Antimalarial Drug Combination Therapy: Report of a WHO Informal Consultation

Full-Text Report (144 pp, PDF)
- Conclusions & Recommendations
- Future Research & Other Activities

Contents: Introduction
Part I: Policy Implications
1. Current status of antimalarial drug resistance
2. Combination therapy (CT)
3. Chemoprophylaxis and treatment of malaria in special groups
4. Antimalarial treatment policies
5. Conclusions and recommendations

Part II: Antimalarial Drugs
1. Antimalarial drugs for malaria prevention and treatment
2. Status and potential of combination therapies

References   |   Annexes
1. List of participants
2. Guidance on the selection of drugs for national antimalarial treatment policies
3. Common antimalarial drugs that should be considered in drug selection

- Access to Antimalarial Medicines: Improving the Affordability and Financing of Artemisinin-Based Combination Therapies
- Antimalarial Drug Combination Therapy: Report of a WHO Consultation

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WHO Malaria Page:
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The WHO Informal Consultation on the Use of Antimalarial Drugs was held from 13 to 17 November 2000 in Geneva, Switzerland. The participants reflected a broad range of expertise in the development and use of antimalarial drugs, and in the implementation and adaptation of antimalarial treatment policies.

Early diagnosis and prompt treatment are fundamental components of the WHO global strategy for malaria control. Correct use of an effective antimalarial drug will not only shorten the duration of malaria illness but also reduce the incidence of complications and the risk of death. Antimalarial drug resistance has spread and intensified over the last 15–20 years, however, leading to a dramatic decline in the efficacy of the most affordable antimalarial drugs.

Development of new drugs is not keeping pace, and problems related to the distribution and use of these drugs have compounded the situation. In many malarious areas, a majority of the population does not have ready access to antimalarial drugs and to reliable and consistent information about malaria treatment and prevention. Moreover, those drugs that are available are frequently obtained from informal sources and may be counterfeit; they are of variable quality, may be partially or completely ineffective against local parasite strains, and are often used in inappropriate dosages.

Many endemic countries are beginning to face a situation in which there are no affordable, effective antimalarial drugs available. Combination therapy offers hope for preserving the efficacy of antimalarial drugs and prolonging their useful therapeutic life, although it may not necessarily provide better treatment for consumers. The development of artemisinin and its derivatives-the most rapidly acting of all the current antimalarial drugs-and recognition of their potential role as a component of combination therapy have led to several large trials aimed at assessing different combinations of existing drugs, and to the specific development of new combination drugs. In addition, several countries have felt the need to evaluate, as potential first-line treatments, drug combinations that do not include artemisinin. These changes have provided an impetus for updating and rationalizing antimalarial treatment policies.

National antimalarial treatment policies are essential to provide countries with a framework for the safe and effective treatment of uncomplicated and severe malaria as well as for the prevention of malaria in travellers and in vulnerable groups, such as pregnant women and young children. As a general principle, such policies should aim at the greatest possible reduction of malaria mortality and morbidity, while containing the development of resistance and remaining compatible with limited national health budgets and health care infrastructures. All health care providers in both the public and private health sectors must be aware of, understand the rationale for, and implement the national policy. Such national policies should be updated to take account of the development of antimalarial drug resistance in the country. A framework for this purpose has been developed for use in Africa.

The treatment of severe malaria is covered comprehensively in the Transactions of the Royal Society of Tropical Medicine and Hygiene supplement Severe falciparum Malaria. The use of antimalarial drugs for chemoprophylaxis and the prevention and treatment of uncomplicated malaria was last reviewed at a WHO informal consultation in September 1995 , which also considered diagnosis and the principles of clinical management. Since then, considerable additional experience has been gained in the use of existing and new antimalarial drugs, alone and in combination.

In view of the new evidence available on malaria prevention and treatment and on the further spread of resistance to antimalarial drugs, WHO considered it timely to convene an informal consultation to:

• review and update recommendations on the use of antimalarial drugs for malaria prevention and the treatment of uncomplicated malaria; and
• assess the implications of the latest drug developments for national antimalarial treatment policies.

The informal consultation took the form of presentations of prepared papers, followed by discussions during which specific conclusions and recommendations were agreed. The proceedings of the consultation and the working papers form the basis of this report.

The report is aimed at managers of national malaria control programmes and those involved in implementing antimalarial treatment policies. Part I provides information on the current status of antimalarial resistance throughout the world, considers the potential for combination therapy, updates recommendations on the prevention and treatment of malaria in specific target groups, and outlines the development and implementation of an antimalarial treatment policy. Part II describes the antimalarial drugs and recommended regimens in current use for malaria prevention and for the treatment of uncomplicated malaria. It also covers antimalarial drugs under development. The report also presents options for different treatment scenarios according to specific epidemiological situations. Individual countries will need to adapt the recommendations made in this report to their own epidemiological and health-care context.

