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1 (FCH/HIV, 22 April 2002) Application for Inclusion of efavirenz on the WHO Model List of Essential Medicines The drugs is a member of the therapeutic class of HIV-1 nonnucleoside 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 non-nucleoside reverse transcriptase inhibitor efavirenz is proposed for listing on the WHO Model List of Essential Medicine. Other members of this class of drugs may serve as alternatives, depending on quality, price and local availability. It should be noted that HIV-2 reverse transcriptase is not inhibited by nonnucleosides reverse transcriptase inhibitors. 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. Extensive library searches compiled by the Cochrane Review Group for HIV/AIDS resulted in the retrieval of a total of 15 good quality randomised clinical trials. As initial therapy (6 trials), efavirenz in combination with two nucleoside reverse transcriptase inhibitors (in five trials zidovudine and lamivudine), was superior to two nucleoside reverse transcriptase inhibitors alone. Efavirenz-containing regimens were equal or superior to protease inhibitor-containing regimens in achieving long-term viral suppression, and efavirenz-containing regimens that lacked nucleoside reverse transcriptase inhibitors were inferior to those that contained them. As salvage therapy in failing regimens, efavirenz has been examined in 5 trials. These studies showed that efavirenz was an effective drug for non-nucleoside 2 reverse transcriptase-naïve patients who were failing nucleoside reverse transcriptase inhibitor regimens, and efavirenz plus protease inhibitors (either nelfinavir or indinavir) was superior to efavirenz or to a single protease inhibitor. Efavirenz has also been tested (4 trials) as an alternative to protease inhibitors in patients who are susceptible to the lipodystrophy syndrome induced by these drugs (switch therapy). The three trials for which data are available showed that efavirenz was comparable to, or superior to, continuing existing protease inhibitors in maintaining viral suppression; that efavirenz was comparable to nevirapine and abacavir in maintaining viral suppression; and that efavirenz was more likely than nevirapine or abacavir to be associated with hypercholesterolemia and hypertriglyceridemia. Overall efavirenz was quite well tolerated. Although certain side effects were common (for instance rash, CNS effects, including dizziness, impaired concentration, dreaming), the rates of discontinuation because of toxicity were equivalent to, or lower than, those seen with combination therapy that included protease inhibitors. Efavirenz can be administered as once daily treatment. It is presently not available as a fixed dose combination with other antiretroviral agents. The costs of a year’s treatment vary from $US485 (Aurobindo) $US500 (Merck) to $US1040 Hetero). 1. Proposal for inclusion, change or deletion. Efavirenz is proposed for inclusion on the WHO Model List of Essential Medicines, as part of a multi-drug antiretroviral regimen for the treatment of HIV1/AIDS within an appropriately monitored program. 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/mm3, but only in symptomatic patients.1,2 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 submitted – please contact Dr Robin Gray (WHO/EDM) at [email protected] 4. International Nonproprietary Name: efavirenz 5. Listing Type Requested: 3 Listing is requested on the Model List of Essential Medicines as an example of the therapeutic class of HIV-1 non-nucleoside reverse transcriptase inhibitors. Other members of this class of drugs may serve as alternatives, depending on quality, price and local availability. HIV-2 reverse transcriptase is not inhibited by nonnucleosides reverse transcriptase inhibitors. 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. 