12th Expert Committee on the Selection and Use of Essential Medicines Meeting
15-19 April 2002


** Notes on the inclusion of new items on the Model List

Antiretroviral drugs

The Expert Committee reviewed written submissions containing information on 12 anti-retroviral drugs from the HIV/AIDS Department of the World Health Organization for inclusion on the Model List. All of the proposed drugs are included as antiretroviral drug combinations recommended in the new WHO treatment guidelines for antiretroviral treatment in resource-poor settings2.

The written submissions comprised summaries of the evidence related to the clinical benefits, adverse effects, practical details of treatment, and comparisons with other members of their drug class. The clinical evidence had been assembled from comprehensive literature reviews for each drug and drug combination, several of which were conducted by staff working for the Cochrane Collaboration. The submissions also provided a summary of background information on the public health impact of HIV infection world-wide, the overall impact of anti-retroviral therapy on the course of illness in HIV-infected subjects, the value of surrogate markers as measures of treatment response, and a summary of the experience and impacts of delivering anti-retroviral therapy in resource-limited settings3.

The meeting commenced with a series of oral presentations from staff in the HIV/AIDS and EDM departments of the WHO. These presentations included summaries of the submitted written material, a history of the development of WHO guidelines for use of ARVs in resource-limited settings, and a description of the experiences of the use of ARVs in some developing countries. The logic behind the selection of first line and alternative regimens, and the development of appropriate criteria for case selection and minimum standards for monitoring treatment response and toxicity were of particular interest and concern to the Expert Committee.

Having considered the data, the expert committee agreed that there was substantial evidence supporting the claims of efficacy for ARV combinations comprising at least three drugs. Typically, these combinations include two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with either a non-nucleoside reverse transcriptase inhibitors (NNRTI), or a third NRTI, or a protease inhibitor. It was considered that there was convincing evidence from meta-analyses of randomized clinical trials, and from large well conducted cohort studies, that combination ARV treatment reduces mortality substantially. The committee accepted the validity of surrogate markers (CD4 cell counts and viral load estimates), which have been used in the majority of clinical trials of these agents. The survival gains were not off-set by severe adverse effects; consequently, effective treatment leads to large absolute reductions in mortality, and restoration of a worthwhile quality of life. However, highly active anti-retroviral therapy is not a cure for the disease and long-term suppressive therapy is necessary.

There were a number of issues of general concern to the Committee. These were the need for listing of what was seen to be a large number of drugs, the safety and efficacy of therapy when delivered with the minimal levels of laboratory monitoring advocated in the WHO treatment guidelines, the advantages and disadvantages of fixed dose combinations and the specific toxicity of certain agents (see consideration of specific drug classes for the latter).

The issue of the number of drugs proposed for listing was addressed by staff from the HIV/AIDS department of the WHO. While accepting that there were many circumstances in medicine where one essential drug may substitute easily for other members of a class, thus allowing the placement of a single agent on the Model List (with appropriate advice about substitution), this was not possible with HIV treatment. Effective therapy requires commencement of three drugs simultaneously, and alternative regimens are necessary to meet specific requirements at start-up, to substitute for first-line regimens in the case of toxicity, or to replace failing regimens. The committee considered various approaches to the listing of these agents but agreed finally that if they were to be listed, all drugs recommended should be included in the Model List.

The availability of adequate laboratory monitoring of anti-retroviral therapy was a particular concern of several members of the committee. The new WHO ARV guidelines appear to allow a low level of monitoring, which can be provided at basically equipped health facilities. This raises questions about the safety of ARV therapy, the failure to recognize drug toxicity and failure of regimens, which may in turn lead to viral resistance. It was noted that there have not been large field studies demonstrating the efficacy and safety of ARV therapy provided under such circumstances. Discussion and debate on these issues was extensive. In the end, there was a consensus within the Expert Committee that the treatment guidelines regarding case selection and monitoring should be accepted. However, it was recommended by the Committee that: the issues discussed should be reviewed at its next meeting, that suitable footnotes should be added to specific drugs in the Model List, and that relevant organizations should be strongly encouraged to fund field trials of low level monitoring of ARV treatments.

The Committee also supported the proposal that CD4 count laboratory facilities be made more widely available and encouraged the Global Fund to support the provision of such services.

There was also discussion regarding the advantages and disadvantages of fixed dose combinations of ARV drugs. The principal advantage is the improved adherence with treatment due to simplifications of regimens. This in turn should result in higher levels of efficacy and lower rates of viral resistance. The main disadvantages are inflexibility in dosing, and doubts about the pharmaceutical quality of fixed-dose combination products that are produced in the absence of strict regulatory and quality standards. Generally, the Committee favoured the increased availability of assured quality fixed dose combination products, incorporating suitable doses of appropriate drug combinations. It was noted that, at present, only a limited number of such combinations are available internationally. However, there is likely to be increased availability of fixed dose combinations in future from a range of manufacturers and it is hoped that relevant products will quickly be tested under the WHO's prequalification program.

Following these discussions the Expert Committee moved onto a consideration of the ARV drugs proposed for listing by the HIV/AIDS Department of the WHO.

