular interest focused on bly a key marker in this respect), and tation is a polymorphism (not infre- unique resistance patterns, or the slow T215Y appear to reduce, although not quently observed in the absence of PI development of resistance. As further negate, clinical efficacy; nevertheless, the therapy). By contrast, in PI experienced clinical trial data are presented for new widespread use of tenofovir in salvage patients, some level of cross resistance drugs, it is important for HIV physicians therapy and promising first line treat- between atazanavir and other PIs was to ask two specific questions. Firstly, ment trial data suggest that it represents apparent.16 and therefore the utility of what are the resistance patterns at base- an important addition to our antiviral this drug as a second line PI may be lim- 8–10 line, which define success or failure of armoury. ited. Clinical data for this scenario are this new drug in antiretroviral experi- awaited at the time of writing. Clinical enced patients and, secondly, what are NON-NUCLEOSIDE REVERSE data have also been presented for ti- the resistance correlates of failure when TRANSCRIPTASE INHIBITORS pranavir, which shows potency against used as a first line drug? It is answers to The phenomenon of extensive cross viruses containing a large variety of PI 17 these questions that will contribute to resistance between nNRTIs is one of the resistant mutants in vitro. Clinical identifying the optimal role of these more widely accepted truths of HIV drug activity was indeed observed in PI expe- promising new drugs in routine clinical resistance, owing to the small binding rienced patients, with a suggestion that a site for this group of drugs within the very large number of PI resistant muta- practice. viral reverse transcriptase.11 The key tions were required to compromise Sex Transm Infect 2003;79:176–178

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...... 8 Squires K, Pierone G, Berger D, et al. 16 Robinson B, Riccardi K, Gong Y, et al. Sex Transm Infect: first published as 10.1136/sti.79.3.174 on 1 June 2003. Downloaded from Authors’ affiliations Tenofovir DF: a 48-week final analysis from a BMS-232632, a highly potent human phase III randomised, double blind placebo immunodeficiency virus protease inhibitor that A Isaac, Whittal Street Clinic, Birmingham, UK controlled study in antiretroviral experienced can be used in combination with other D Pillay, PHLS Antiviral Susceptibility Reference patients. Ninth Conference on Retroviruses available antiretroviral agents. Antimicrob Unit, Birmingham, UK and Opportunistic Infections, Seattle, abstract Agents Chemother 2000;44:2093–9 P 413-W, 2002. 17 Larder BA, Hertogs K, Bloor S. Tipranavir Correspondence to: Dr Deenan Pillay, 9 Staszewski S, Gallant J, Pozniak A, et al. Department of Virology, Windeyer Institute, inhibits broadly protease inhibitor-resistant Efficacy and safety of tenofovir disoproxil HIV-1 clinical samples. AIDS University College Hospital, 46 Cleveland fumarate (TDF) versus stavudine (d4T) when 2000;14:1943–8. Street, London W1T 4JF, UK; [email protected] used in combination with lamivudine (3TC) 18 Schwartz R, Kazanjian P, Slater L, et al. and efavirenz (EFV) in HIV-1 infected patients Resistance to tipranavir is uncommon in a Accepted for publication 27 February 2003 naive to antiretroviral therapy (ART): 48-week randomized trial of tipranavir/ritonavir interim results. Fourteenth International AIDS REFERENCES Conference, Barcelona, abstract 17, 2002. (TPV/RTV) in multiple-PI-failure patients (BI 10 Miller MD, Margot NA, Cheng AK, et al. 1182.2). Ninth Conference on Retroviruses 1 Pillay D, Taylor S, Richman DD. 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Ninth Conference on prodrug diaminopurine dioxolane, is a potent treatment-emergent resistance to T-20 Retroviruses and Opportunistic Infections, inhibitor of drug-resistant HIV-1 isolates from (enfuvirtide) observed in Phase II clinical trials: Seattle, abstract 5, 2002. patients for whom standard nucleoside substitutions in gp41 amino acids 36–45 and therapy fails. J Acquir Immune Defic Syndr 14 Potts KE, Fujiwara T, Sato A, et al. Antiviral enfuvirtide susceptibility of virus isolates. 2002;29:11–20. activity and resistance profile of AG-1549, a Antiviral Therapy 2002;7(Suppl 1):S16. 6 Eron J, Kessler H, Thompson M, et al. Clinical novel HIV-1 non-nucleoside reverses Xu L HIV suppression after short-term monotherapy transcriptase inhibitor. Sixth Conference on 22 , Hue S, Pillay D, et al. Minimal variation with DAPD. 40th Interscience Conference on Retroviruses and Opportunistic Infections, in T-20 binding domain of different HIV-1 Antimicrobial Agents and Chemotherapy, Chicago, 1999, abstract 12. subtypes from antiretroviral naïve and Toronto, abstract 690, 2000. 15 Colonno RI, Friborg J, Rose RE, et al. experienced patients. AIDS 7 Jeffrey J, et al. Amdoxovir, a nucleoside Identification of amino acid substitutions 2002;16:1684–6. reverse transcriptase inhibitor, is active correlated with atazanavir susceptibility in 23 Greenberg ML, Davison D, Jin L, et al.In http://sti.bmj.com/ against HIV mutants resistant to a standard patients treated with atazanavir-containing vitro antiviral activity of T-1249: a second nucleoside therapy. Antiviral Therapy regimens. Antiviral Therapy 2002;7(suppl generation fusion inhibitor. Antiviral Therapy 2001;6(supp1):10–11. 1):S56. 2002;7(Suppl 1):S10. on September 28, 2021 by guest. Protected copyright.