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1 (FCH/HIV, 22 April 2002) Application for Inclusion of zidovudine and lamivudine (included fixed-dose combinations) on the WHO Model List of Essential Medicines Both drugs are members of the therapeutic class of HIV nucleoside analogue reverse transcriptase inhibitors Summary of Proposal Since the first clinical evidence of AIDS was reported over twenty years ago, an estimated 25 million people have died as a result of HIV infection. Current estimates suggest that around 40 million persons world-wide are infected with HIV and more than 90% of infected persons live in the developing world. Growing experience of the provision of anti-retroviral therapy in resource-poor settings (eg. Brazil, Côte d’Ivoire, Senegal, Haiti, India) indicates that treatment can be provided in an effective and safe manner. The delivery of anti-retroviral treatment in low-income countries has been aided by the development of fixed drug combinations and substantial reductions in the prices of certain products. The nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine (ZDV, AZT) and lamivudine (3TC) are proposed for listing on the WHO Model List of Essential Medicines. The drugs are generally used together to form a ‘nucleoside core’ to which other drugs are added. The drugs are being proposed for listing jointly because they are the most widely investigated, and most commonly used, dual nucleoside regimen in contemporary multi-drug antiretroviral regimens. They are a part of the three first-line treatments in the draft WHO Guidelines for use of antiretroviral drugs in resource-poor settings (ARV Guidelines). They are available as a fixed drug combination from 7 manufacturers internationally. The combination of ZDV and 3TC is recommended for treatment within an appropriately monitored program, in combination with one or two other antiretroviral drugs, including nucleoside or non-nucleoside reverse transcriptase inhibitors, or protease inhibitors. Antiretroviral therapy is recommended for HIVinfected children, adolescents and adults with symptomatic disease, and also for asymptomatic patients with CD4+ cell counts at or below 200/mm 3. A search of several data-bases, including the Cochrane Library, Medline and Embase, retrieved systematic reviews and articles supporting the use of HIV-1 RNA levels and CD4 cell counts as valid surrogate measures for changes in the rates of clinical outcomes during treatment of HIV-infected subjects. The literature search also provided evidence that combinations of 3 or 4 anti-retroviral drugs are superior to dual or single drug therapy. The latter are no longer regarded as satisfactory treatment, because of low efficacy rates and the development of resistance. 2 The literature search retrieved a large number of citations describing randomised controlled trials involving ZDV + 3TC used as sole therapy, or in combination with a range of other ARV agents. From these were selected 3 meta-analyses and 11 randomised controlled trials, which provided information on the performance of ZDV/3TC compared with other dual nucleoside combinations which are recommended as alternative regimens in the draft WHO ARV Guidelines. This set of trials is informative, not only in providing unambiguous evidence of the efficacy of ZDV+3TC as a dual nucleoside ‘core’ to combine with a range of other ARVs, but also because the data establish the efficacy of alternative regimens recommended in the draft WHO ARV Guidelines. In several comparisons d4T+3TC and ddI+d4T were found to be at least as efficacious as ZDV+3TC and as well tolerated (although qualitatively the nature of adverse reactions tended to be different). In a large direct comparative study a fixed dose combination of ZDV+3TC was found to have equivalent efficacy to concomitant use of the individual drugs, and to lead to a higher level of adherence to treatment. The data confirmed the efficacy of dual nucleoside regimens combined with protease inhibitors, other nucleoside, and non-nucleoside reverse transcriptase inhibitors, which appear to be as effective as the former, and in the case of efavirenz, better tolerated. 1. Proposal for inclusion, change or deletion. Zidovudine and lamivudine are proposed for inclusion on the WHO Model List of Essential Medicines, as part of a multi-drug antiretroviral regimen for the treatment of HIV/AIDS within an appropriately monitored program. Currently zidovudine is listed, but only for the indication of reducing the risk of mother to child transmission of HIV infection. Zidovudine and lamivudine are both nucleoside reverse transcriptase inhibitors. The drugs are being proposed jointly because they are the most widely investigated, and most commonly used, nucleoside ‘core’ in contemporary multidrug antiretroviral regimens. They are a part of the three first-line treatments in the draft WHO guidelines for use of anti-retroviral drugs in resource-poor settings (Table 1). They are available internationally individually, and in the form of several fixed dose combination preparations. However, combinations of both drugs with other nucleoside reverse transcriptase inhibitors (NRTIs) are possible. Because of the risk of antagonism, leading to reduced efficacy, zidovudine (ZDV) should not be used with stavudine (d4T) and lamivudine (3TC) should not be used with didanosine (ddI). Antiretroviral therapy is recommended for HIV-infected children, adolescents, and adults with symptomatic disease, and also for asymptomatic patients with CD4+ cell counts at or below 200/mm3. Where CD4+ cell testing is unavailable, clinicians can use the presence of a total lymphocyte count below 1200/mm 3, but only in symptomatic patients.1,2 3 2. Name of the focal point in WHO submitting the application: HIV/AIDS Department at WHO; the person responsible is Dr Dr Bernhard Schwartländer, Director of Evidence and Policy. 