Application for Inclusion of Nelfinavir Mesylate On

(FCH/HIV, 22 April 2002)

Application for Inclusion of nelfinavir mesylate on

The WHO Model List of Essential Medicines

Drug is a member of the therapeutic class of HIV protease 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 worldwide are infected with HIV and more than 90% of infected persons live in the developing world. In 2001, 5 million persons worldwide became infected with HIV, and 3 million others died from HIV/AIDS-related causes. 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 protease inhibitor drug nelfinavir is proposed for listing on the WHO Model List of Essential Medicines. Nelfinavir is recommended as a first line therapy in combination with zidovudine and lamivudine in the (Draft) WHO guidelines for use of ARV drugs in resource poor settings. It should be used within an appropriately monitored program in combination with two or more other anti-retroviral drugs, including nucleoside or non-nucleoside reverse transcriptase inhibitors, or another protease inhibitor. 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.

Twelve randomised controlled clinical trials of nelfinavir were recovered by the search. In total these trials evaluated 21 treatment arms, of which 11 included nelfinavir as part of triple therapy; 9 arms included nelfinavir in combination with 2 nucleoside reverse transcriptase inhibitors. In these trials nelfinavir-containing combinations displayed similar efficacy to other protease inhibitor-containing combinations, with some evidence of superior tolerability. The most common adverse effect was diarrhea.

Currently, nelfinavir can be sourced from only two manufacturers internationally. Nelfinavir is not available in fixed dose combinations and at current prices is substantially more expensive than other protease inhibitors.

1. Proposal for inclusion, change or deletion of a drug.

Nelfinavir 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/AIDS within an appropriately monitored program. Nelfinavir should be viewed as an example of the class of protease inhibitors. Other examples of this group may sometimes be preferred when local factors such as availability and price are taken into account. Current practice is to combine protease inhibitors with two or more other drugs, typically nucleaoside reverse transcriptase inhibitors (NRTIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs).

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: nelfinavir mesylate

5. Listing Type Requested:

Listing is requested on the Model List of Essential Medicines as an example of the therapeutic class of HIV protease 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/AIDS. 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 20013.

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 pervasive antiretroviral therapy. In the USA, the introduction of triple combination antiretroviral therapy in 1996 lead 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%. Between 1997 and 2000, Brazil saved approximately US $677 million in averted hospitalisations and treatment of HIV-related infections[4].

In Argentina a program similar to that of Brazil provides even greater coverage. A special fund has been established to pay for antiretrovirals 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, and the evidence from randomised clinical trial (reviewed below), 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:

Recommended Dosage: Adults and adolescents: 1250 mg (5 x 250 mg tablets) twice daily. An alternative regimen is 750mg three times daily, which has been trialed quite extensively.

Nelfinavir should be taken with food as the maximum plasma concentrations and area under the plasma concentration-time curve (AUC) were 2- to 3-fold higher under fed conditions compared to fasting.

Concomitant Antiretroviral Therapy: Nelfinavir 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 nelfinavir (in combination with two nucleoside analogue reverse transcriptase inhibitors) 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 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 that 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

Search terms used were:

Anti-retroviral or antiretroviral

Nucleoside reverse transcriptase inhibitors

Non-nucleoside reverse transcriptase inhibitors

Protease inhibitors

Trial and Clinical Trial (including exploded terms)

Individual drug names: zidovudine, stavudine (d4T), lamivudine (3TC), abacavir, nelfinavir, lopinavir, indinavir, ritonavir, efavirenz, nevirapine.

Note: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. The results should be viewed as a fairly representative listing of trials that are readily available through Medline and Embase searching.

Study selection:

Randomised comparative parallel-group controlled clinical trials
Compared NFV in combination with one or more NRTIs, NNRTIs, or other PIs against:
Non PI-containing drug combinations
PI-containing drug combinations
Combinations of NFV with 2 NRTIs were of particular interest as these are regimens recommended in the WHO draft guidelines (Table 1).

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 combinations of 3 or 4-regimes that include a PI.

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

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

Simplicity (frequency of dosing, number of tablets)

Tolerability

Cost

Co-morbidity

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 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 nelfinavir?

Note: in addressing this question studies were selected in which nelfinavir had been used in at least one arm in a combination that involved 2 or more additional anti-retroviral drugs from the NRTI, NNRTI or PI classes.

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-retroviralcompounds 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 outcomes[12]. 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 suppression[13]. 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 progression[14]. This review included data from 15038 patients, of whom 3532 patients progressed clinically. 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. 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)