(FCH/HIV, 22 April 2002)

Application for Inclusion of nevirapine onWHO Model List of Essential Medicines

Drug is a member of the therapeutic class of HIV-1 non-nucleoside 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-limited 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 nevirapine is proposed for listing on the WHO Model List of Essential Medicine. Nevirapine is currently listed for prevention of mother to child transmission of HIV. Here it is proposed for treatment (in combination with other anti-retroviral agents) of HIV-infected children, adolescents, and adults with symptomatic disease, and for asymptomatic patients with CD4+ cell counts at or below 200/mm3 . Other members of this class of drugs may serve as alternatives, depending on quality, price and local availability. 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 in collaboration with the Cochrane Review Group for HIV/AIDS resulted in the retrieval of a substantial number of randomised controlled trials of nevirapine, and 5 uncontrolled single arm studies. Several of the RCTs were included in a published meta-analysis that documented a clear advantage of NVP in combination with 2 NRTIS over dual NRTI therapy. The meta-analysis also demonstrated that combinations of NVP with 2 NRTIs were about as effective, and possibly better tolerated, than highly active antiretroviral therapy, which included a protease inhibitor. Randomised trials not included in the published meta-analysis provided further information supporting once daily dosing, improved quality of life and a regression in lipid abnormalities in NVP-containing regimens.

Because the popular combination on NVP+d4T+3TC had only been included in a single arm of one RCT, information was retrieved from uncontrolled studies that evaluated this

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2regimen. These data tend to support the efficacy of this regimen, and evidence reviewed in other submissions indicates that the d4T+3TC nucleoside pair is as effective as the more widely used combination of ZDV+3TC.

The principal adverse effect seen in these studies was rash, observed in 20% or more of individuals, and occurring with a higher frequency than with other ARVs. However withdrawal from therapy because of ADRs was not commoner with NVP than other drugs. Severe liver damage was observed rarely, and was seen with other ARVs. Risk factors for its development with ARVs include heavy alcohol use, and co-infection with HCV. Although the rare occurrence of severe liver toxicity is a legitimate concern when NVP is used in post-exposure prophylaxis (a low risk situation), there was no evidence reviewed here which would seriously discourage its use in individuals who are infected with HIV.

Nevirapine can be administered once daily and is one of the cheaper anti-retroviral drugs, with annual costs of therapy ranging from $US 112 to 438. A fixed dose combination of nevirapine, stavudine and lamivudine (administered twice daily) is available from several manufacturers at prices for a year’s treatment ranging from $US 295 to 350.

1. Summary statement of the proposal for inclusion, change or deletion.

Nevirapine is proposed for inclusion on the WHO Model List of Essential Medicines, as part of a multi-drug antiretroviral regimen for the treatment of HIV-1/AIDS within an appropriately monitored program. Nevirapine should be viewed as an example of the class of HIV-1 non-nucleoside reverse transcriptase inhibitors. Other examples of this group may sometimes be preferred when local factors such as availability and price are taken into account. HIV-2 reverse transcriptase is not inhibited by nevirapine.

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:

1 Blatt SP et al. Total lymphocyte count as a predictor of absolute CD4+ count and CD4+ percentage in HIV-infected 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.

Supporting letters may be submitted – please contact Dr Robin Gray (WHO/EDM) at grayr@who.int

4. International Nonproprietary Name: nevirapine

5. Listing Type Requested:

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 non-nucleosides 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.

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4In 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 HIV-related 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, 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 and adolescents: one 200 mg tablet once daily for the first 14 days (this lead-in period must be followed because it has been found to lessen the frequency of rash), followed by one 200 mg tablet twice daily, in combination with other antiretroviral drugs. Patients experiencing rash during the 14-day lead-in period of 200 mg nevirapine once daily should not have their nevirapine dose increased until the rash has resolved.

The fixed dose combination of NVP 200 mg, d4T 40mg and 3TC 150mg is administered as a single tablet twice daily.

Paediatric: Children 2 months to 8 years of age: 4 mg/Kg once daily for 14 days, followed by 7 mg/Kg twice daily thereafter. For children aged 8 years and older, the dose is 4 mg/Kg once daily for 14 days, followed by 4 mg/Kg twice daily thereafter. The dosage should not exceed 400 mg daily for any patient.

Concomitant Antiretroviral Therapy: nevirapine 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 lists nevirapine (in combination with two nucleoside analogue reverse transcriptase inhibitors) as a first-line therapy (see Table 1).

Special Requirements: Adequate resources for monitoring and specialist oversight are a pre-requisite for the introduction of this class of drugs.