3. Name of the organization(s) consulted and/or supporting the application: Supporting letters may be provided 4. International Nonproprietary Name: zidovudine, lamivudine and compounded fixed-dose lamivudine + zidovudine 5. Listing Type Requested: Listing of both drugs is requested on the Model List of Essential Medicines as examples of the therapeutic class of HIV nucleoside analogue reverse transcriptase inhibitors. Other members of this class of drugs may serve as alternatives, depending on quality, price and local availability. 6. Information supporting the public health relevance of the submission: Since the first clinical evidence of AIDS was reported over twenty years ago, an estimated 25 million people have died as a result of HIV infection. Current estimates suggest some 40 million persons worldwide are infected with HIV and more than 90% of infected persons live in the developing world3. In 2001, 5 million persons worldwide became infected with HIV, and 3 million others died from HIV/AIDS-related causes. In sub-Saharan Africa, the region most severely affected by HIV, 28.1 million individuals are living with this infection. Eastern Europe — especially the Russian Federation — continues to experience the fastest-growing epidemic in the world. In 2001, there were an estimated 250 000 new infections in this region, bringing to 1 million the number of people living with HIV. In Asia and the Pacific, an estimated 1 million people became infected in 2001; about 7.1 million people in this region are now living with HIV/AIDS3. More than 1.8 million people in Latin America and the Caribbean are living with HIV/AIDS, including the 190,000 adults and children who became infected in 2001 In countries often already burdened by huge socio-economic challenges, HIV/AIDS threatens human social welfare, developmental progress, and social stability on an unprecedented scale. HIV/AIDS cripples the economic development of entire countries, because it often strikes people during their most productive working years. Of the 14,000 persons who became infected each day in 2001, about 12,000 were aged 15 to 49 years3. Left untreated, HIV infection results in a period of clinical latency that may last a median of 3 to 10 years. Once symptomatic disease or AIDS develops, without access to antiretroviral treatment, death results within an average of two years. 4 In high-income countries, an estimated 1.5 million people live with HIV, many of them productively, thanks to antiretroviral therapy. In the USA, the introduction of triple combination antiretroviral therapy in 1996 led to a decline of 42% in deaths attributable to HIV/AIDS in 1996-973. The feasibility efficacy and adherence with antiretroviral therapy has been demonstrated in a number of national and smaller pilot programs in middle- and low-income countries. In Brazil, the policy of universal access to antiretroviral drugs has reduced the number of AIDS-related deaths by nearly 50% and cut the incidence of opportunistic infections by 60 - 80%4. Between 1997 and 2000, Brazil saved approximately US $677 million in averted hospitalisations and treatment of HIVrelated infections. In Argentina a program similar to that of Brazil provides even greater coverage. A special fund has been established to pay for antiretroviral drugs for those not covered by social security (such as street vendors, small business people, the unemployed, low-income pregnant women) 5. Through the UNAIDS Drug Access Initiative Pilot Program, 6 treatment centres in Abidjan, Côte d’Ivoire, offer antiretroviral therapy. Of the patients who received therapy, 72% were heavily symptomatic upon initiation. Nonetheless, the overall survival rate of was 93% at 6 months, 90% at 12 months, and 86% at 18 months. When survival rates are re-calculated using a worst-case scenario in which patients lost to follow-up are assumed to have died immediately after their last clinic visit, 75% survived at 6 months, 64% at 12 months, and 55% at 18 months6. The Senegal Initiative on Antiretroviral Therapy was launched in August 1998. A partnership between the Senegalese government and the International Therapeutic Solidarity Fund, it aims to have 7,000 patients on triple combination therapy by the end of 2007. At the end of 2001, an estimated 550 adults and children had received treatment. A prospective observational cohort study was undertaken to assess the feasibility, effectiveness, adherence, toxicity and viral resistance of antiretroviral therapy. The clinical and biological results of the study were comparable to those seen in western cohorts, despite differences in HIV-1 subtype and an advanced disease stage when treatment was initiated. Fifty-eight patients with advanced HIV disease demonstrated by CDC staging (16 patients in CDC Stage B, 42 in CDC Stage C) and CD4+ cell count (median CD4+ cell count = 108.5, IQR = 34 - 217) were given triple combination antiretroviral therapy (2 nucleoside analogues + 1 protease inhibitor). After 18 months of treatment, participants gained a median of 180 CD4+ cells and showed a median drop in plasma viral load of 2.8 log10 copies/ml. During the study period, there were 7 clinical AIDS-defining events with 6 deaths from HIV-related infections7. The antiretroviral regimen was complex: indinavir, the protease inhibitor used in the study, had to be taken in a fasting state every 8 hours, with maintenance of hydration; didanosine (DDI), the nucleoside analogue given to 86% of participants, is a buffered preparation which also had to be taken while fasting 1 to 2 hours 5 after any other medication. Despite the complexity of the regimen, 80% of patients (IQR 72-87%) showed adherence 80% at 18 months. In Cange, a Haitian village, the non-profit organization Partners in Health has