1

(FCH/HIV, 22 April 2002)

Application for Inclusion of zidovudine and lamivudine

(included fixed-dose combinations)

on the WHO Model List of Essential Medicines

Both drugs are members of the therapeutic class of HIV nucleoside analogue reverse transcriptase inhibitors

Summary of Proposal

Since the first clinical evidence of AIDS was reported over twenty years ago, an estimated 25 million people have died as a result of HIV infection. Current estimates suggest that around 40 million persons world-wide are infected with HIV and more than 90% of infected persons live in the developing world. Growing experience of the provision of anti-retroviral therapy in resource-poor settings (eg. Brazil, Côte d’Ivoire, Senegal, Haiti, India) indicates that treatment can be provided in an effective and safe manner. The delivery of anti-retroviral treatment in low-income countries has been aided by the development of fixed drug combinations and substantial reductions in the prices of certain products.

The nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine (ZDV, AZT) and lamivudine (3TC) are proposed for listing on the WHO Model List of Essential Medicines. The drugs are generally used together to form a ‘nucleoside core’ to which other drugs are added. The drugs are being proposed for listing jointly because they are the most widely investigated, and most commonly used, dual nucleoside regimen in contemporary multi-drug antiretroviral regimens. They are a part of the three first-line treatments in the draft WHO Guidelines for use of anti-retroviral drugs in resource-poor settings (ARV Guidelines). They are available as a fixed drug combination from 7 manufacturers internationally.

The combination of ZDV and 3TC is recommended for treatment within an appropriately monitored program, in combination with one or two other anti-retroviral drugs, including nucleoside or non-nucleoside reverse transcriptase inhibitors, or protease inhibitors. 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.

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.

The literature search retrieved a large number of citations describing randomised controlled trials involving ZDV + 3TC used as sole therapy, or in combination with a range of other ARV agents. From these were selected 3 meta-analyses and 11 randomised controlled trials, which provided information on the performance of ZDV/3TC compared with other dual nucleoside combinations which are recommended as alternative regimens in the draft WHO ARV Guidelines.

This set of trials is informative, not only in providing unambiguous evidence of the efficacy of ZDV+3TC as a dual nucleoside ‘core’ to combine with a range of other ARVs, but also because the data establish the efficacy of alternative regimens recommended in the draft WHO ARV Guidelines. In several comparisons d4T+3TC and ddI+d4T were found to be at least as efficacious as ZDV+3TC and as well tolerated (although qualitatively the nature of adverse reactions tended to be different). In a large direct comparative study a fixed dose combination of ZDV+3TC was found to have equivalent efficacy to concomitant use of the individual drugs, and to lead to a higher level of adherence to treatment.

The data confirmed the efficacy of dual nucleoside regimens combined with protease inhibitors, other nucleoside, and non-nucleoside reverse transcriptase inhibitors, which appear to be as effective as the former, and in the case of efavirenz, better tolerated.

1. Proposal for inclusion, change or deletion.

Zidovudine and lamivudine are proposed for inclusion on the WHO Model List of Essential Medicines, as part of a multi-drug antiretroviral regimen for the treatment of HIV/AIDS within an appropriately monitored program. Currently zidovudine is listed, but only for the indication of reducing the risk of mother to child transmission of HIV infection.

Zidovudine and lamivudine are both nucleoside reverse transcriptase inhibitors. The drugs are being proposed jointly because they are the most widely investigated, and most commonly used, nucleoside ‘core’ in contemporary multi-drug antiretroviral regimens. They are a part of the three first-line treatments in the draft WHO guidelines for use of anti-retroviral drugs in resource-poor settings (Table 1). They are available internationally individually, and in the form of several fixed dose combination preparations. However, combinations of both drugs with other nucleoside reverse transcriptase inhibitors (NRTIs) are possible. Because of the risk of antagonism, leading to reduced efficacy, zidovudine (ZDV) should not be used with stavudine (d4T) and lamivudine (3TC) should not be used with didanosine (ddI).

Antiretroviral therapy is recommended for HIV-infected children, adolescents, and adults with symptomatic disease, and also for asymptomatic patients with CD4+ cell counts at or below 200/mm3. Where CD4+ cell testing is unavailable, clinicians can use the presence of a total lymphocyte count below 1200/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 provided

4. International Nonproprietary Name: zidovudine, lamivudine and compounded fixed-dose lamivudine + zidovudine

5. Listing Type Requested:

Listing of both drugs is requested on the Model List of Essential Medicines as examples of the therapeutic class of HIV nucleoside analogue reverse transcriptase inhibitors. Other members of this class of drugs may serve as alternatives, depending on quality, price and local availability.