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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 Reviewso The ACP Journal Club reviews of published trialso The data-base of reviews of abstracts of reviews of effectiveness (DARE)o The Cochrane controlled trials register (CCTR)o Medlineo Embaseo AIDSLINEo AIDSTRALSo AIDSDRUG

Search terms included:

o Anti-retroviral or antiretroviralo Nucleoside reverse transcriptase inhibitorso Non-nucleoside reverse transcriptase inhibitorso Protease inhibitorso Randomised clinical trial (exploded and as text word)o Individual drug names: eg nevirapine (NVP).

Study selection:

o Randomised comparative parallel-group controlled clinical trialso Examined the performance of nevirapine when included in combinations

comprising 3 or more drugs, involving concomitant use of NRTIs, other NNRTIs or PIs.

Categorisation of levels of evidenceThe 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 anti-retroviral 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 questions3. Which combinations of drug classes have the best evidence in relation to

benefits and harms?

Agent-specific questions4. What is the evidence for the efficacy and toxicity of anti-retroviral drug

combinations that include abacavir?

Results1. 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 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

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8patients, 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.

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 co-morbidity, 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 long-term (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 Pregnancy Considerations

Major Toxicities

ZDV/3TC plus EFV* or NVP*

- Substitute NVP for EFV in pregnant women or women for whom effective contraception cannot be assured

- ZDV-related anemia- EFV-associated CNS symptoms- Possible teratogenicity of EFV- NVP-associated hepatotoxicity and severe rash

ZDV/3TC/ABC* - ABC safety data limited

- ZDV-related anemia- ABC hypersensitivity

ZDV/3TC** plus RTV enhanced PI or NFV

- LPV/r safety data limited - NFV: most supportive safety data

- 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 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 nevirapine? (Level 1 and Level 2 evidence)

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Nevirapine and efavirenz, as the 2 non-nucleoside reverse transcriptase inhibitors in common use have been investigated quite extensively in combination with 2 NRTI as an alternative to triple combination regimens involving protease inhibitors. In part this is to avoid the toxicity associated with PIs, but it is also out of a sense that PI-containing regimens, often known as highly active anti-retroviral therapy (HAART) should be kept in reserve. The success and popularity of this approach is reflected in NNRTI-containing regimens being listed as the preferred first line therapies in the WHO ARV guidelines (Table 1). The combination of ZDV+3TC+(EFV or NVP) is recommended for use In resource limited settings. Several dual nucleoside pairs can substitute for ZDV and 3TC, including d4T and 3TC. NVP+d4T+3TC is available as a fixed dose combination from several manufacturers. This is a popular and relatively low cost combination for use in resource-limited settings. However, as noted later this is a lack of randomised trials involving this particular combination.

NVP-containing triple drug regimens compared with dual nucleoside combinationsThis review of the evidence relating to the use of NVP-containing regimens starts with a consideration of the evidence regarding the incremental effects of adding NVP to a dual nucleoside regimens. While the latter are no longer considered adequate therapy on their own, the relevant trials provide critical evidence regarding the anti-viral effects of NVP. Fortunately the relevant studies have been the subject of a meta-analysis published recently (Torre et al 200122). Torre summarises data from 6 RCTs comparing NNRTI-containing triple drug regimens. Four of these trials, comprising a total of 1930 participants, involved NVP, and 2 trials with a total of 200 participants involved efavirenz. These numbers indicate that most of the statistical power in the meta-analysis is derived from the NVP trials. Notably the meta-analysis of trials with a clinical outcome (disease progression) involved only the 4 RCTs of NVP.

In summary, the addition of NVP to dual nucleoside therapy was associated with an odds ratio (OR) of 0.80 (95% CI 0.6, 1.0) for disease progression. The addition of any NNRTI was associated with an OR for virological response of 3.6 (2.2, 6.0) (3.6; 1.7, 7.3 in the case of NVP), but was 7.4 (4.1, 13.5) in ARV-naïve patients, who are more representative of those who presently receive ARVs in resource-limited settings.

The odds ratio for moderate to severe adverse events developing following the addition of a NNRTI was 1.1 (0.9, 1.3), but was 2.2 (1.5, 3.2) in the case of rashes. it should be noted that the NRTI combination used in the NVP trials was exclusively ZDV+ddI, not ZDV+3TC or d4T+3TC, the combinations most commonly recommended.