introduced antiretroviral therapy to a small number of seriously ill AIDS patients, based on their Directly-Observed Therapy (DOT) programme for multiple-drug resistant tuberculosis. This DOT programme has been successful, with 90% of all registered TB cases in the Cange catchment area considered cured, compared with just 26% in other regions of Haiti. Sixty-five patients were selected to receive triple combination antiretroviral therapy on the basis of clinical indicators of severe HIV disease (e.g. wasting, recurrent opportunistic infections, severe neurological complications, etc.). Shortly after initiating treatment, most patients showed clinical improvement. To counter critics and test the effectiveness of the programme, blood samples were sent to Boston for viral-load analysis. The results showed that 83% of patients on triple therapy had unquantifiable viral load measures. For the most part, side effects have been minimal and easily managed and there are support groups to encourage adherence.8 At HIV clinics in Pune and Ahmedabad, India, a recent study demonstrated the benefit of triple combination antiretroviral therapy (nevirapine + 2 nucleoside analogue RTs) in 347 patients with advanced HIV disease. At 12 months, 64.6% of the study participants experienced an increase of more than 20% in CD4+ cell counts. Twenty-three secondary clinic events during the study were reported, including 6 deaths (4 TB-related, 1 cryptococcal meningitis, 1 non-Hodgkin’s lymphoma) — an AIDS-associated mortality rate of 5.7% at six months. This program was also significant for the fact that it relied on generic drugs supplied by Indian pharmaceutical manufacturers.9 Thus, in addition to the large amount of clinical data from high-income countries, there is a small but growing body of clinical evidence to support the use of ARVs in developing countries. Significant price reductions have also been achieved in many developing countries and new funding and delivery mechanisms are being developed to expand their availability. These factors warrant the addition of this class of drugs to the Model List of Essential Drugs (with appropriate consideration of their use in resource-limited settings). 7. Treatment details: Zidovudine Recommended Dosage: Adults and adolescents over the age of 12 years: 600 mg daily, in two divided doses, in combination with other antiretroviral medications. Children 6 weeks to 12 years of age: 160 mg/m2 every 8 hours (480 mg/m2/day to a maximum of 200 mg every 8 hours). Concomitant Antiretroviral Therapy: Zidovudine must be given in combination with other antiretroviral medications. Duration: Antiretroviral treatment is usually regarded as life-long. 6 Guidelines: Guidelines The draft “WHO Antiretroviral Guidelines for Resource Limited Settings”10 indicates zidovudine and lamivudine (in combination with one or more additional other antiretroviral medicines) as a preferred first-line regimen for the treatment of HIV/AIDS. Special Requirements: Adequate resources for monitoring and specialist oversight are a pre-requisite for the introduction of this class of drugs. Lamivudine Recommended Dosage: Adults and adolescents at least 12 years old: 150 mg twice daily. Children (3 months up to 16 years of age) 4 mg/kg twice daily (up to a maximum of 150 mg twice a day). Concomitant Antiretroviral Therapy: Lamivudine must be given in combination with other antiretroviral medications. Duration: Antiretroviral treatment is usually regarded as life-long. Guidelines: The draft “WHO Antiretroviral Guidelines for Resource Limited Settings10 indicates zidovudine and lamivudine (in combination with one or more additional other antiretroviral medicines) as a preferred first-line regimen for the treatment of HIV/AIDS. Special Requirements: Adequate resources for monitoring and specialist oversight are a pre-requisite for the introduction of this class of drugs. Fixed dose combinations of ZDV and 3TC Recommended Dosage: Adults and adolescents over the age of 12 years: 1 tablet (containing 150 mg lamivudine and 300 mg zidovudine), taken twice daily. This fixed-dose formulation is not suitable for children under 12 years of age. Concomitant Antiretroviral Therapy: Fixed-dose lamivudine + zidovudine must be given in combination with other antiretroviral medications. Duration: Antiretroviral treatment is usually regarded as life-long. Guidelines: The draft ‘WHO Antiretroviral Guidelines for Resource Limited Settings’10 indicates zidovudine and lamivudine (in combination with one or more additional other antiretroviral medicines) as a preferred first-line regimen for the treatment of HIV/AIDS: Special Requirements: Adequate resources for monitoring and specialist oversight are a pre-requisite for the introduction of this class of drugs. 7 8. Comparative effectiveness in clinical settings: In compiling the evidence for this and related submissions for anti-retroviral drugs we have created a common ‘stem’ in the form of information that is relevant to all of the antiretroviral group. This is followed by information that is relevant to use of this class of drug under the conditions described in this application, followed by information which is specific to the individual agent under consideration. Because of time constraints and the growing acceptance of the efficacy of highly active anti-retroviral drug regimens in the last 5 years, we have relied in part on secondary data sources – systematic reviews of randomised and non-randomised studies conducted by the Cochrane Collaboration, or by independent groups who have generally met standards that are considered appropriate to this type of work. We have relied on individual trials where these provided data and insights not available from systematic reviews. Details of literature searches conducted The principal data-bases maintained by