6. Information supporting the public health relevance of the submission:

Since the first clinical evidence of AIDS was reported over twenty years ago, an estimated 25 million people have died as a result of HIV infection. Current estimates suggest some 40 million persons worldwide are infected with HIV and more than 90% of infected persons live in the developing world[3]. 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 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 months[6].

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 infections[7]. 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:

Zidovudine

Recommended Dosage: Adults and adolescents over the age of 12 years: 600 mg daily, in two divided doses, in combination with other antiretroviral medications. Children 6 weeks to 12 years of age: 160 mg/m2 every 8 hours (480 mg/m2/day to a maximum of 200 mg every 8 hours).

Concomitant Antiretroviral Therapy: Zidovudine must be given in combination with other antiretroviral medications.

Duration: Antiretroviral treatment is usually regarded as life-long.

Guidelines: Guidelines The draft “WHO Antiretroviral Guidelines for Resource Limited Settings”[10] indicates zidovudine and lamivudine (in combination with one or more additional other antiretroviral medicines) as a preferred first-line regimen for the treatment of HIV/AIDS.

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

Lamivudine

Recommended Dosage: Adults and adolescents at least 12 years old: 150 mg twice daily. Children (3 months up to 16 years of age) 4 mg/kg twice daily (up to a maximum of 150 mg twice a day).

Concomitant Antiretroviral Therapy: Lamivudine must be given in combination with other antiretroviral medications.

Duration: Antiretroviral treatment is usually regarded as life-long.

Guidelines: The draft “WHO Antiretroviral Guidelines for Resource Limited Settings10 indicates zidovudine and lamivudine (in combination with one or more additional other antiretroviral medicines) as a preferred first-line regimen for the treatment of HIV/AIDS.

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

Fixed dose combinations of ZDV and 3TC

Recommended Dosage: Adults and adolescents over the age of 12 years: 1 tablet (containing 150 mg lamivudine and 300 mg zidovudine), taken twice daily. This fixed-dose formulation is not suitable for children under 12 years of age.

Concomitant Antiretroviral Therapy: Fixed-dose lamivudine + zidovudine must be given in combination with other antiretroviral medications.

Duration: Antiretroviral treatment is usually regarded as life-long.

Guidelines: The draft ‘WHO Antiretroviral Guidelines for Resource Limited Settings’10 indicates zidovudine and lamivudine (in combination with one or more additional other antiretroviral medicines) as a preferred first-line regimen for the treatment of HIV/AIDS:

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

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:

  • The Cochrane Data-base of Systematic Reviews
  • The ACP Journal Club reviews of published trials
  • The data-base of reviews of abstracts of reviews of effectiveness (DARE)
  • The Cochrane controlled trials register (CCTR)
  • Medline
  • Embase
  • AIDSLINE
  • CENTRAL

Search terms used were:

  • Anti-retroviral or antiretroviral
  • Nucleoside reverse transcriptase inhibitors
  • Non-nucleoside reverse transcriptase inhibitors
  • Protease inhibitors
  • Randomised clinical trial (exploded and as text word)
  • Individual drug names: zidovudine (or AZT or ZDV) AND lamivudine (or 3TC),

Study selection:

  • Randomised comparative parallel-group controlled clinical trials
  • Compared ZDV in combination with 3TC with:
  • Other dual nucleoside regimens (this part of the search was confined to relevant published meta-analyses).
  • Examined the performance of ZDV and 3TC when included in combinations comprising 3 or more drugs, involving concomitant use of another NRTI, NNRTI or PI.

Note: The examination of 2-drug combinations does not imply any endorsement of such regimens as effective treatments; these data are included here to help establish the efficacy and safety of the combination of ZDV and 3TC as a ‘nucleoside core’. The literature search used here, although comprehensive, is not complete. In particular, trials presented at conferences, and available only as published conference proceedings, were not included and no attempt was made to retrieve unpublished data.

Categorisation of levels of evidence

The following rating scheme was used[11]:

Level 1 – evidence from relevant high quality systematic reviews of unbiased randomised comparative clinical trials