Disease Prevention and Control / Communicable Diseases / Malaria

Antimalarial Drug Combination Therapy: Report of a WHO Consultation

Antimalarial Drug Combination Therapy

Report (36 pp, PDF)
- Conclusions & Recommendations

1. Combination therapy in the context of treatment policy

- Purpose of drug policy
- Combination therapy with antimalarial drugs

2. Antimalarial therapy combination drugs
- Non-artemisinin based combinations
- Artemisinin-based combinations
- Combinations in the pipeline

3. Implementation issues
- Criteria for selection of combinations of antimalarial drugs
- Technical requirements and process for introducing combination therapy
- Industrial partnerships and their roles

4. Conclusion and Recommendations
References   |   Annexes

1. List of participants
2. Matrix for comparing therapies
3. Projected time line for new drug availability
4. Possible scenarios for policy change

- Access to Antimalarial Medicines: Improving the Affordability and Financing of Artemisinin-Based Combination Therapies
- The Use of Antimalarial Drugs: Report of a WHO Informal Consultation

PAHO Malaria Page
WHO Malaria Page: English   |   français

A WHO Technical Consultation on Antimalarial Combination Therapy was held in Geneva, Switzerland on 4–5 April 2001. Participants reflected a wide range of expertise in the development and use of antimalarial drugs. Early diagnosis and prompt treatment is one of the principal technical components of the global strategy to control malaria. The effectiveness of this intervention is highly dependent on antimalarial drugs, which should not only be safe and effective, but also available, affordable and acceptable to the population at risk. The rational use of an effective antimalarial drug not only reduces the risk of severe disease and death and shortens the duration of the illness, but also contributes to slowing down the development of the parasite's resistance to antimalarial drugs.

The emergence and rapid spread of P. falciparum resistance to commonly used antimalarial drugs poses a serious challenge to the effectiveness of early diagnosis and prompt treatment as a priority strategy within current malaria control efforts. In November 2000, an Informal Consultation on the Use of Antimalarial Drugs was convened by WHO in Geneva. This meeting reviewed and updated recommendations on the use of antimalarial drugs for chemoprophylaxis and treatment, based on the information available. The meeting acknowledged the limited number of treatment options that are available to countries to improve their treatment policies. This is of particular concern in areas of highest resource constraints such as sub-Saharan Africa where a lack of resources has contributed to the continued use of drugs whose effectiveness have been compromised by drug resistance. The potential value of malaria therapy using combinations of drugs was identified as a strategic and viable option in improving efficacy, and delaying development and selection of resistant parasites. However, the systematic review of existing data on combination therapy for malaria and identification of specific candidate drugs, especially for Africa, was beyond the scope of the November meeting.

Thus, in view of this recognition of the role of combination therapy, RBM considered it timely to convene a technical consultation to

  • review current evidence on combination therapy with antimalarial drugs;
  • recommend the minimal criteria for selection and use of combination therapies of antimalarial drugs in different epidemiological settings;
  • select appropriate combinations for use, particularly in African countries; and
  • identify priority research, product development and production needs to facilitate the implementation of antimalarial combination therapies.

The technical consultation took the form of presentations based on working papers and plenary discussions, on the basis of which specific conclusions and recommendations were agreed. The proceedings of the meeting and working papers form the basis of this report.

The conclusions and recommendations of the meeting strongly endorse the potential of combination therapy for use in Africa. Appropriate national and regional based studies should be initiated with all possible speed to assess their potential for incorporation into National Policies in preference to monotherapy. There are however two practical caveats:

  • There is limited clinical experience for many of the combinations being considered. It is acknowledged that full safety and efficacy needs to be demonstrated on a case by case basis involving appropriate prospective studies, including where necessary regulatory and Phase IV studies, and appropriate surveillance, particularly of adverse events.
  • It is acknowledged that in the case of artemisinin-based combinations the cost of treatment will increase significantly over traditional monotherapies such as chloroquine or SP (by a factor of up to tenfold). In countries where healthcare systems cannot afford the introduction of combination therapies, other alternatives may need to be considered.

These caveats epitomise the dilemma facing many national malaria control programmes. Increased global funding will be required to facilitate the appropriate exploration of use, and purchase, of optimal antimalarial drugs. Failure to assure increased funding for antimalarials will provide a major obstacle for many countries in Africa in moving to combination therapy.

Specific Recommendations

  1. Increasing resistance to chloroquine and sulfadoxine/pyrimethamine will probably lead to an increase of malaria morbidity and mortality, particularly in children, and urgent action is needed to replace antimalarial drugs which have become, or are rapidly becoming, ineffective.
  2. Combination therapies preferably using "novel" antimalarial drugs with different modes of action is the way forward for improving therapeutic efficacy and delaying development of resistance in antimalarial chemotherapy.
  3. Artemisinin-based combinations have several distinct advantages in that they produce rapid clinical and parasitological cure, there is as yet no documented parasite resistance, they reduce gametocyte carriage rate, and are generally well tolerated.
  4. Based on available safety and efficacy data, the following therapeutic options are available now and have potential for deployment (in prioritized order) if costs were not an issue:
    1. artemether-lumefantrine (CoartemTM);
    2. artesunate (3 days) plus amodiaquine;
    3. artesunate (3days) plus SP in areas where SP efficacy remains high; and
    4. SP plus amodiaquine in areas where efficacy of both amodiaquine and SP remain high.
    This is mainly limited to countries in West Africa.
  5. These combination options need continued documentation of safety and efficacy as part of any potential implementation process, especially among very young children, pregnant women, and breastfeeding mothers and their babies.
  6. Artemisinin-based combination therapies are at an early stage in Africa and there is a need for extensive Phase IV studies and post-marketing surveillance.
  7. Other artemisinin-based combination therapies in the pipeline are recommended for accelerated development, particularly piperaquine-DHA combination (ArtecomTM, CV8TM), Lapdap-artesunate and pyronaridine-artesunate.
  8. Options that are not recommended for policy at this time include:
    1. chloroquine-based combinations (CQ + SP and CQ + artesunate);
    2. one-day treatment of artesunate + SP; and
    3. mefloquine-based combinations (e.g. mefloquine plus artesunate) in areas of high malaria transmission iv. one-day treatment of artesunate plus mefloquine in the acute phase of a complex emergency or malaria epidemics.
  9. The lack of safe and effective preventive therapies for use in pregnancy in SP-resistant high-transmission areas and in epidemic situations was noted. This issue needs to be addressed urgently.