NVP-containing triple drug regimens compared with PI-containing triple drug regimensThe meta-analysis of Torre et al22 summarises data from 5 RCTs in which the efficacy of a NNRTI was compared with a protease inhibitor when either was combined with 2 NRTIs. In most cases the protease inhibitor was nelfinavir or indinavir (both recommended by the WHO ARV guidelines). These trials included a total of 1027 participants, and 3 trials (and 382 participants) involved NVP. The overall OR for virological response compared with a PI-containing regimen was 1.6 (1.1, 2.1), indicating a possible advantage of NNRTIs in this situation. Certainly it can be concluded that they are not less effective. The overall OR for disease progression was 0.7 (0.2, 2.0), indicating possible equivalence, although the event rate was low in these trials leading to a broad range of uncertainty in the estimates. The OR for virological

response in the 3 trials of NVP was 0.8 (0.5, 1.3) indicating that the drug is probably not inferior to protease-inhibitor combinations.

Overall, the OR for adverse events with NNRTI – containing regimens (compared with PI-containing regimens) was 0.6 (0.4, 0.9) indicating a possible advantage for NNRTIs. However as with the dual nucleoside comparisons the rate of rash was higher (OR 2.8, 1.4, 5.4) than with PI-containing regimens.

Key randomised trials not included in the Torre meta-analysis 22 In this section we have concentrated on presentation of data from RCTs that provide insights additional to those provided by the Torre meta-analysis.

There are 3 trials in which NVP replaced a protease inhibitor included in a 3-drug combination (involving 2 NRTIs), where patients had maintained adequate viral suppression with existing therapy. The details of some of these studies are summarised in Attachment 1. In the ‘Swatch’ trial23 both NVP and EFV led to viral suppression rates that were indistinguishable from those achieved with continued use of PI (all over 90% for HIV-RNA <80 copies/ml). In the NVP group cholesterol levels were lower with NVP than with continued PI, or with EFV. Discontinuation rates were similar between the 3 drugs. Similar improvements in plasma lipids with NVP were seen in the study of Van der Valk et al (2001)24. The virological responses from this latter trial were included in the Torre meta-analysis reviewed earlier. Barreiro et al (2000)25 found that viral rebound occurred in 11% of those randomised to NVP, compared with 29% of those who remained on a PI-containing regimen (P=0.007). In contrast, CD4 counts fell slightly with NVP compared with a modest rise with a PI, although the differences were not statistically significant. Martinez et al (2002)26 found similar rates of viral suppression when subjects on stable ARV treatment were randomised to NVP, EFV or ABC in addition to existing NRTI therapy, and similar rises in CD4 cell counts (Attachment 1).

Two trials have specifically studied quality of life (QOL) during treatment with NVP-containing combinations. Bucciardini et al (2000)27 found that NVP+2NRTIs led to short-term deterioration in QOL, compared with 2NRTIs as sole therapy in previously untreated patients. This happened despite predictable improvements in virological measures. In contrast, when Barreiro et al24 (reviewed above) compared triple therapy with NVP with continuing PI treatment there were significant QOL improvements with the former, and by 6 months around half had partial reversal of PI-induced lypodystrophy.

The frequency of administration of NVP and ddI was evaluated in the trial of Garcia et al (2000)28 (Attachment 1). Reductions in viral load and rates of discontinuation because of ADRs were virtually identical between the once and twice daily regimens.

Although not strictly relevant to regimens that are recommended in the ARV guidelines 2 RCTs have evaluated NVP as part of a 4-drug regimen in heavily pre-treated patients. Jensen Fangel et al (2001)29 found the combination of NVP nelfinavir and 2 NRTIs produced superior viral suppression to the NFVI-2NRTI combination. In a more complex study Wiznia et al (2000)30 compared NFV or ritonavir (RTV) (plus 2 NRTIs) with NVP+NFV+2NRTIs in ARV-experienced patients and found similar rates of viral suppression, but a higher overall retention rate with the 4-drug NVP-containing regimen. Of note, the NRTI combination used in this trial was d4T+3TC – the only example we

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12have been able to find of the use of this nucleoside combination with NVP in a randomised trial (see below for summary of the non-randomised observational studies with this combination).

Finally, the addition of NVP to triple therapy including abacavir may lead to an increased rate of hypersensitivity reactions to the latter drug (Wit et al, 200131)

In summary, the randomised trials retrieved through this literature review show that addition of NVP to dual nucleoside reverse transcriptase therapy leads to increased viral suppression, and in combination with dual NRTIs NVP suppresses or maintains viral loads about as well as protease inhibitor-containing regimens. In addition, NVP can be used successfully as salvage therapy. Generally, combination regimens including NVP are fairly well tolerated and retention rates may be higher than equivalent PI-containing regimens.

The most common adverse effect in these trials was skin reactions, with an approximate doubling of the frequency of this problem compared with dual NRTIs or PI-containing regimens. NVP treatment appears to be associated with a partial reversal of the plasma lipid abnormalities and lypodystrophy seen in some subjects taking protease inhibitors.