In considering each application the Committee considered the following:
- Applications for each medicine, some of which had been available on the WHO web site
- Additional written material from external stakeholders
- Oral presentations (also provided in hard copy) by staff from WHO and UNAIDS.

In general terms, evidence in the applications was described according to the following classification:
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.

There was discussion as to whether listing of these drugs should be on the core or complementary sections of the Model List. Complementary listing could be used to signal that experience to date of their use in resource-poor settings was limited. However, while accepting concerns about the problems of limited laboratory monitoring, the Committee considered that core listing was appropriate with the addition of suitable footnotes. It was felt that complementary listing would be inconsistent with previous decisions regarding drugs that require monitoring and the decision might be used inappropriately as an argument against the wider access to ARV drugs.

It was noted that the most recent draft of the ARV guidelines recommended the use of total lymphocyte count as a surrogate for CD4 count only for HIV-infected individuals who were, or had been, symptomatic. It was requested that the permanent copies of the submissions for ARV drugs be amended to reflect this.

After discussion, the Committee recommended to include the following medicines on the core list: the nucleoside reverse transcriptase inhibitors zidovudine (ZDV or AZT), lamivudine (3TC), stavudine (d4T), didanosine (ddI) and abacavir (ABC); the non-nucleoside reverse transcriptase inhibitors nevirapine (NVP) and efavirenz (EFV or EFZ); and the protease inhibitors indinavir (IDV), lopinavir/low dose ritonavir (LPV/r), nelfinavir (NFV), ritonavir (r), and saquinavir (SQV).

The committee also requested that the following footnotes be added to the Model List:

"The antiretroviral drugs do not cure the HIV infection, they only temporarily suppress viral replication and improve symptoms. They have various adverse effects and patients receiving these drugs require careful monitoring by adequately trained health professionals. For these reasons, continued rigorous promotion of measures to prevent new infections is essential and the need for this has not been diminished in any way by the addition of antiretroviral drugs to the Model List. Adequate resources and trained health professionals are a prerequisite for the introduction of this class of drugs. Effective therapy requires commencement of three or four drugs simultaneously, and alternative regimens are necessary to meet specific requirements at start-up, to substitute for first-line regimens in the case of toxicity, or to replace failing regimens. The Committee strongly recommends the use of three- or four-drug combinations as specifically recommended in the WHO treatment guidelines. The use of fixed dose preparations for these combinations is also recommended, with assured pharmaceutical quality and interchangeability with the single products as approved by the relevant drug regulatory authority."

"Selection of two or three protease inhibitors from the Model List will need to be determined by each country after consideration of local treatment guidelines and experience, as well as the comparative costs of available products. Ritonavir is used in combination with indinavir, lopinavir and ritonavir as a booster, and not as a drug in its own right."

Fixed combination of artemether and lumefantrine

The first application for the inclusion of artemether/lumefantrine in the WHO Model List of Essential Drugs was reviewed by the Expert Committee on Essential Drugs in 1999 (WHO, 2000a). The Committee considered that the combination had the potential to play an important role in the management of uncomplicated falciparum malaria but that it was not appropriate at that time to include it in the WHO Model List of Essential Drugs since (i) there was no data on operational use of the combination; (ii) the Company proposed two dosage regimens to be used in non-immune and semi-immune patients which was might lead to confusion; (iii) there were concerns regarding the degree of compliance that may be obtained in rural health settings with a drug combination that required a relatively long and complex treatment regimen (i.e. 6 doses over 60 hrs); and (v) the affordability of the combination for populations in greatest need.

The Committee then considered the revised application4. The Committee noted that the prevalence of drug resistant falciparum malaria has increased so that, in some countries, resistance to all of the available antimalarial drugs, except artemisinin and its derivatives, exists. For patients with falciparum malaria resistant to chloroquine, sulfadoxine/ pyrimethamine, mefloquine and quinine, the use of artemisinin and its derivatives is essential.

The Committee also appreciated the differential pricing arrangement that has been made with the company, leading to a long-standing arrangement for a differential price for developing countries (when compared to developed countries) as well as an agreed price differential within developing countries between the private sector and the public and not-for-profit health care systems. The three markets are separated by different product names and packages.

The Committee noted that the recommendation to use artemisinin combinations would, in the medium term, require a review of the need to maintain single artemisinin derivatives on the Model List; but concluded that it was too early to delete these immediately. In the mean time it recommended that single artemisinin and its derivatives would be reserved for severe malaria when there is resistance to quinine.

Despite the absence of detailed clinical data on the use of artemether and lumefantrine in children below 10 kg and the limited data on use in pregnancy, the Committee recommended the inclusion of artemether/lumefantrine on the core list of the Model List of Essential Drugs, with the following footnote: "Recommended for use in areas with significant drug resistance and not in pregnancy or in children below 10 kg".

The Committee encouraged the development of more fixed-dose combinations of artemisinin and long-acting antimalarial medicines for future comparative review.

2 Scaling up antiretroviral therapy in resource-limited settings: guidelines for a public-health approach. Geneva: World Health Organization, April 2002 (in print)

3 See Applications for antiretroviral medicines

4 See Application for artemether + lumefantrine

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