In 2000, WHO convened an Informal Consultation on the Use of Antimalarial Drugs (13-17 November 2000)i to review and update recommendations on the use of antimalarial drugs for malaria prevention and treatment of uncomplicated malaria and to assess the implications of the latest drug developments for national treatment policies.
i WHO (2000) The Use of Antimalarial Drugs Report of a WHO Informal Consultation. WHO unpublished report WHO/CDS/RBM/2001.33.
A total of 41 participants, reflecting a broad range of expertise in the development and use of antimalarial drugs, and in the implementation of antimalarial treatment policies, made specific recommendations to national malaria control programs after reviewing and discussing working paper prepared by specific experts in the respective technical areas. Among the main recommendations, the meeting highlighted the value of combination therapy as a strategic and viable option:
“The potential value of drug combinations, notably those containing an artemisinin derivatives, to improve efficacy, delay development and selection of drug-resistance parasites and thus prolog the 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.”
The meeting provided specific definition of antimalarial combination therapy, i.e. simultaneous use of two or more blood schizontocidal drugs with independent mode of action and different biochemical targets in the parasite, and listed examples of specific multiple-drug therapies or synergistic fixed-dose combinations which are not considered to be combination therapy. Examples of fixed-dose combinations, that strictly speaking fit the criteria of synergistic fixed-dose combinations, but are operationally considered as single products, include, in addition to S/P, chlorproguanil/dapsone and atovaquone/proguanil (for these drugs neither of the individual components can be given alone for antimalarial therapy).
In April 2001, WHO convened a Technical Consultation on Antimalarial Combination Therapy (4-5 April 2001) to undertake a systematic review of existing data on combination therapy for malaria and to identify appropriate combinations for use, particularly in African countries. 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 formed the basis of a WHO report. i
i WHO (2001) Antimalarial Drug Combination Therapy Report of a WHO Technical Consultation, WHO unpublished report, WHO/CDS/RBM/2001.35.
The conclusions of Technical Consultation was based on the following:
• in-depth reviews of existing non-artemisinin FDCs [chloroquine plus sulfadoxine/pyrimethamine (SP), amodiaquine plus SP, mefloquine-SP and quinine plus tetracycline or doxycycline];
• an independent review of artemether/lumefantrine (Coartem®), the only existing fixed-dose artemisinin-based combination therapy, i.e.;
• the results of individual patient data meta-analysis of clinical efficacy and safety of artemisinin combinations coordinated by the International Artemisinin Group (ACTs available as multiple drug therapies: chloroquine plus artesunate; SP plus artesunate; amodiaquine plus artesunate and mefloquine plus artesunate);
• Expert reviews of artemisinin-based combination therapies FDCs under development, i.e. piperaquine/dihydroartemisinin/trimethoprim, pyronaridine/artesunate, chlorproguanil/dapsone/artesunate and naphthoquine/dihydroartemisinin.
The Technical Consultation strongly endorsed the potential of combination therapy for use in Africa. On the basis of the available safety and efficacy data, it recommended 4 therapeutic options with potential for deployment (in prioritized order) if costs were not an issue:
1. artemether/lumenfantrine (Coartem®);
2. artesunate (3 days) plus amodiaquine as FDC;
3. artesunate (3 days) plus SP as FDC, in areas where SP efficacy is high;
4. amodiaquine plus SP as FDC, in areas where efficacy of both drugs remains high.
The consultation recognized that increased funding would be required to facilitate the appropriate exploration of use and purchase of optimal antimalarial drugs. Failure to assure funding for antimalarial drugs will provide a major obstacle for many countries in Africa in moving to combination therapy.