Of note is the range of dual nucleoside regimens included in randomised clinical trials of NVP. Of a total of 19 RCTs, ZDV+3TC and ZDV+ddI were both used in 5, ddI+d4T in 4, and unspecified regimens were used in 4. As noted earlier, the combination of d4T and 3TC has been used in only 1 RCT, and for this reason we have made a separate review of the non-randomised studies below.

Non randomised combination studies of the efficacy and safety of NVP+d4T+3TCThis combination involves a stavudine-lamivudine nucleoside reverse transcriptase backbone plus a non-nucleoside reverse transcriptase inhibitor. The principal advantage of this regimen is that its pharmacokinetics allow for twice-per-day dosing in a fixed combination with a presumed (but unproven) increase in adherence. The three drugs penetrate well into the seminal compartment (Taylor 200032).

The evidence for the efficacy of this regimen is limited. There has been only one randomised trial involving NVP+d4T+3TC combination therapy (see above30). There have been three uncontrolled prospective studies (Kaspar 199833, Pujari 200234, Shalit 200135) and two retrospective series (Bal 199936, Yoziak 200137;Table 2 and Attachment 1).

Two of the prospective studies were from the U.S.A. and one from India; the two retrospective studies were from Australia and the U.S.A. The dose of the drugs (stated in only one of the five studies) was nevirapine 200 mg twice daily, stavudine 40 mg twice daily and lamivudine 150 mg twice daily (Kaspar 1998).

Table 2. Uncontrolled prospective and retrospective studies of nevirapine plus stavudine plus lamivudine combination therapy

Study and Site

Type Patients N Results

Kaspar (1998)33

USA

Prospective ART naïve 25 23/25 (92%) HIV RNA <400 copies/ml at median 20 weeks

Pujari (2002)34

India

Prospective ART naïve 347 Compared with ZDV+3TC backbone, no difference in relative hazard of increasing CD4 cell count at 1 year

Shalit (2001)35

USA

Prospective ART naïve 26 24/26 (92%) HIV RNA <50 copies/ml at median 31 months

Bal (1999)36

Australia

Retrospective ART naïve 54 41/54 (76%) undetectable HIV RNA at 1 year, no difference if baseline HIV RNA high (>80,000 copies/ml) or low

Yozviak (2001)37

USA

Retrospective ART experienced(84%)

73 HIV RNA <400 copies/ml at 16 weeks by intention-to-treat analysis 57/73 (78%), persisting effect [16/18 (89%)] through 48 weeks by on-treatment analysis

Each of the five studies showed medium-term to long-term efficacy in terms of suppression of HIV replication to non-detectable levels and/or immunologic improvement as measured by increases in CD4 cells. The longest follow-up period was a median of 31 months (Shalit 2001)35. In the largest study, a prospective comparison of a stavudine-lamivudine nucleoside reverse transcriptase inhibitor backbone and a zidovudine-lamivudine backbone with nevirapine in 347 patients, there was no difference in immunologic improvement at 1 year as measured by increases in CD4 cell counts (relative hazard by Cox proportional hazard analysis, 1.25; 95% confidence interval, 0.96-1.63), and overall CD4 cell counts increased by more than 20% in 65% of patients in both arms combined (Pujari, 2002)34. In a prospective community-based study 24 of 26 antiretroviral therapy-naïve patients had non-detectable viral loads (<50 copies/ml) at a median of 31 months of follow up. These 24 patients had maintained their virologic suppression for a mean of 19 months (range, 7-38 months). In the three studies that reported side effects (Pujari 200234, Shalit 200135, Yozviak 200137), rash was the reported in two studies (10.5% in Pujari 200234 and 13.7% in Yozviak 200137), and stavudine-associated peripheral neuropathy was reported by 7.7% in the third (Shalit, 200135). For a discussion of NVP-related liver damage see section below.

There are no ongoing trials of this combination listed in the U.S. AIDTRIALS register.

Serious adverse events with nevirapineAs noted above, the rates of all serious adverse events are not notably higher with NVP than with other ARV drugs. The occurrence of rashes stands out as a particular feature, and the meta-analysis of RCTs noted earlier documents an approximate doubling of the odds of this complication with NVP compared to other ARVs. However many rashes are not severe and are not necessarily an indication to stop therapy. Indeed the overall retention rate on NVP regimens (a function of both effectiveness and toxicity) has tended to be higher than with PI-containing regimens.