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 4 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 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, 5 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: Dosage: Adults: 600 mg efavirenz once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors. Efavirenz may be taken with or without food; however, a high fat meal may increase the absorption of efavirenz and should be avoided. In order to improve the tolerability of nervous system side effects, bedtime dosing is recommended during the first two to four weeks of therapy and in patients who continue to experience these symptoms. Paediatric patients: Efavirenz should be taken on an empty stomach, once daily, preferably at bedtime. Doses for paediatric patients 3 years of age or older and weighing between 10 and 40 Kg are as follows: 10 to < 15 Kg = 200 mg 15 to < 20 Kg = 250 mg 20 to < 25 Kg = 300 mg 25 to <32.5 Kg = 350 mg 32.5 to <40 Kg = 400 mg 40 Kg or more = 600 mg Concomitant Antiretroviral Therapy: efavirenz must be given in combination with other antiretroviral medications. Duration: Antiretroviral treatment is usually regarded as life-long. 6 Guidelines: The draft “WHO Antiretroviral Guidelines for Resource Limited Settings”10 indicates efavirenz (in combination with two nucleoside analogue reverse transcriptase inhibitors) is recommended as a 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. 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 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: efavirenz Study selection: o Randomised comparative parallel-group controlled clinical trials 7 o Examined the performance of efavirenz when included in combinations comprising 3 or more drugs, involving concomitant use of NRTIs, other NNRTIs or PIs. 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 treatment on the major clinical outcomes12. 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 8 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, 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. 9 The most recent review of the importance of multiple drugs in treatment of HIV/AIDS was recently published in the BMJ21. These investigators pooled data from 54 randomised clinical trials. The odds ratio for disease progression with 3 drugs compared with 2 drugs was 0.62 (95% CI 0.50, 0.78), but data were considered inadequate to determine if a general advantage was achieved by addition of a fourth drug. 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 10 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 diarrhea - IDV-related nephrolithiasis - PI-related metabolic side effects *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 countryspecific 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 efavirenz? (Level 2 evidence) Efavirenz has been the subject of multiple trials that comprise three different uses of the drug: (1) as initial therapy, (2) as salvage therapy for patients who are failing initial regimens and (3) as “switch” therapy for patients who are being successfully treated with protease inhibitors but who have protease inhibitorrelated lipodystrophy. Efavirenz as initial therapy For initial therapy, efavirenz has been examined in six well conducted randomized controlled trials (see Table 2 for brief summaries; for fuller details of trials see Attachment 1. References are linked to Tables 2-4). The trials retrieved by the literature search established that efavirenz, in combination with two nucleoside reverse transcriptase inhibitors (in five trials zidovudine and lamivudine), was superior to two nucleoside reverse transcriptase inhibitors alone; that efavirenz-containing regimens were equal or superior to protease inhibitor-containing regimens in achieving long-term viral suppression; and that efavirenz-containing regimens that lacked nucleoside reverse transcriptase inhibitors were inferior to those that contained them. 11 Table 2. Trials of efavirenz-containing antiretroviral regimens as initial therapy. Trial ACTG 388 Authors Fischl 200222 N 517 Regimen ZDV+3TC and 1. EFV+IDV 2. NFV+IDV 3. IDV ZDV+3TC and 1. EFV 200 mg 2. EFV 400 mg 3. EFV 600 mg 4. Placebo Summary of Findings EFV+IDV superior in achieving smaller proportion of virologic failures at 2.1 years (p=0.04). Grade 3 or 4 toxicities equivalent among arms. All three doses superior to placebo. No difference among three EFV doses. No difference in adverse effects among four arms. DMP 266005 Gallant 199823 Haas 199824 Hicks 199825 Labriola 199826 Manion et al 199927 MoralesRamirez 199828 Staszewski 199829 Staszewski 199930 Tashima 199931 137 450 1. EFV+ZDV+ 3TC 2. EFV+IDV 3. IDV+ZDV+ 3TC Levy 200132 1266 DPC 083201 Ruiz 200233 134 Merck 067 Isaacs 199834 71 1. EFV+ZDV+ 3TC 2. EFV+IDV 3. IDV+ZDV+ 3TC ZDV+3TC and 1. DPC 083 50 mg qd 2. DPC 083 100 mg qd 3. DPC 083 200 mg qd 4. EFV 1. IDV 1.2 gm bid + EFV 300 mg bid 2. IDV 1 gm tid + EFV 600 mg qd EFV+ZDV+3TC superior to other two regimens in achieving viral suppression by two tests at 48 weeks. Both