the WHO that were searched were: o The Cochrane Data-base of Systematic Reviews o The ACP Journal Club reviews of published trials o The data-base of reviews of abstracts of reviews of effectiveness (DARE) o The Cochrane controlled trials register (CCTR) o Medline o Embase o o AIDSLINE CENTRAL Search terms used were: o o o o o o Anti-retroviral or antiretroviral Nucleoside reverse transcriptase inhibitors Non-nucleoside reverse transcriptase inhibitors Protease inhibitors Randomised clinical trial (exploded and as text word) Individual drug names: zidovudine (or AZT or ZDV) AND lamivudine (or 3TC), Study selection: o o o Randomised comparative parallel-group controlled clinical trials Compared ZDV in combination with 3TC with: Other dual nucleoside regimens (this part of the search was confined to relevant published meta-analyses). Examined the performance of ZDV and 3TC when included in combinations comprising 3 or more drugs, involving concomitant use of another NRTI, NNRTI or PI. 8 Note: The examination of 2-drug combinations does not imply any endorsement of such regimens as effective treatments; these data are included here to help establish the efficacy and safety of the combination of ZDV and 3TC as a ‘nucleoside core’. The literature search used here, although comprehensive, is not complete. In particular, trials presented at conferences, and available only as published conference proceedings, were not included and no attempt was made to retrieve unpublished data. Categorisation of levels of evidence The following rating scheme was used11: Level 1 – evidence from relevant high quality systematic reviews of unbiased randomised comparative clinical trials Level 2 – evidence from at least one relevant unbiased randomised comparative clinical trial. Level 3 – evidence from relevant controlled observational studies Additional considerations for use in resource-poor settings Co-morbidity Simplicity (frequency of dosing, number of tablets) Tolerability Cost Prior exposure to ARVs General therapeutic issues: (common to the therapeutic category of antiretroviral drugs) 1. What is the validity of surrogate markers as predictors of morbidity and mortality in patients with HIV/AIDS? 2. What evidence is there that triple (or quadruple) ARV therapy is superior to single or dual therapy? Class specific questions 3. Which combinations of drug classes have the best evidence in relation to benefits and harms? Agent-specific questions 4. What is the evidence for the efficacy and toxicity of anti-retroviral drug combinations that include didanosine? Results 1. What is the validity of surrogate markers as predictors of morbidity and mortality in patients with HIV/AIDS? (Level 3 evidence) Trials of anti-retroviral compounds have relied heavily on measuring the effects of drugs on surrogate markers, usually CD4 cell counts and plasma HIV-1 RNA levels. The validity of these markers depends on showing that they are correlated with clinical outcomes, and that they should be able to capture the effects of 9 outcomes12. treatment on the major clinical Both of these markers may be viewed as being on the ‘causal pathway’ between viral infection and disease outcomes, but more directly in the case of viral measures. The viral end-point has come to be regarded as superior to a measure as a prognostic marker, although results have not been entirely consistent. A meta-analysis of trials of 2 NRTIs (plus NNRTI or PI), which included 36 treatment arms, found that baseline CD4 counts were significantly correlated with virologic suppression at 6 and 12 months, whereas a similar correlation was not found with baseline viral load and subsequent viral suppression13. The authors concluded that baseline CD4 cell count was a better predictor of drug induced viral suppression than baseline viral load. In the other meta-analysis of surrogate measures uncovered by the literature search, Hill et al reviewed results from 15 randomised trials that used surrogate markers and also included measures of disease progression14. This review included data from 15038 patients, of whom 3532 patients progressed to clinical outcomes. The analyses documented that there were significant correlations between the relative hazards for clinical progression and changes in both HIV-1 RNA levels and CD4 cell counts. The authors concluded that these markers, together, were useful in monitoring treatment responses. However the data also indicate the value of using CD4 cell counts alone. Another meta-analysis has quantified the relationship between changes in surrogate measures and development of AIDS or death. In an analysis based on 16 randomised trials of NRTIs, Babiker et al. estimated that the average hazard reduction was 51% (95% CI 41, 59%) for each reduction in HIV RNA levels of 1*log10, and 20% (95% CI 17, 24%) for each increase of 33% in CD4 cell count15. These studies are supported by a wealth of observational data from developed countries, showing that the use of highly active anti-retroviral therapy, tested on the basis of surrogate markers in many trials, has profoundly influenced the outcomes for patients with HIV infection. 2. What evidence is there that triple (or quadruple) ARV therapy is superior to single or dual therapy? (Level 1 evidence) There is extensive clinical experience suggesting that multiple drugs with different modes of action are necessary to achieve sustained viral suppression (induction). Such combination treatments are standard recommendations in clinical practice guidelines. 