13

14The main concern expressed regarding the safety of NVP relates to hepatic reactions. This was highlighted in a report in early 2001 of 2 serious cases of liver damage/failure, one leading to transplantation in health care workers who had used NVP-containing regimens as post-exposure prophylaxis (PEP) following contact with potentially infective material (MMWR 2001)38. The report contains further details of an additional 10 events involving hepatic damage with median ALT levels increased to 5-10X reference, usually with symptoms. Nevirapine (used for PEP) was believed to be implicated in these cases, although all of these subjects had taken other ARVs. An accompanying editorial comment questions the safety of NVP for PEP, but supports the continued use of the drug in mother to child transmission and in treatment of HIV-infected individuals. Subsequent changes to the product information for NVP have highlighted the period of maximum risk for liver damage which appears to be the first 12 weeks of therapy.

The difficulties in attributing causality in cases of putative drug-induced liver damage are highlighted in a recent report of acute liver failure (6 cases, 5 fatal) occurring in patients receiving ARV therapy (Clark et al 200239). The ultimate regimens used by subjects before the development of liver damage (duration 4-12 weeks) were complex and included d4T in 5 cases, 3TC in 3 cases, ddI, EFV, NVP and SAQ in 2 cases each, and Del, and ZDV in 1 case each. So in this small series of all fatal cases of ARV-associated liver injury admitted to one centre, NVP did not appear to be over-represented. However the sample size was small and the study uncontrolled, so confident conclusions cannot be drawn from the data.

There have been several studies of risk factors for liver damage with ARVs. Plasma NVP concentrations greater than 6ug/ml have been suggested as a risk factor in patients co-infected with Hepatitis C (Gonzalez de Requena et al 200240). In a study of 222 ARV users, of whom 38% were co-infected with Hep C, the rates of development of severe liver reactions were 10% with users of PIs, 9% users of NNRTIs (including NVP) and 9% with combined use of NNRTIs and PIs (Nunez M et al 200141). In a multivariate analysis the predictor variables for any ARV-associated severe liver injury were alcohol abuse (RR 5.9), HCV positive (RR 4.0), older age (RR1.1 for each additional year). This importance of other factors, in particular HCV co-infection is emphasised in the study of Proenca et al (200042). This evaluated the success of NVP-containing therapy in IV drug users who had become infected with HIV. Ninety-two percent were co-infected with HCV and 20% developed ALT levels 3X baseline after introduction of ARVs.

38 Anon 2001. Serious adverse events attributed to nevirapine regimens for post-exposure prophylaxis after HIV exposure – Worldwide 1997-2000. MMWR 2001;49: 1153-1156.

39 Clark SJ et al. Acute liver failure associated with antiretroviral treatment for HIV: a report of 6 cases. J Hepatol. 2002; 36: 295-301.

40 Gonza lez de Requena D et al. Liver toxicity caused by nevirapine. AIDS 2002; 16: 290-291.

41 Nunez LR et al. Risk factors for severe hepatic injury after introduction of highly active antiretroviral therapy. J AIDS 2001; 27: 426-431.

42 Proenca P, Sa J, Xavier A, Brito P, Soares S, Pocas J. Once daily therapy with nevirapine (Nev) /Didanosine (ddI) /Lamivudine (3TC) in a non adherent population. Int Conf AIDS 2000 Jul 9-14;13 (abstract no. TuPeB3231).

In conclusion, severe liver reactions with NVP appear to a rare but occasionally catastrophic event. In unselected series it is difficult to find clear evidence that it is associated with a higher risk than other ARV medications. What seems clearer is that severe hepatic reactions can occur after introduction of a range of ARV drugs and the risk is heightened in the presence of HCV co-infection, and in those who drink heavily. While concerns about NVP hepatotoxicity may justifiably raise concerns about the use of the drug for the relatively low risk situation of post-exposure prophylaxis, the evidence does not seem to warrant similar concerns when the drug is used in mother to child transmission and treatment of established HIV infection.

9. Comparative evidence on safety of Nevirapine from product information

b. Adverse effects/reactions: rash, nausea, headache, abnormal liver function test, fatigue, fever, vomiting, myalgia, diarrhoea, somnolence, abdominal pain, arthralgia, hepatitis, ulcerative stomatitis.

Laboratory abnormalities (Grade 3 or 4): neutropaenia, anaemia, thrombocytopaenia; elevated ALT, AST, GGT, and total bilirubin.

Warnings:

Nevirapine must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen.

Severe or life-threatening skin reactions including deaths, have occurred in patients treated with nevirapine. These reactions have included Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reaction characterized by rash, constitutional findings, and visceral involvement. Nevirapine must be discontinued in patients developing a severe rash or a rash accompanied by constitutional symptoms such as fever, blistering, oral lesions, conjunctivitis, facial oedema, swelling, muscle or joint aches, general malaise, severe elevations in liver function tests, eosinophilia, granulocytopaenia, hepatitis, renal dysfunction, or signs of other visceral involvement.