EFVcontaining regimens had lower rates of discontinuation for adverse events than IDV+ZDV+3TC. EFV-containing regimens had higher incidence of dizziness, impaired concentration, insomnia and abnormal dreaming. EFV+ZDV+3TC superior to other regimens in achieving viral suppression at 2 years (80% v. 60% v. 65%). DPC006 DMP 266006 No difference in viral suppression at 24 weeks among four arms. No differences in premature discontinuation. Dizziness was more common with EFV than with DPC 083 (a new third-generation nonnucleoside reverse transcriptase inhibitor) Twice per day and thrice per day dosing regimens comparable. Presumably patients also received NRTIs, but no information in abstract. Also not clear if this study was for initial therapy or for NRTI failure. 3TC, lamivudine; EFV, efavirenz; IDV, indinavir; NFV, nelfinavir; NRTI, non-nucleoside reverse transcriptase inhibitor; ZDV, zidovudine Efavirenz-containing initial antiretroviral therapy regimens are additionally the subject of several ongoing trials (ACTG A5095, AIEDRP AI-02-01 [in acute HIV infection], AIEDRP AI-07-001, CPCRA 058, FDA 229R [Hoffman LaRoche], FDA 229S [Roche Laboratories], FDA 259H [Agouron Pharmaceuticals], FDA 302C [Bristol-Meyers Squibb], FDA 308B [Glaxo SmithKline], Initio [MRC]). These trials 12 largely focus on protease inhibitor-sparing initial regimens (e.g., ACTG A5095 [zidovudine + lamivudine + abacavir and/or efavirenz] or AIEDRP AI-07-001 [stavudine + didanosine and indinavir/low-dose ritonavir or efavirenz]). The Initio trial goes a step beyond these and tests a three-arm induction/maintenance regimen with induction therapy with didanosine + stavudine + efavirenz and/or nelfinavir followed by maintenance therapy with Trizivir (a fixed combination of zidovudine, lamivudine and abacavir) + nelfinavir or efavirenz or saquinavir/lowdose ritonavir (Babiker 2001)35. Efavirenz as salvage therapy Efavirenz has been examined in five well conducted randomized controlled trials as salvage therapy for failing regimens (see Table 3). In all five of these studies the regimens that had failed contained nucleoside reverse transcriptase inhibitors only, and most typically these were dual therapy. These studies showed that efavirenz was an effective drug for non-nucleoside reverse transcriptase-naïve patients who were failing nucleoside reverse transcriptase inhibitor regimens and that efavirenz plus protease inhibitors (either nelfinavir or indinavir) were superior to efavirenz or to a single protease inhibitor. Additionally, a meta-analysis of the three DMP 266 salvage trials showed that efavirenz could provide prolonged viral suppression in patients with HIV RNA levels of over 100,000 copies/ml. However, since dual therapy is no longer a recommended option (only triple nucleoside reverse transcriptase inhibitor therapy with abacavir as the third drug is currently recommended), these studies may not be the best evidence for whether or not efavirenz is an effective salvage drug. This is because failure is due to viral resistance mutation, and without participants having been exposed to protease inhibitors in their initial regimens the efficacy of efavirenz-containing regimens for salvage therapy cannot be directly examined in these studies. Use of efavirenz for treatment of patients who have failed protease inhibitor-containing initial regimens has, however, been the subject of multiple uncontrolled studies and is also the subject of current ongoing randomized controlled trials (e.g., CPCRA 057, FDA 245F). 13 Table 3. Trials of efavirenz as component of salvage therapy for patients failing NRTI-containing regimens. Trials Author N ACTG 364 Albrecht 199836 Albrecht 199937 Albrecht 200038 Winters 199939 196 1 or 2 new NRTS and 1. NFV 2. EFV 3. NFV+ EFV ACTG 368 Squires 199940 Squires 200041 123 1. IDV 1 gm tid + EFV 600 mg qd 2. IDV 1.2 gm bid + EFV 300 mg bid NRTIs DMP 266003 Cohort IV DMP 266004 Havlir 1998a42 Kahn 199843 Riddler 1998a44 Riddler 1998b45 Riddler 200046 Mayers 199847 101 1. EFV+IDV 2. IDV (arm 2 added d4T+EFV at week 12) ZDV+3TC and 1. EFV 400 mg 2. EFV 600 mg 3. Placebo NRTIs DMP 266020 Fessel 199848 Haas 199849 Havlir 1998b50 Manion et al 199926 Haas 200151 327 ≤2 NRTIs and 1. EFV + IDV 2. Placebo + IDV NRTIs 93 Regimen Failed regimen NRTIs NRTIs Findings NFV+EFV superior to NFV alone and to EFV alone in achieving viral suppression at 40-48 weeks. EFV alone superior to NFV alone. No difference in grade 3 or 4 events. Trend toward IDV tid + EFV qd achieving superior viral suppression compared to IDV bid + EFV bid. This study had two other arms examining these regimens ± ABC. EFV+IDV achieved superior viral suppression compared to IDV (with EFV+d4T added later). Both EFV-containing regimens achieved superior viral suppression at 16 weeks. 