Breaking the cycle of malaria treatment failure

Abstract

Treatment of symptomatic malaria became a routine component of the clinical and public health response to malaria after the second world war. However, all antimalarial drugs deployed against malaria eventually generated enough drug resistance that they had to be removed from use. Chloroquine, sulfadoxine-pyrimethamine, and mefloquine are well known examples of antimalarial drugs to which resistance did and still does ready evolve. Artemisinin-based combination therapies (ACTs) are currently facing the same challenge as artemisinin resistance is widespread in Southeast Asia and emerging in Africa. Here, I review some aspects of drug-resistance management in malaria that influence the strength of selective pressure on drug-resistant malaria parasites, as well as an approach we can take in the future to avoid repeating the common mistake of deploying a new drug and waiting for drug resistance and treatment failure to arrive. A desirable goal of drug-resistance management is to reduce selection pressure without reducing the overall percentage of patients that are treated. This can be achieved by distributing multiple first-line therapies (MFT) simultaneously in the population for the treatment of uncomplicated falciparum malaria, thereby keeping treatment levels high but the overall selection pressure exerted by each individual therapy low. I review the primary reasons that make MFT a preferred resistance management option in many malaria-endemic settings, and I describe two exceptions where caution and additional analyses may be warranted before deploying MFT. MFT has shown to be feasible in practice in many endemic settings. The continual improvement and increased coverage of genomic surveillance in malaria may allow countries to implement custom MFT strategies based on their current drug-resistance profiles.

Keywords: artemisinin combination therapies; artemisinin resistance; drug resistance; malaria; multiple first-line therapies.

Figure 1

Different long-term deployment strategies of when multiple ACTs are available. (A) A 5-year cycling strategy where each ACT is pre-scheduled to be used for 5 years exactly; after each 5-year period the national first-line recommendation is switched to a different ACT. (B) An adaptive cycling strategy, currently recommended by WHO, where ACTs (or other therapies) are replaced when 10% treatment failure is surpassed. This means that over long periods, different therapies will be used for different amounts of time. It also means that switches from an old therapy to a new one will typically occur with a delay, sometimes with a substantial delay if surveillance is delayed. (C) Multiple first-line therapies (MFT) deployed with random allocations of therapies to clinics, pharmacies, and other health facilities. In this scenario, three individuals in the same community could be simultaneously treated with three different ACTs. (D) MFT deployed by village or health post or health facility. In this scenario, a central point of contact in the health system—e.g., a village health worker, or a health facility director—would be responsible for ensuring that all malaria cases in their catchment area were treated with one ACT, chosen at a higher administrative level. (E) MFT deployed at the district or province level and coordinated nationally. In this scenario, distribution of different ACTs to different administrative regions would be controlled centrally by the National Malaria Control Program.