Combination Therapy for Malaria: Mission Accomplished?

Abstract

In the war against malaria, the tide turned dramatically in our favor in the mid-20th century with the development of chloroquine, a highly effective antimalarial drug that was the linchpin of a global campaign to eradicate malaria. But our brief ascendancy was cut short when malaria parasites became resistant to chloroquine. For the next 50 years, we engaged in a long, hard slog against drug-resistant malaria, eventually losing on almost all fronts. Time and again, resistance emerged, and it spread more quickly than new drugs could be developed and deployed. Drug resistance has repeatedly arisen in Asia and then spread globally in inexorable sweeps that have left disease, death, and economic disability in their wake. The battle may be turning once again in our favor with new antimalarial combination therapies designed to deter the emergence of resistance that are increasingly becoming the first line against malaria. The artemisinins are a new class of potent compounds derived from an ancient Chinese herbal remedy for malaria. These drugs exert a powerful, percussive blow, with extremely rapid killing of parasites at all stages of their life cycle, followed by equally rapid elimination of the drug from the body, thus avoiding the lingering subtherapeutic blood levels that create conditions conducive to selection of resistance after treatment with slower and longer-acting drugs. In hopes of delaying the emergence of resistance to the artemisinins, the World Health Organization (WHO) recommends that they be used exclusively in combination with partner drugs that attack malaria parasites through different mechanisms. Artemisinin-based combination therapies (ACTs) are now