600 mg regimen achieved higher proportion of viral suppression than 400 mg regimen. EFV+IDV superior to IDV alone in achieving viral suppression by ultrasensitive assay (HIV RNA <50 copies/ml) at 24 weeks. Discontinuation due to adverse events higher in EFV regimen. 3TC, lamivudine; ABC, abacavir; d4T, stavudine; EFV, efavirenz (also known as DMP 266); IDV, indinavir; NFV, nelfinavir; NRTI, nucleoside reverse transcriptase inhibitor; ZDV, zidovudine. Efavirenz as “switch” therapy from protease inhibitors Switching from protease inhibitors to efavirenz in patients with virologic suppression has been examined in four randomized controlled trials (Table 4). Because patients on protease inhibitor therapy are susceptible to disorders of lipid metabolism (the lipodystrophy syndrome), there is interest in switching from protease inhibitors to drug classes, such as the non-nucleoside reverse transcriptase inhibitors, that are believed to have a lower incidence of this disorder. The three trials for which data are available (see table 4) showed that efavirenz was comparable to or superior to continuing existing protease inhibitors 14 in maintaining viral suppression; that efavirenz was comparable to nevirapine and abacavir in maintaining viral suppression; and that efavirenz was more likely than nevirapine or abacavir to be associated with hypercholesterolemia and hypertriglyceridemia. Protease inhibitor switching is also the subject of three ongoing trials (e.g., ACTG A5039, ACTG A5103, DMP 266-027); DMP 266-027 was reported in an abstract at the International Conference on AIDS in 2000, but tabular results were not available. Table 4. Trials of efavirenz as switch therapy for patients with viral suppression on nucleoside reverse transcriptase inhibitor- and protease inhibitor- containing regimens. Trials Author N Regimen Prior regimen DMP 049 Becker 200152 346 NRTIs and 1. EFV 2. Continue existing PIs NRTIs, PIs SWAT CH Negredo 2001A53 Negredo 200254 77 Existing NRTIs and 1. NVP 2. EFV 3. Continue existing PI(s) NRTIs, PIs Martinez 200255 460 Existing NRTIs and 1. NVP 2. EFV 3. ABC NRTIs, PIs Katalma 200056 165 Existing NRTIs and 1. EFV 2. Continue existing PI(s) NRTIs, PIs DMP 266027 Findings EFV maintained superior viral suppression at 24 weeks, EFV associated with fewer missed doses. No difference in premature discontinuation of study. All three arms maintained comparable viral suppression at 12 months. NVP associated with lowest total cholesterol and triglyceride levels. Discontinuation due to adverse events similar. All three arms maintained comparable viral suppression. Hypercholesterolemia and discontinuation due to adverse events significantly lower in ABC arm. No results available ABC, abacavir; d4T, EFV, efavirenz (also known as DMP 266); NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor. 9. Comparative evidence on safety of efavirenz b. Adverse effects/reactions: nausea, rash, dizziness, impaired concentration, vomiting, insomnia, headache, diarrhoea, abnormal dreams, somnolence, pruritus, depression, anorexia, nervousness, dyspepsia. Laboratory abnormalities (Grade 3 or 4) include neutropenia; elevated bilirubin, AST, ALT, GGT, amylase, glucose, CPK. Increases in total cholesterol of 10 - 20 15 % have been observed in some uninfected volunteers receiving efavirenz. Increases in non-fasting total cholesterol and HDL of approximately 20 % and 25 %, respectively, were observed in patients treated with efavirenz + zidovudine + lamivudine and of approximately 40 % and 35 %, in patients treated with efavirenz + indinavir. The effects of efavirenz on triglycerides and LDL were not wellcharacterised. The clinical significance of these findings is unknown. Warnings: Efavirenz must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. Significant central nervous system birth defects (anencephaly, anophthalmia, cleft palate) were observed in 3 of 20 infants born to pregnant monkeys who received efavirenz during early pregnancy at doses resulting in plasma concentrations comparable to those seen with human therapeutic exposure (CDC, Nightingale). There have been two case reports