Averting a malaria disaster

Abstract

Authors' reply Sir—There are several reasons to believe that the artemisinin derivatives will not suffer the same fate that chloroquine and sulphadoxine-pyrimethamine did in Cambodia. Repeated mass drug administrations and medication of salt with these slowly eliminated antimalarial drugs provided intense selective pressure to the emergence of resistant malaria parasites, which will not occur with artemisinin combination treatment of symptomatic malaria. The rapid emergence of resistance to the combination of sulphadoxine and pyrimethamine cannot be equated with the potential development of artemisinin resistance in P falciparum. The rationale underlying the use of antimalarial combinations to prevent the emergence of resistance is that of mutual protection; malaria parasites with mutations conferring resistance to one component will be killed by the other component. This killing requires unlinked resistance mechanisms, and therefore, usually, independent modes of action. The degree of protection depends on the antimalarial activity of the combination partner. This protective combination (eg, with artesunate and mefloquine) differs from the synergic or potentiating sulphadoxine pyrimethamine combination. Sulphadoxine and pyrimethamine do not act independently. The sulphonamides are weakly active antimalarial drugs that cannot be used alone to treat malaria, but they do provide potent synergy with pyrimethamine through sequential blockade of folate synthesis. The sulphonamides therefore provide only weak protection against pyrimethamine resistance in combination. Mutations in the P falciparum dihydrofolate reductase (dhfr) gene (the target of pyrimethamine confer significantly reduced susceptibility to the sulphadoxine combination. Furthermore, these DHFR mutations occur frequently, whereas no significant resistance to artemisinin has been documented either clinically or in laboratory experiments. Chloroquine, pyrimethamine, and sulphadoxine are eliminated slowly and persist for weeks or months at low blood concentrations, whereas these subtherapeutic, selective concentrations never occur with the very rapidly eliminated artemisinin derivatives. If artemisinin and its derivatives are used only with an effective combination partner no malaria parasite will ever see an artemisinin derivative in the absence of a second unrelated antimalarial drug. The opportunity for the selection of artemisinin-resistant mutant parasites, should they ever arise, is thus massively reduced. Artemisinin and its derivatives are now freely available in many countries. Resistance will probably develop if these drugs are not protected. The earlier combinations are deployed, the greater is the benefit in terms of delaying the emergence of resistance to artemisinin and delaying further progression of resistance to the other antimalarials. Waiting until resistance is already established before deploying these antimalarials is not logical. Averting a malaria disasterThe rationale for combining drugs with independent modes of action to prevent the emergence of resistance in Plasmodium falciparum in Nick White and colleagues' study (June 5, p 1965)1 is not new, and had been developed some 30 years ago. On the basis of the same simple calculation and on studies on the development of resistance of P berghei and P gallinaceum to dapsone, pyrimethamine, and sulphadoxine, alone or in combination, we concluded, in 1968, that there was only a minimum risk of emergence of resistant strains with the drug combination. Full-Text PDF