Severe or life-threatening hepatoxicity, including fatal fulminant hepatitis (transaminase elevations, with or without hyperbilirubinaemia, prolonged partial thromboplastine time, or eosinophilia), has occurred in patients treated with nevirapine. Some of these cases began in the first few days to weeks of therapy and some were accompanied by rash. Nevirapine administration must be interrupted in patients experiencing moderate or severe liver function test abnormalities until these return to baseline values. Nevirapine should be permanently discontinued if liver function abnormalities recur upon readministration. Frequent monitoring of ALT and AST is strongly recommended, especially during the first 6 months of nevirapine treatment

Precautions:

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.

15

16

Drug Interactions:

Nevirapine has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes (CYP3A, CYP2B) and may result in lower plasma concentrations of other concomitantly administered drugs that are extensively metabolised by CYP3A or CYP2B.

Drugs that should not be coadministered with nevirapine: ketoconazole, rifampin, St. John's wort (Hypericum perforatum) or St. John's wort-containing products.

Drugs which require a dose increase when coadministered with nevirapine: Coadministration of methadone with nevirapine may result in decreased plasma levels of methadone and signs of opiate withdrawal. Patients using methadone should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.

Other potentially significant drug interactions with nevirapine: Nevirapine may decrease plasma concentrations of oral and other hormonal contraceptives; therefore, these drugs should not be administered concomitantly with nevirapine for the purpose of contraception. When oral contraceptives are used for hormonal regulation during administration of nevirapine, therapeutic effect should be monitored.

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.]

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 therapyThe most recent list of price offers (dated February 25th 2002 – see attachment 1) compiled by MSF lists six suppliers of nevirapine with price offers ranging from $US112

(Aurobindo, India) to $US 438 (Boehringer Ingelheim, Germany) for a year’s treatment. By comparison, efavirenz costs range from $US 438 to 668. The current prices for the fixed dose combination of NVP+d4T+3TC range from $US 295 (Ranbaxy, India) to $US 350 (Cipla, India).

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

17

18Attachment 1 Results of some nevirapine (NVP) trials not included in the Torre meta-analysis22

Negredo et al 200123

SWATCH

On PI(s) ≥12 months, NNRTI naïveCD4>300HIV RNA<80

N=77

RCT:OpenExisting NRTIs plus1. NVP2. EFV3. Continue

existing PI(s)

HIV RNA <80 copies/ml Discontinuation because of adverse eventsEFV 92% NVP 96%

PI(s) 92%

EFV 12% NVP 8%

PI(s) 8%Total cholesterol (mg/dl) at 12 months

EFV 218±52 NVP 199±38 (p<0.03)

PI(s) 229±42Triglyceride level (mg/dl)

EFV 218±214 NVP 160±94 (p<0.01)

PI(s) 229±158Martinez et al 200226

Treated with PI plus 2 NRTIsHIV RNA <200 for ≥6 monthsN=460

RCTExisting NRTIs plus1. NVP2. EFV3. ABC

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 41ABC 51

19

20

Garcia et al 200043

RCT: Opend4T+ddI(OD)d4T+ddI(OD) +NVP(OD)ord4T+ddI(BD)d4T+ddI(BD)+NVP(BD)N= 94; ARV-naïve

Change in HIV RNA levels at 52 weeks Severe adverse reactions

d4T+ddI(OD)d4T+ddI(OD) +NVP(OD)

d4T+ddI(BD)d4T+ddI(BD)+NVP(BD) Rates of discontinuation because of adverse events were nearly identical in the two groups-1.84 log10

p NS-1.78 log10

HIV_1 RNA levels <200 copies/ml at 48 weeks73%p NS

68%

3 Joint United Nations Programme on HIV/AIDS. ‘AIDS epidemic update -- December 2001.’ Available at: http://www.unaids.org/epidemic_update/report_dec01/index.html

4 AIDS Drug Policy. Ministry of Health Brazil. Available at http://www.aids.gov.br/assistencia/aids_drugs_policy.htm

5 Improving access to antiretroviral therapy in Latin America. reference to Argentina program. Family Health International. Available at http://www.fhi.org/en/aids/impact/iohiv/ioh11/ioh16.html

6 Djomad G, Roels T, Chorba T, Diomandé F, Nkengasong J, Monga B, Maurice C, Wiktor SZ. HIV/AIDS Drug Access Initiative: Preliminary report covering the period August 1998-March 2000. Ministère de la Santé, Programme National de Lutte contre le SIDA/MST/TUB, République de Côte d’Ivoire, May 2000. Available at: www.unaids.org/publications/documents/care/UNAIDS_DAI/cote_ivoire_drug_access_initiative.doc

7 Source: Laurent C, Diakhaté N, Ngom Gueye NF, Touré MF, Sow PS, Faye MA, Gueye M, Lanièce I, Touré Kane TC, Liégeois F, Vergne L, Mboup S, Badiane S, Ndoye I, Delaporte E. The Senegalese government HAART initiative: an 18- month follow- up study of feasibility, effectiveness, adherence, toxicity and viral resistance. [Abstract and Poster 460-W] 9 th Conference on Retroviruses and Opportunistic Infections, Seattle, Washington, USA, February 24 - 28, 2002.