of myelomeningocele in human infants born to women who was receiving efavirenz at the time of conception and during the first trimester (DeSanti, Fundaro).Thus, the use of efavirenz should be avoided in women who may become pregnant. Women of childbearing potential should undergo pregnancy testing prior to initiation of antiretroviral therapy. Special populations: Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with chronic liver disease, caution must be exercised in administering efavirenz to patients with mild-to-moderate liver disease. Patients should be monitored carefully for dose-related adverse events, especially nervous system symptoms. Laboratory tests should be performed to evaluate their liver disease at periodic intervals. In patients with known or suspected history of Hepatitis B or C infection and in patients treated with other medications associated with liver toxicity, monitoring of liver enzymes is recommended. In patients with persistent elevations of serum transaminases to greater than 5 times the upper limit of the normal range, the benefit of continued therapy with efavirenz needs to be weighed against the unknown risks of significant liver toxicity. Convulsions have been observed rarely in patients receiving efavirenz, generally in the presence of known medical history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolised by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels. Caution must be taken in any patient with a history of seizures. Precautions: Nervous system symptoms: There have been reports of delusions and inappropriate behaviour in patients receiving efavirenz. Severe acute depression (including suicidal ideation/attempts) have also been reported in both efavirenztreated and control-treated patients. Fifty-two per cent of patients receiving efavirenz reported CNS system and psychiatric symptoms. These symptoms included, but were not limited to, dizziness, impaired concentration, somnolence, abnormal dreams, and insomnia. In controlled trials, these symptoms were severe in 2.6 % of patients receiving 600 mg efavirenz daily and in 1.4 % of patients 16 receiving control regimens. Rash: Mild-to-moderate rash has been reported in clinical studies with efavirenz and usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. Severe rash associated with blistering, moist desquamation or ulceration has been reported in less than 1 % of patients treated with efavirenz. The incidence of erythema multiforme or Stevens-Johnson Syndrome was approximately 0.1 %. Efavirenz must be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. If therapy with efavirenz is discontinued, consideration should also be given to interrupting therapy with other antiretroviral agents to avoid development of resistant virus. 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: Efavirenz has been shown in vivo to induce CYP3A4 (cytochrome P450 3A4). Other compounds that are substrates of CYP 3A4 may have decreased plasma concentrations when coadministered with efavirenz. In vitro studies have demonstrated that efavirenz inhibits 2C9, 2C19, and 3A4 isozymes in the range of observed efavirenz plasma concentrations. Coadministration of efavirenz with drugs primarily metabolised by these isozymes may result in altered plasma concentrations of the coadministered drug. Therefore, appropriate dose adjustments may be necessary for these drugs. Drugs that should not be coadministered with efavirenz: astemizole, terfenadine, midazolam, triazolam, cisapride, ergot derivatives. Drugs which require a dose increase when coadministered with efavirenz: When coadministered with efavirenz, indinavir doses must be increased from 800 mg to 1000 mg every 8 hours. Coadministration of methadone with efavirenz resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. When coadministered with efavirenz, the daily dose of rifabutin must be increased by 50 per cent. Other potentially clinically significant drug interactions with efavirenz: warfarin, saquinavir, ritonavir, clarithromycin, rifampin, ethinyl estradiol. Concomitant use of efavirenz and St. John's wort (Hypericum perforatum) or St. John's wort-containing products is not recommended. There is a potential for additive CNS system effects when efavirenz is used concomitantly with alcohol or psychoactive drugs. c) Variation in safety due to health systems and patient factors: 17 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.] 