Conclusions and Recommendations

1. There are regional differences in patterns of antimalarial drug resistance in countries and policy options should reflect these differences.
2. Previous documentation has suggested that a therapeutic failure rate of ? 25% is a useful indicator for change in antimalarial treatment policy. However, it is acknowledged that the decision to change will depend on country circumstances. Because of the time required to implement a change in policy (usually 2–3 years), the evaluation of potential alternatives should begin as soon as failure of the specific drug starts to emerge.
3. It is broadly acknowledged that the options available to countries for improved antimalarial treatment policies are limited, especially in regions of highest resource constraints such as sub-Saharan Africa. In many instances, the lack of resources has resulted in countries continuing the use of drugs whose effectiveness is limited by drug resistance.
4. The potential value of drug combinations, notably those including an artemisinin derivative, to improve efficacy, delay development and selection of drug-resistant parasites and thus prolong the useful therapeutic life of existing antimalarial drugs is widely accepted. Combinations that do not contain an artemisinin derivative could be a preferred option for reasons of cost and accessibility in some countries.
5. Combination therapy could be a viable option for countries that already have widespread resistance of P. falciparum to chloroquine, amodiaquine and sulfadoxine- pyrimethamine, provided issues of cost and complexity of implementation can be addressed.
6. Amodiaquine, not recommended for chemoprophylaxis by WHO due to bone marrow and hepatic toxicity following prophylactic use, deserves re-evaluation as a potential therapeutic replacement for chloroquine. It may have particular value as a low-cost component in combination therapy. Results from further clinical trials on safety and efficacy are awaited.
7. Amodiaquine should be given at a therapeutic dose of 30 mg/kg over 3 days (10 mg/kg daily for 3 days) for simplicity of administration in place of the previously recommended 25–35 mg/kg.
8. The role of intramuscular artemether/arteether as an alternative to intravenous quinine because of simplicity of administration and less frequent dosing schedule in the management of severe malaria in complex emergency situations is re-emphasized.
9. The lack of validated, safe and effective preventive therapies for use in pregnancy in epidemic situations, especially in areas with multidrug-resistant P. falciparum was noted and needs to be addressed urgently.
10. Choice of specific options for antimalarial combination therapy for different epidemiological settings, particularly in Africa, was not on the agenda of this meeting. Given the agreed potential of such options, a further technical meeting to review available evidence and make recommendations on antimalarial combination therapy should be convened.
11. Effective antimalarial treatment policies will rely on access to drugs that are significantly more expensive than chloroquine, amodiaquine and sulfadoxine-pyrimethamine. Appropriate political and institutional actions and improved financing are prerequisites to successful advances in this area. These issues deserve immediate serious attention, especially for Africa.

Future Research and Other Activities

1. There is an urgent need for field research, linked to appropriate pharmaceutical product development, to assess the effectiveness of potential combination therapies that include artemisinin and its derivatives in different epidemiological and health system settings in Africa.
2. The effectiveness of other combinations (not including an artemisinin derivative) with cheaper and already available antimalarial drugs such as 4-aminoquinoline and sulfa drugs for use in Africa should also be explored. This should also be linked to appropriate pharmaceutical product development.
3. Amodiaquine toxicity and its potential cross-resistance with chloroquine require further evaluation as these characteristics may limit the useful therapeutic life of this antimalarial drug.
4. Studies should be conducted to determine whether the continued use of certain drugs as monotherapy will compromise their usefulness as a component of combination therapies.
5. There is an urgent need for more information on and improved options for preventive intermittent treatment in pregnancy and for treatment in complex emergency situations.
6. Studies should be conducted to evaluate the potential of pre-referral use of a single application of rectal artesunate capsules in endemic countries in Africa.
7. Further data are required on factors affecting access to treatment, including healthseeking behaviours, in endemic countries.
8. There is a need for a continuing monitoring system for antimalarial sensitivity patterns, especially in Africa where stronger information bases and inter-country exchanges are required. Efforts should be made to intensify support for resistance monitoring and to develop improved easy-to-use tools, kits and methodologies to facilitate this activity.
9. Sustainable drug discovery and development activities are required to ensure future improvements in malaria chemotherapy.
10. Greater engagement between researchers and decision-makers is essential to ensure that research informs policy and that policy and control needs inform research.
11. Substantial strengthening of health systems is needed to enable them to deliver and promote rationale use and wider access to antimalarial chemotherapy.