9 S. Pujari, E. Naik, A. Patel, and S. Bhagat. Safety, Tolerability, and Efficacy of Nevirapine-Based HAART amongst Antiretroviral Naïve HIV-1-Infected Patients in India. Paper presented at the 9th Retrovirus Conference, Washington State Convention and Trade Center, Seattle, February 24th-28th 2002. Available at www.retroconference.org

10 World Health Organization. ‘Scaling up antiretroviral therapy in resource-limited settings: Guidelines for a public health approach’. WHO 2002.

21

22Attachment 1 (continued) non-randomised studies of NVP+d4T+3TC

AUTHOR METHODS BENEFITS TOLERABILITY AND ADVERSE EFFECTSBal 1999 ART naïve

N=54

Non randomized Retrospective analysis1. NVP+d4T

+3TC

HIV RNA undetectable at 1 year None reportedStarting HIV RNA >80,000:NVP+d4T+3TC 20/25 (80%)Starting HIV RNA <80,000:NVP+d4T+3TC 21/29 (72%)

No comparison arm

Kaspar 1998 ART naïve

N=25

Non randomizedProspective1. NVP 200

mg +d4T 40 mg + 3TC 150 mg bid

HIV RNA <400 copies/ml at median 20 weeks None reportedNVP+d4T+3TC 23/25 (92%)

No comparison arm

Pujari 2002 ART naïve

N=347

Non randomizedProspective1. NVP+d4

T +3TC (N=174)

2. NVP+ZDV + 3TC (N=173)

Increase in CD4 cells/ml at 1 year “Rash was documented in 10.5% patients (4 with SJS), self-limiting GI disturbances in 21% patients, and sub-clinical hepatitis in 4.7% patients. Skin rashes developed within 1 month of initiation. Female gender was significantly associated with development of rash (RR, 1.27, 1.09-1.49)…”

NVP+d4T+3TC RH, 1.25 (0.96-1.63).

“Overall 64.6% had more than 20% increase in CD4 counts at 12 months.”

NVP+ZDV+3TC

Shalit 2001 ART naïve

N=26

Non randomizedProspective1. NVP +d4T

+3TC

HIV RNA <50 copies/ml at median 31 months “This regimen also proved to be remarkably well tolerated, with reports of two cases of peripheral neuropathy secondary to stavudine, but no nevirapine-associated clinical side-effects.”

NVP+d4T+3TC 24/26 (92%)

No comparison arm

Increase in CD4 cells/ml at median 31 monthsNVP+d4T+3TC +215 No comparison arm

Yozviak 2001 ART experienced 84%

N=73

Non randomizedRetrospective analysis1. NVP+d4T

+3TC

HIV RNA <400 at16 weeks “Rash was the most common adverse event (13.7%)..”ITT:

NVP+d4T+3TC 57/73 (78%)OT:NVP+d4T+3TC 57/66 (86%)

No comparison arm

22 Torre D, et al. Nevirapine or efavirenz combined with two NRTIs compared with HAART: a meta-analysis of randomized clinical trials. HIV Clinical Trials 2001; 2: 113-121.

23 Negredo E, Martinez-Picado J, Ruiz L, et al. SWATCH Study: a multicenter trial of proactive treatment switching. Results at 9 months of follow-up.. 8 th Conf Retroviruses Opportunistic Infect 2001 Feb 4-8; 8:245 (abstract no. 669).

24 Van der Valk M et al. Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile. AIDS 2001; 15: 2407-2414.

25 Barreiro P et al. Risks and benefits of replacing protease inhibitors by nevirapine in HIV-infected subjects under long-term successful triple combination therapy.

26 Martinez E, Podzamczer D, Ribera E, et al. Switching protease inhibitors to nevirapine (NEV), efavirenz (EFA) or abacavir (ABA): a randomized, multicenter, open-label, simplification trial. . 9th Conf Retroviruses Opportunistic Infect 2002 Feb 24-28; 9: (abstract no. LB17).

27 Bucciardini et al. Quality of life outcomes of combination zidovudine-didanosine-nevirapine and zidovudine-didanosine for anti-retroviral naïve advanced HIV infected patients AIDS 2000; 14: 2567-2574.