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. 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 four suppliers of efavirenz: Aurobindo (India) $US 485 annual cost of treatment, Merck (US) $US 500, Cipla (India) $US 668, and Hetero (India) $US 1040. By comparison, nevirapine (an alternative NNRTI) costs range from $US 150 to 438. 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 18 Attachment 1: results of efavirenz studies Pages 18-24 19 Attachment 1: Results of efavirenz (EFV) trials 1. Efavirenz as a component of initial antiretroviral regimens AUTHOR Fischl 2002 ACTG 388 Gallant et al 1998 Haas et al 1998 Hicks et al 1998 Labriola et al 1998 Manion et al 1999 DMP 266005 Isaacs R et al 1998 Merck 067 METHODS PATIENTS DETAILS No or limited prior ART CD4≤200 and HIV RNA ≥80,000 N=517 Asymptomatic or mildly symptomatic; no prior ART exposure N=137 PI and NNRTI naïve CD4≥100, HIV RNA ≥10,000 N = 71 RCT:Open ZDV+3TC Blind 1. EFV+IDV 2. NFV+IDV 3. IDV RCT: Open ZDV 300 mg bid + 3TC 150 mg bid Blind 5. EFV 200 mg qd 6. EFV 400 mg qd 7. EFV 600 mg qd 8. Placebo RCT: Open 4. IDV 1.2 gm bid + EFV 300 mg bid 5. IDV 1gm tid + EFV 600 mg qd BENEFITS Efavirenz regimen Comparator regimen Virologic failure (mean follow up 2.1 years) EFV+IDV 23% (p=0.04 NFV+IDV 46% c/w other 2 arms) (p=0.006 c/w/ other 2 arms) IDV 31% HIV-1 RNA plasma levels < 400 copies/ml At W16: EFV 200 mg 96% Placebo 48% EFV 400 mg 85% EFV 600 mg 88% At W24: EFV 200 mg 96% EFV 400 mg 91% EFV 600 mg 100% TOLERABILITY AND ADVERSE EFFECTS Efavirenz regimen Comparator regimen Grade 3 or 4 signs and symptoms EFV+IDV 24% (NS) NFV+IDV 28% IDV 21% Grade 3 or 4 laboratory abnormalities EFV+IDV 34% (NS) NFV+IDV 36% IDV 34% Nausea and/or headache and/or fatigue EFV 200 mg 67% EFV Placebo 73% 400 mg 82%; EFV 600 mg 74%. Placebo 65% HIV RNA <400 copies/ml at 16 weeks bid 86% tid 75% At W12: bid 79% tid 58% At W8: bid 58% tid 39% Study drugs were generally well tolerated; two patients in the BID group and one in the TID group required discontinuation of study medications attributed to drug toxicity 20 Efavirenz as a component of initial antiretroviral regimens (continued) MoralesRamirez et al 1998, Staszewski et al 1998, Manion et al 1999, Staszewski et al 1999*, Tashima et al 1999 DMP 266006 Asymptomatic or mildly symptomatic; PI, NNRTI, and 3TC naïve (only 15% had prior NRTI therapy) CD4>50 HIV RNA>10,000 N= 450 RCT: Open 4. EFV 600 mg qd + ZDV 300 mg bid + 3TC 150 mg bid 5. EFV 600 mg qd + IDV 1 gm q8h 6. IDV 800 mg q8h + ZDV 300 mg bid + 3TC 150 mg bid HIV RNA <400 copies/ml at 48 weeks (ITT) EFV+ZDV+3TC 70% IDV+ZDV+3TC 48% (p<0.05 c/w IDV+ZDV+3TC or EFV+IND) EFV+IND 53% HIV RNA <50 copies/ml at 48 weeks (ITT) EFV+ZDV+3TC 64% IDV+ZDV+3TC 47% (p<.05 c/w IDV+ZDV+3TC or EFV+IND) EFV+IND 43% Discontinuation because of any reason EFV+ZDV+3TC 27% IDV+ZDV+3TC 43% (p=0.005). Discontinuation because of adverse event EFV+ZDV+3TC 6% IDV+ZDV+3TC 20% (p=0.001 c/w either EFV+IND 6% EFV-containing regimen) Rash EFV+ZDV+3TC 34% EFV+IND 34% IND+ZDV+3TC 18% CNS symptoms (dizziness, impaired concentration, insomnia, abnormal dreaming) EFV+ZDV+3TC 58% IDV+ZDV+3TC 26% EFV+IND 53% (p<0.001) 21 2. Efavirenz as a component of salvage therapy AUTHOR Albrecht et al 1998 Albrecht et al 1999 Albrecht et al 2000* Winters et al 1999 ACTG 364 METHODS PATIENTS DETAILS NRTI exposure in prior ACTG trials (ACTG 175; rollover studies ACTG 302/303) and who remained on same treatment at entry HIV RNA ≥500 N=196 RCT: Open 1 or 2 new NRTIs (ddI+d4T, 3TC+d4T, or ddI+3TC) Blind 1. NFV 750 mg tid 2. EFV 600 mg qd 3. NFV + EFV BENEFITS Efavirenz regimen Comparator regimen Plasma HIV RNA at 16 weeks <400 copies/ml: NFV+EFV 81% (p=0.03 NFV 64% c/w NFV) EFV 69% <50 copies/ml: NFV+EFV 67% (p=0.001 c/w NFV) NFV 39% EFV 62% (p=0.01 c/w NFV) HIV RNA at 40-48 weeks <400 copies/ml: NFV+EFV 74% (p=0.001 c/w NFV) NFV 35% EFV 60% (p-0.004 c/w NFV) NFV 22% <50 copies/ml: NFV+EFV 67% (p=0.008 c/w EFV, p=0.001 c/w NFV) EFV 44% (p=0.008 c/w NFV) TOLERABILITY AND ADVERSE EFFECTS Efavirenz regimen Comparator regimen “There was no significant difference among the three treatment groups with respect to time to the development of the first grade 3 (severe) or grade 4 (life-threatening) signs or symptoms, which occurred in a total of 36 patients (18%) – 12 in the NFV group, 10 in the EFV group and 14 in the NFV+EFV group (p>0.3 for all pairwise comparisons). The most frequent grade 3 or 4 signs or symptoms reported were