16,17,18 There is insufficient space and time to present all of the relevant studies documenting the success of multi-drug induction therapy to the Expert Panel. However, a smaller number of trials have documented the value of various maintenance regimens introduced after successful induction therapy and these studies are relevant. Four trials that compared 3 or 4 drug maintenance regimens with 2 drug regimens were included in a Cochrane Review19. Use of a two-drug maintenance regimen was associated with an odds ratio for virologic failure (loss of HIV suppression) of 5.55 (95% CI 3.14, 9.80). These results complement an earlier systematic review, which synthesised data from 6 trials that compared the results of zidovudine monotherapy with treatment combinations comprising ZDV with DDI or DDC20. Although mainly of historical interest now, the review studies clinical outcomes and showed that the addition of DDI to ZDV resulted in a reduced odds of disease progression and death (OR 0.74, 95% CI 0.67, 0.82) and (0.72, 95% CI 0.64, 0.82) respectively. The addition of DDC gave similar results: disease progression, 0.86 (95% CI 0.78, 0.94); and death, 0.87 (95% CI 0.77, 10 0.98). After 3 years the rates of mortality were ZDV 59%, ZDV+DDC 63% and ZDV+DDI 68%. The reviewers concluded that the combination of ZDV and DDI was probably superior to ZDV plus DDC. 3. Which combinations of drug classes have the best evidence in relation to benefits and harms? (Level 2 evidence) Unfortunately this is a question that is not yet addressed in published systematic reviews. Enquiries directed to the AIDS/HIV review group in the Cochrane Collaboration revealed that relevant reviews are underway but results are not yet available. Some of the data from the limited number of trials comparing different combinations of 3 or more anti-retroviral drugs will be reviewed in relation to the individual drugs (see below). However there are broad questions about which combinations should be used as first line treatment, and in what sequence should they be employed. The clinical practice guidelines mentioned earlier address some of these issues and point out that choice is determined not only by direct evidence of comparative clinical efficacy, but also by tolerability and toxicity, presence of comorbidity, concern about the development of viral resistance, and more pragmatic considerations such as pill burden and adherence to therapy. With recognition that none of the available regimens eradicates the virus, but suppression is desirable, HIV infection has come to be regarded as a chronic disease, which requires longterm (albeit sometimes intermittent) drug therapy. An additional consideration is a wish to ‘preserve’ more active anti-retroviral regimens for later in the course of therapy. This has led to recommendations to conserve PI-containing regimens, using those based on combinations of NRTIs and NNRTIs early in therapy. These considerations are reflected in the advice contained in the draft WHO Antiretroviral Guidelines for Resource Limited Settings. The summary of regimens recommended in this document is reproduced as Table 1. Table 1. Recommended First-Line Antiretroviral Regimens in Adults Regimen ZDV/3TC plus EFV* or NVP* ZDV/3TC/ABC* ZDV/3TC** plus RTV enhanced PI or NFV Pregnancy Considerations - Substitute NVP for EFV in pregnant women or women for whom effective contraception cannot be assured - ABC safety data limited - LPV/r safety data limited - NFV: most supportive safety data Major Toxicities - ZDV-related anemia - EFV-associated CNS symptoms - Possible teratogenicity of EFV - NVP-associated hepatotoxicity and severe rash - ZDV-related anemia - ABC hypersensitivity - ZDV-related anemia - NFV-associated diarrhoea - IDV-related nephrolithiasis - PI-related metabolic side effects 11 *ZDV/3TC is listed as the initial recommendation for dual NsRTI component based on efficacy, toxicity, clinical experience and availability of fixed dose formulation. Other dual NsRTI components can be substituted including d4T/3TC, d4T/ddI and ZDV/ddI depending upon country-specific preferences. ZDV/d4T should never be used together because of proven antagonism. ** RTV-PI includes IDV/r, LPV/r, and SQV/r. 4. What is the evidence for the efficacy and toxicity of anti-retroviral drug combinations that include lamivudine and zidovudine? (Level 1 and Level 2 evidence) Zidovudine (ZDV or AZT) has been in clinical use for a number of years, initially as mono-therapy, then in various dual treatment combinations and more recently as part of multi-drug combinations involving a range of other antiretroviral drugs. Most commonly ZDV has been used in combination with lamivudine (3TC), and this has become the standard nucleoside ‘core’ combination treatment on which more complex regimens are based. Consistent with the wide experience of this combination of nucleoside RTIs, there is a large literature base. Searching on the combination of ‘zidovudine’ (or ‘ZDV’ or ‘AZT’) and ‘lamivudine’ (or ‘3TC’) along with appropriate terms for ‘randomised clinical trials’ yielded well over 200 citations. A full summary of this extensive literature would be a demanding and time-consuming task, and to some degree is academic, because many of the early studies (prior to 1997/98) generated data that have been superseded, and are not particularly informative for contemporary practice. So, the presentation of studies here is selective, directed by the recommendations for ‘nucleoside cores’ in the draft WHO Guidelines (Table 1). A brief consideration of dual and monotherapy comparisons is followed by a studyby-study consideration of the performance of ZDV/3TC in combination with other anti-retroviral drugs. Dual and monotherapy regimens The meta-analysis of Staszewski et al (1997)21 summarized 4 randomised clinical trials comprising data from 972 HIV-infected patients with baseline CD4 counts of 100-500*106/L. Subjects were randomised to treatment with ZDV/3TC or ZDV monotherapy (3 trials) or ZDV+ddC (1 trial). In all, 118 patients progressed to new AIDS clinical events and the risk was reduced significantly by ZDV/3TC therapy (RR 0.51; 95% CI 0.37, 0.71) relative to control treatments (mainly ZDV monotherapy). In a draft (unpublished) Cochrane Review22 of three trials that compared ZDV+3TC with ZDV monotherapy, the average reduction in HIV-1 RNA viral count was 0.84 log10 copies/mm3. In a pooled analysis of 6 RCTs of ZDV+3TC (with different comparators), including data from 1083 participants, Opravil et al (1998), found that baseline HIV-RNA levels, and the duration of prior ZDV treatment both negatively influenced the anti-viral efficacy of ZDV/3TC23. 