28 Garcia, F et al. Comparison of Twice-Daily Stavudine plus Once or Twice Daily Didanosine and Nevirapine in Early Stages of HIV Infection: The Scan Study. AIDS 2000; 14: 2485 – 2494.

29 Jensen-Fangel, S et al. The Effect of Nevirapine in Combination with Nelfinavir in Heavily Pretreated HIV-1-Infected Patients: A Prospective, Open-Label, Controlled, Randomized Study. J AIDS 2001; 27: 124 – 129.

30 Wiznia, A et al. Combination Nucleoside Analog Reverse Transcriptase Inhibitor(s) plus Nevirapine, Nelfinavir, or Ritonavir in Stable Antiretroviral Therapy-Experienced HIV-Infected Children: Week 24 Results of a Randomized Controlled Trial (PACTG 377). AIDS Research and Human Retroviruses 2000; 16: 1113 – 1121.

31 Wit FWNM et al. Prednisolone does not prevent hypersensitivity reactions in anti-retroviral drug regimens containing abacavir with or without nevirapine. AIDS 2001; 15: 2423-2429.

23

24HIV RNA <50 at 24 weeks (OT)

NVP+d4T+3TC 33/39 (85%)

No comparison arm

HIV RNA <50 at 48 weeks (OT)NVP+d4T+3TC 16/18 (89%)

No comparison arm

Change in CD4 cells/ml (time not specified)NVP+d4T+3TC +170 No comparison arm

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 Key: 3TC, lamivudine; ART, antiretroviral therapy; bid, twice daily; d4T, stavudine; ITT, intention-to-treat analysis; NVP, nevirapine; OT, on-treatment analysis; RH, relative hazard; RR, relative risk; SJS, Stevens-Johnson syndrome; ZDV, zidovudine

Attachment 2

Characteristics of non-nucleoside reverse transcriptase inhibitors

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; nevirapine shown to be hepatoxic

* use of NNRTIs spares protease inhibitor class * low genetic barrier to resistance

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 well-tolerated;*penetrates blood/brain barrier;* can be used in pregnancy;

*requires step-up dosing; *potentially life-threatening 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;

32 Taylor S, van Heeswijk RP, Hoetelmans RM, Workman J, Drake SM, White DJ, Pillay D. Concentrations of nevirapine, lamivudine and stavudine in semen of HIV-1-infected men. AIDS 2000 Sep 8;14(13):1979-84.

33 Kaspar R, Werntz G, DuBois DB. Early results of combined stavudine, lamivudine, and nevirapine: a twice daily, well-tolerated, protease inhibitor-sparing regimen for the treatment of HIV-1 infection. 5 th Conf Retroviruses Opportunistic Infect 1998 Feb 1-5; 5:209 (abstract no. 696).

34 Pujari S, Naik E, Patel A, Bhagat S. Safety, Tolerability, and Efficacy of Nevirapine-Based HAART amongst Antiretroviral Naïve HIV-1-Infected Patients in India. 9th Conference on Retroviruses and Opportunistic Infections 2002 Feb 20-24; 9: (abstract no. 463-W).

35 Shalit P, Farrell P, Lindgren P. Long-term safety and efficacy of nevirapine, stavudine and lamivudine in a real-world setting [Letter]. AIDS 2001 Apr 13;15(6):804-5.

36 Bal J, Russell BD, Anderson JSC, Moore R. Efficacy of nevirapine at high and low starting viral loads - 18 month data. Annu Conf Australas Soc HIV Med 1999 Dec 9-11;11:138 (abstract no. P26).

37 Yozviak JL, Doerfler RE, Woodward WC. Effectiveness and tolerability of nevirapine, stavudine, and lamivudine in clinical practice. HIV Clin Trials 2001 Nov-Dec;2(6):474-6.

25

* not active against Group O subtypes;

efavirenz $485 (Aurobindo, India) to $1040 (Hetero, India)

*once-daily dosing;* can be taken with or without food; * penetrates the blood-brain barrier;

*high level resistance to efavirenz occurs after only one specific gene mutation in HIV. Resistance to efavirenz confers cross-resistance 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;

26

8 d’Adesky A-C, HIV meds come to rural Haiti, The AmFAR Treatment Insider, October-November 2001 2(5):5-8. Available at: http://199.105.91.6/treatment/HIV+/insidermenu.html.

43 Garcia, F et al. Comparison of Twice-Daily Stavudine plus Once or Twice Daily Didanosine and Nevirapine in Early Stages of HIV Infection: The Scan Study. AIDS 2000; 14: 2485 – 2494.

27