aches, pain, or discomfort (in 13 patients [7%]) and diarrhea or loose stools (in 7 patients [4%]). A grade 3 or 4 rash developed in only three patients (2%). Grade 2 (moderate) peripheral neuropathy developed in six patients (3%).” (Albrecht, 2001) 22 Efavirenz as a component of salvage therapy (continued) Squires et al 1999* Squires et al 2000 ACTG 368 NRTIexperienced but PI, NNRTInaive pts with CD4 cell <250 with ≥2 months ZDV (or d4T) + 3TC (rollover of ACTG 320) All pts randomized to ABC v. placebo N=283 Pts with CD4>50 rerandomized to IDV tid + EFV + ABC v. IND bid + ABC N=123 RCT: For pts with CD4≤50: 1. ABC 300 mg bid 2. Placebo For pts with CD4 50-249: 1. IDV 1 gm tid + EFV 600 mg qd + ABC 300 mg bid 2. IDV 1.2 gm bid + EFV 300 mg bid + ABC 300 mg bid 3. IDV 1 gm tid + EFV 600 mg qd 4. IDV 1.2 gm bid + EFV 300 mg bid HIV RNA level ≥500 copies/ml at 16 weeks (virologic failure) IDV tid + EFV qd 21% IDV bid + EFV bid 28% (p=0.22) At W32: IDV tid + EFV qd 33% (p=0.07) IDV bid + EFV bid 48% IDV bid + EFV bid 47% At W48: IDV tid + EFV qd 37% (p=0.17) 23 Efavirenz as a component of salvage therapy (continued) Havlir et al 1998 Kahn et al 1998* Riddler et al 1998a Riddler et al 1998b Riddler et al 1998c Riddler et al 2000 DMP 266-003, Cohort IV Mayers et al 1998 DMP 266-004 Asymptomatic or mildly symptomatic NRTI experienced (71%) N=101 NNRTI and PI naïve, ZDV + 3TC treatment for ≥ 8 weeks, HIV RNA ≥2,500 copies/ml, CD4 > 50 N=93 RCT: Blind 1. EFV 200 mg qd + IDV 800/1000mg tid 2. IDV 800/1000 mg tid (Arm 2 added d4T + EFV at W12) Both arms increased EFV to 600 mg qd at W36 RCT: Blind 1. EFV 400 mg + ZDV + 3TC 2. EFV 600 mg + ZDV + 3TC 3. ZDV + 3TC + placebo HIV RNA <400 copies/ml at 72 weeks EFV + IDV 73% IDV + (EFV+d4T) 57% (p=0.037) At W60: EFV + IDV 91% “The most frequently reported treatment-related adverse events among all patients receiving EFV (n=93) were diarrhea and nausea (Riddler 2000).” IDV + (EFV+d4T) 79% IDV + (EFV+d4T) 68% At W48: EFV + IDV 89% Mean increase in CD4 cells/ml at 120 weeks EFV+IDV 374.8 IDV + (EFV+d4T) 266.3 ± 36.1 ± 36.1 Decrease in HIV RNA (in log 10) copies/ml, CD4 cells/mm3 at 16 weeks ZDV + 3TC + EFV (400 ZDV + 3TC + mg) 0.65 ± 0.75 (p≤0.05 placebo 0.05 c/w placebo) ±0.11 ZDV + 3TC + EFV (600 mg) 0.49 ± 0.15 (p≤0.05 c/w placebo) Increase in CD4 cells/ml ZDV + 3TC + EFV (400 ZDV + 3TC + mg) 50.34 ± 14.37 EFV placebo (p=0.05 c/w placebo) 9.48 ± 17.35 ZDV + 3TC + EFV (600 mg) 43.19 ± 24.8 (NS) “Some patients in all treatment groups described potentially drug-related adverse events, most of which were mild to moderate in intensity. Overall, EFV did not alter the general tolerability or safety of the combination of ZDV + 3TC.” 24 Efavirenz as a component of salvage therapy (continued) Fessel et al 1998 Haas et al 1998 Manion et al 1999 Haas et al 2001* DMP 266020 NRTI experienced ≥8 weeks, no prior PI or NNRTI HIV-1 RNA ≥10,000 copies/ml; CD4 >50 cells/mm3; N=327 Manfredi & Chiodo 2001 Manion et al 1999 ≥12 months of NRTI monotherapy and ≥15 months of IDV- or RTVcontaining HAART N=59 HIV RNA ≥100,000 RCT Blind ≤2 NRTIs plus 4. IDV 800 mg tid + EFV placebo or 5. EFV 600 mg qd + IDV 1000 mg tid NRTI-experienced patients not on NRTIs at entry began 1 or 2 NRTls on Day 1. HIV RNA <400 copies/ml at 24 weeks (ITT, non-completers counted as treatment failures) EFV 60% (p=0.114) Placebo 51% HIV RNA <50 copies/ml at 24 weeks (ITT) EFV 49% (p=0.031) Placebo 38% Further details not available at time of writing Reanalysis of DMP 266-003, DMP 266005, DMP 266-020 Trial DMP 266- HIV RNA<400 copies/ml (%) HIV RNA <50 copies/ml (%) Wk OBS LOCF NC=F Wk 003 84 84 70 65 60 76 74 70 005 48 91 77 60 16 67 53 53 020 36 77 66 50 24 74 54 54 OBS LOCF NC=F Discontinuation because of adverse events EFV 11.5% Placebo 5.3% (p=0.043) 25 3. Efavirenz as a component of switch therapy Katalma 2000 DMP 266027 PI and NRTI experienced pts with HIV RNA <50 N=165 Negredo et al 2001a Negredo et al 2001b Negredo et al 2002* SWATCH Martinez et al 2002 On PI(s) ≥12 months, NNRTI naïve CD4>300 HIV RNA<80 N=77 Treated with PI plus 2 NRTIs HIV RNA <200 for ≥6 months N=460 RCT: Open 5. EFV 600 mg + continue existing NRTIs 6. Continue existing PI(s) + NRTIs RCT: Open Existing NRTIs plus 4. NVP 5. EFV 6. Continue existing PI(s) RCT Existing NRTIs plus 1. NVP 2. EFV 3. ABC HIV RNA ≥50 copies/ml No data available HIV RNA <80 copies/ml NVP 96% EFV 92% PI(s) 92% Total cholesterol (mg/dl) at 12 months EFV 218±52 Discontinuation