12 The literature search yielded several studies that made direct comparisons of ZDV/3TC with other established dual nucleoside regimens that are recommended by WHO (d4T/3TC and ddI/d4T). Aboulker et al (1998) randomised subjects on a range of different NRTIs to 3TC or placebo24. However the other regimens were not determined at random. The study is significant in documenting the inferior performance of a combination of ddI/3TC, which is not recommended by WHO. McKinney et al (1998) found both ZDV/3TC and ZDV/ddI to be superior to ddI alone25. Comparisons of ZDV/3TC with more relevant dual nucleoside regimens are summarised in Attachment 1. Kuritzkes et al 1999 (references are linked to the Attachment) found ZDV/3TC to be equivalent in efficacy to d4T/3TC. Interestingly, this study also found ddI/3TC to be effective, although it is generally viewed as a sub-optimal combination. Molina et al 1999 (Attachment 1) found ZDV/3TC to be effective in treatment-naïve individuals, although significantly less so than a combination of ddI/d4T. All of these studies documented fairly low rates of serious adverse reactions and the regimens were well tolerated. While these studies of dual therapy are helpful in establishing the efficacy and tolerability of DZV/3TC, they do not reflect contemporary practice where dual nucleoside combinations are combined with a 3rd or 4th anti-retroviral drug. Trials of multiple drug regimens that included ZDV/3TC Foudraine et al 1998 (Attachment 1) compared ZDV/3TC (+IDV if HIV levels remained elevated) with d4T/3TC (+IDV if HIV levels remained elevated) and found no significant difference between the regimens, although there was a trend in favour of the latter combination. Carr et al (2000) found no differences between ZDV+3TC and ddI+d4T or d4T+3TC (both are alternative dual nucleoside combination recommended in the draft WHO guidelines) when they were both combined with IDV. However, this study found a smaller rate of ADRs leading to cessation of treatment with d4T+3TC than with the alternatives. Eron et al found that ZDV+3TC and ddI+d4T (when combined with IDV) had similar suppressive effects on HIV RNA levels, although the rise in CD4 counts was higher with the d4T+3TC regimen. A similar pattern was observed when the same nucleoside combinations with IDV were compared by Squires et al. The overall rates of severe ADRs were similar but Squires et al found a higher rate of nausea and vomiting with ZDV+3TC and a higher rate of diarrhea and rash with d4T+3TC. The study of Haas et al (2000) (Attachment 1) is significant for highlighting the need to use IDV three times daily when combined with ZDV+3TC. Staszewski et (1999) (Attachment 1) found that efavirenz (EFV) in combination with ZDV+3TC was superior to IDV+ZDV+3TC. This finding is reflected in a recently published meta-analysis (Torre et al 2001)26, which found that in 5 randomised trials combining 2 NRTIs with one non nucleoside reverse transcriptase inhibitor (EFV or NVP), the rate of virological response was somewhat higher than with 2 NRTIs combined with a protease inhibitor (pooled 13 Odds Ratio 1.6; 95% CI 1.1, 2.1), although no difference was seen in terms of disease progression. Staszewski et al (2001) (Attachment 1) also compared ZDV+3TC combined with abacavir (ABC) and found this combination to have similar efficacy to ZDV+3TC+IDV, although there was a trend favouring the IDV combination when suppression of HIV levels below 50 copies/ml in subjects with high baseline levels was considered. It should be noted that this was a sub-group analysis and the statistical significance is borderline. Of note is the fact that this study employed a ZDV/3TC fixed dose combination product. Finally, the study of Eron et al (2000) has particular significance because it is a clinical equivalence (rather than a bioequivalence) comparison of a fixed combination preparation of ZDV/3TC with concurrent use of the individual agents. In conclusion, this set of trials is helpful, not only in establishing the efficacy and tolerability of ZDV+3TC as an established dual nucleoside core to combine with other ARVs, but also because the review helps establish the efficacy of alternative regimens recommended in the draft WHO ARV Guidelines. In several comparisons d4T+3TC and ddI+d4T were found to be at least as efficacious as ZDV+3TC and at least as well tolerated, although qualitatively the nature of adverse reactions tended to be different. This review has also confirmed the efficacy of dual nucleoside regimens combined with protease inhibitors, and with non-nucleoside reverse transcriptase inhibitors which appear to be at least as effective as the former, and in the case of efavirenz, better tolerated. 9. Comparative evidence on safety (combination treatment with zidovudine and lamivudine) b. Adverse effects/reactions: headache, malaise and fatigue, nasal signs and symptoms, cough, diarrhoea, nausea and vomiting, neuropathy, musculoskeletal pain, insomnia and other sleep disorders, dizziness, fever or chills, abdominal pain, depressive disorders, skin rashes, myalgia, abdominal cramps, arthralgia, dyspepsia. Laboratory abnormalities (Grade 3 or 4): neutropaenia, anaemia, thrombocytopaenia; elevated amylase, ALT, AST, bilirubin. Warnings: Combinations of lamivudine + zidovudine should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count <1,000 cells/mm3 or haemoglobin <9.5 g/dL. Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with fixeddose lamivudine + zidovudine. For HIV-infected individuals and patients with asymptomatic or early HIV disease, periodic blood counts are recommended. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine, zidovudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged exposure to antiretroviral 14 nucleoside analogues may be risk factors. Particular caution should be exercised when administering zidovudine to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with zidovudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Myopathy and myositis, with pathological changes similar to that produced by HIV disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with fixed-dose lamivudine + zidovudine. Changes in skin and nail pigmentation have been reported with the use of zidovudine. Precautions: Reduction of the dosages of lamivudine + zidovudine is recommended for patients with impaired renal function. Patients with creatinine clearance <50 mL/min should not receive fixed-dose lamivudine + zidovudine. Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Drug Interactions: Lamivudine: Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of fixed-dose lamivudine + zidovudine in combination with zalcitabine is not recommended. Zidovudine: Coadministration of ganciclovir, interferon-alpha, and other bone marrow suppressive or cytotoxic agents may increase the haematologic toxicity of zidovudine. Concomitant use of fixed-dose lamivudine + zidovudine with stavudine should be avoided since an antagonistic relationship with zidovudine has been demonstrated in vitro. In addition, concomitant use of zidovudine with doxorubicin or ribavirin should be avoided because an antagonistic relationship has been demonstrated in vitro. c) Variation in safety due to health systems and patient factors: Antiretroviral therapy cannot be successfully introduced in a healthcare system vacuum. However, facilities and personnel infrastructure can be expanded in parallel with the implementation of antiretroviral agent delivery programmes. Health care provider and patient education, an essential health care package, and the ability to do at least limited clinical and laboratory monitoring are all necessary to try to insure programmatic success. [WHO Draft Antiretroviral Guidelines for Resource Limited Settings, p. 2.]10 15 It is well established that the introduction of any antimicrobial therapy for an infectious disease is association with the induction and spread of drugs resistance as an inevitable consequence. Although an obvious concern, this is not a reason to delay introduction of large-scale antiretroviral therapy programmes. Rather, education of providers and patients, attention to drug adherence, monitoring the population for drug resistance, and institution of strategies to try to limit drug resistance are the components of an appropriate response. It is possible that the risk of the spread of resistant viral strains in the population may be balanced by the potential for the reduction of HIV transmission by the introduction of antiretroviral therapy. [WHO Draft Antiretroviral Guidelines for Resource Limited Settings, p. 15.]10 10. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group: Cost of therapy The most recent list of price offers (dated February 25th 2002) compiled by MSF lists seven suppliers of fixed-dose lamivudine + zidovudine: Aurobindo (India) annual cost of treatment $US 270, Cipla (India) $US 285, Hetero (India) $US 288, FarManguinh (Brazil) $US 351, GPO (Thailand) $US 475, Ranbaxy (India) $US 548, and Glaxo SmithKline (UK) $US 730. By comparison, lamivudine costs range from $US 91 – 248; zidovudine costs range from $US 193 to 584; stavudine from $US 44 to $US 137; and didanosine from $US 190 – 891. 11. Summary of regulatory status of the medicine (in country of origin and preferably in other countries as well): TBA 12. Availability of pharmacopoieal standards: TBA 16 Attachment 1 : Results of trials involving ZDV and 3TC as a dual nucleoside combination therapy (Pages 17 – 20) 17 Attachment 1(cont): Results of ZDV/3TC Trials (2-drug comparisons) Kuritzkes et al 199927 Molina et al 199928 Study details RCT: Open ddI or d4T then (factorial)Blind ddI/3TC or d4T/3TC v ZDV+3TC (2 arms) N=299; treatment-naïve RCT: Open ddI+d4T or ZDV+3TC or ddI+d4T followed by ZDV+3TC N=151; treatment naïve Change in HIV-RNA levels at 24 weeks ZDV+3TC d4T/3TC ZDV+3TC ddI/3TC - 1.28 log10 -1.23 log10 -1.20 log10 -1.16 log10 pNS Toxicity (grade 3 or worse) ZDV+3TC (pooled data – 2 arms) 24/108 (22%) Comparators (pooled) 48/184 (26%) pNS Note this combination seems to have been effective Adverse events Change in HIV-RNA levels at 24 weeks ddI+d4T ZDV+3TC ddI+d4T then ZDV+3TC ddI+d4T N 51 -2.26 log10 p<0.001 +124 p=0.02 -1.26 log10 -1.58 log10 Change in CD4 counts +62 +118 Neuropthy 1 Hb<6.5 0 Cessation Due to ADR 1 51 ddI+d4T then ZDV+3TC 49 0 1 2 0 2 0 ZDV+3TC 18 Attachment 1 (cont): Results of ZDV/3TC Trials (3-drug comparisons) Foudraine et al 199829 Carr et al 200030 Eron et al. 200031 RCT:Open ZDV/3TC Or d4T/3TC N=47; ARV naïve IDV added at 12/52 if HIV RNA >500 copies/ml RCT: Open ZDV+3TC+IDV Or DdI+d4T+IDV Or D4T+3TC+IDV N=109 treatment naïve RCT: Open ddI+d4T+IDV or ZDV+3TC+IDV Plasma HIV-1 RNA at 24 weeks ZDV/3TC (+IDV) d4T/3TC (+IDV) -1.65 log10 -1.95 log10 pNS HIV-1 RNA <500 copies/ml 15/20 (75%) 18/19 (95%) pNS Change in HIV-RNA levels ddI+d4T+IDV ZDV+3TC+IDV -2.42 log10 -2.94 log10 p NS d4T+3TC+IDV -2.47 log10 HIV-1 RNA levels <500 copies/ml at 40-48weeks ddI+d4T+IDV ZDV+3TC+IDV 54/102 (53%) (p=0.068) 42/103 (41%) HIV_1 RNA levels <50 copies/ml at 48 weeks N=205 <3/52 treatment with ARV PI-naïve Squires et al 200032 RCT: Open ZDV+3TC+IDV Or d4T+3TC+IDV ADRs not mentioned in abstract ADRs leading to cessation of treatment ddI+d4T+ d4T+3TC+ ZDV+3TC+ IDV 41% IDV 34% IDV 18% p=0.06 for differences Overall rates of serious adverse reactions similar in each group (8% in each group) 1 patient on ddI/d4T group had lactic acidosis and 1 had pancreatitis; 1 patient on ZDV/3TC group had severe anemia. 41% (p>0.20) 35% Increase in CD4 counts at 48 weeks +150 (p=0.001) +106 ZDV+3TC+IDV d4T+3TC+IDV HIV RNA <500 copies/ml at weeks 40-48 54% 62% (p NS) Median time-weighted average change in CD4 counts 110 142 (p=0.033) Serious ADRs not different between study arms; however, nausea and vomiting commoner with ZDV-containing treatment and diarrhea and rash commoner with d4Tcontaining treatment 19 Haas et al. 200033 Cohen Stuart et al 199934 RCT: Open ZDV+3TC + IDV (TDS) Or ZDV +3TC+IDV (BD) N=433 but stopped after interim analysis RCT: Open ZDV+3TC+SQV(SGC) Or ZDV+3TC+IDV N=70; ARV-naïve Eron JJ et al 200035 RCT: Open ZDV+3TC+PI Or Fixed dose combination (FDC) of ZDV/3TC (same dose)+PI N=223 – all had used ZDV/3TC+PI for >10 weeks Staszewsk i et al. 199936 RCT: Open ZDV+3TC+EFV Or ZDV+3TC+IDV Or EFV+IDV N=450; naïve to PI, NNRTI or 3TC ZDV+3TC + IDV (TDS) ZDV +3TC+IDV (BD) HIV-RNA levels <400 copies/ml at 24 weeks (87 subjects) 91% 64% p<0.01 ZDV+3TC+SQV(SGC) ZDV+3TC+IDV HIV-RNA levels <50 copies/ml at 24 weeks 74.3% 71.4% No mention of ADRs in abstract (Text suggests that CD4 advantage to SQV disappears after 24 weeks) No ADR data in abstract p=0.73 Change in CD4 count +162 +89 p=0.01 Success (avoiding increase of 0.5 log10 increase in HIVRNA) ZDV/3TC+PI (FDC) ZDV/3TC+PI 92.9% 96.4% pNS Adherence (missed doses at weeks 8 and 16) Overall Adverse Events ZDV/3TC+PI 19% (FDC) ZDV/3TC+PI 21% p NS ZDV/3TC+PI (FDC) ZDV/3TC+PI FDC superior at both times: p=0.007 @ 8/52; p=0.046 @ 16/52 ZDV+3TC+EFV ZDV+3TC+IDV HIV-RNA levels <50 copies/ml at 48 weeks 70% p<0.001 48% ZDV+3TC+EFV ZDV+3TC+IDV Discontinuation because of ADRs 27% p=0.005 43% 20 Staszewski et al. 200137 RCT: Blind (FDC) ZDV+3TC+ABC Or (FDC) ZDV+3TC+IDV N=562 ARV-naïve (FDC) ZDV+3TC+ABC (FDC) ZDV+3TC+IDV HIV-RNA levels <400 copies/ml at 48 weeks 133/262 (51%) 136/265 (51%) HIV-RNA levels <50 copies/ml at 48 weeks (Baseline HIV RNA levels >100K) 30/96 (31%) 45/100 (45%) 95% CI for difference (-27%, 0%) No difference in treatment-limiting ADRs but 1 death from hypersensitivity with ABC 21 Attachment 2: comparisons of nucleoside reverse transcriptase inhibitors (based on a review of product information) Two nucleoside analogue reverse transcriptase inhibitors (NRTIs) usually form the “backbone” of all currently recommended antiretroviral regimens. NRTIs were the first class of antiretroviral drugs to be introduced; consequently the most extensive clinical experience is recorded about these drugs. Advantages *potent, durable antiretroviral activity when combined with a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor Disadvantages * adverse events associated with long-term antiretroviral use, but a causal relationship has yet to be established * clinical benefit established, confirming validity of surrogate marker improvement * resistance profile of recommended dual NRTIs allows for 2nd line combination Non-proprietary name Cost p.a. US $ Advantages Disadvantages zidovudine $193 (Cipla, India) to $584 (GlaxoSmith Kline, UK) * penetrates blood/brain barrier; * resistance profile allows for 2nd and possibly 3rd line NRTI combination; * twice-daily dosing; * can be taken with or without food; * compounded formulations with lamivudine; lamivudine and abacavir; and lamivudine and nevirapine available; * few drug interactions; * can be administered with rifampin *anaemia; *high level resistance to zidovudine usually confers resistance to abacavir; 22 lamivudine $91 (Aurobindo, India) to $248 (Ranbaxy, India) *very well tolerated; *twice-daily dosing and long half-life means potential for once-daily dosing; * can be taken with or without food; *active against hepatitis B virus; * resistance profile allows for 2nd and possibly 3rd line NRTI combination; * compounded formulations with zidovudine; zidovudine and abacavir; zidovudine and nevirapine available; * no significant drug interactions; * can be administered with rifampin *single mutation at codon 184 of reverse transcriptase can confer high-level resistance; Fixed dose zidovudine/lamivudine preparations Cost of originator brand $730/year (GSK). Details as for zidovudine and lamivudine (see above) Details as for zidovudine and lamivudine (see above) didanosine $190 (Aurobindo, India) to $891 (GPO, Thailand) *twice-daily dosing but long half-life allows for once daily dosing; * delayed-release, enteric-coated formulation available; * can be administered with rifampin; * few drug interactions; * buffered formulation must taken on an empty stomach; * peripheral neuropathy; * fatal and nonfatal pancreatitis have occurred during therapy when didanosine was part of a combination regimen that included stavudine stavudine $44 (Cipla, India) to $137 (FarManguinh, Brazil) * well-tolerated; * twice daily dosing; * can be administered with rifampin; * few drug interactions; * peripheral neuropathy; * fatal and nonfatal pancreatitis have occurred during therapy when didanosine was part of a combination regimen that included stavudine Cost of equivalent generic products: $270 (Aurobindo) to $548 (Ranbaxy) 23 abacavir $1387 (Glaxo SmithKline, UK) to $2628 (Hetero, India) * twice-daily dosing; *compounded formulation with zidovudine and lamivudine available; * penetrates blood/brain barrier; *can be used with rifampin; *no significant drug interactions; * serious, potentially fatal hypersensitivity reaction reported in 5% of clinical trials subjects; 24 1 Blatt SP et al. 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