because of adverse events EFV 12% NVP 8% PI(s) 8% NVP 199±38 (p<0.03) PI(s) 229±42 Triglyceride level (mg/dl) EFV 218±214 NVP 160±94 (p<0.01) PI(s) 229±158 HIV RNA <200 copies/ml at 12 months (ITT) EFV 74% (p=0.7) NVP 78% ABC 77% Mean increase in CD4 cells/ml EFV 51 NVP 41 ABC 51 Key: 3TC, lamivudine; ABC, abacavir; ACTG, NIH AIDS Clinical Trials Group; ART, antiretroviral therapy; bid, twice a day (i.e., q12h); c/w, compared with; d4T, stavudine; DMP 266, efavirenz (code in early developmental trials); EFV, efavirenz; HAART, highly active antiretroviral therapy (≥3 drugs from ≥2 different classes); IDV, indinavir; ITT, intention to treat analysis; LOCF, last observation carried forward analysis; NC=F, non-completer equals failure (i.e., intention to treat) analysis; NFV, nelfinavir; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NVP, nevirapine; OBS, “on treatment” analysis; PI, protease inhibitor; RCT, randomized controlled trial; tid, three times per day (i.e., q8h); ZDV, zidovudine 26 Attachment 2 Characteristics of non-nucleoside reverse transcriptase inhibitor-based regimens: Advantages Disadvantages *potent, durable antiretroviral activity *HIV-2 reverse transcriptase is not inhibited by NNRTIs. * improvement in surrogate markers established; longer-term clinical data appears to confirm benefit * efavirenz shown to be teratogenic; * use of NNRTIs spares protease inhibitor class * low genetic barrier to resistance nevirapine shown to be hepatoxic Non-proprietary name Cost p.a. US $ Advantages Disadvantages nevirapine $150 (Aurobindo, India) to $438 (Boehringer Ingelheim, Germany) *1 tablet taken twice daily; * can be taken with or without food; * generally welltolerated; *penetrates blood/brain barrier; * can be used in pregnancy; *requires step-up dosing; *potentially lifethreatening hepatic events and skin reactions; *high level resistance to nevirapine occurs after only one specific gene mutation in HIV. Resistance to nevirapine confers cross-resistance to other nNRTI drugs, including efavirenz. ; * multiple potential drug interactions; * cannot be used with rifampin; * not active against Group O subtypes; 27 efavirenz $485 (Aurobindo, India) to $1040 (Hetero, India) *once-daily dosing; * can be taken with or without food; * penetrates the bloodbrain barrier; *high level resistance to efavirenz occurs after only one specific gene mutation in HIV. Resistance to efavirenz confers crossresistance to other nNRTI drugs, including nevirapine; *mild-to-moderate brain and psychiatric side effects occur in about half of patients taking efavirenz; *teratogenic: must not be used in pregnancy; * multiple potential drug interactions; * cannot be used with rifampin; * not active against Group O subtypes; 28 1 Blatt SP et al. Total lymphocyte count as a predictor of absolute CD4+ count and CD4+ percentage in HIVinfected persons. JAMA 1993 Feb 3;269(5):622-6 2 French N, Mujugira A, Nakiyingi J, Mulder D, Janoff EN, Gilks CF. Immunological and clinical staging in HIV-1-infected Ugandan adults are comparable and provide no evidence of rapid progression but poor survival with advanced disease. J AIDS 1999;22:509-516 Joint United Nations Programme on HIV/AIDS. ‘AIDS epidemic update -- December 2001.’ Available at: http://www.unaids.org/epidemic_update/report_dec01/index.html 3 4 AIDS Drug Policy. Ministry of Health Brazil. 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A randomized trial comparing 2 4-drug antiretroviral regimens with a 3-drug regimen in advanced HIV disease. 9th Conf Retroviruses Opportunistic Infect 2002 Feb 24-28; 9:67 (abstract no. 41). 23 Gallant J, Seekins D, Hicks C, et al. A phase II, double-blind, placebo-control, dose-ranging study to assess the antiretroviral activity & safety of efavirenz (EFZ, sustiva, DMP266) in combination with open-label zidovudine (ZDV) w/ lamivudine (3TC) at>48 weeks. [DMP266-005]. Intersci Conf Antimicrob Agents Chemother 1998 Sep 24-27; 38:441 (abstract no. I-245). 24 Haas DW, Fessel WJ, Delapenha RA, et al. A phase II, double-blind, placebo-controlled, multi-center study to determine the effectiveness and tolerability of the combination of efavirenz (EFV, SUSTIVA, DMP 266) and indinavir (IDV) versus IDV in HIV-1 infected patients receiving nucleoside analogue (NRTI) therapy at >36 weeks. [Study DMP 266-020]. Intersci Conf Antimicrob Agents Chemother 1998 Sep 24-27; 38:441 (abstract no. 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