Abstract
SummaryBackgroundAntimalarial resistance is rapidly spreading across parts of southeast Asia where dihydroartemisinin–piperaquine is used as first-line treatment for Plasmodium falciparum malaria. The first published reports about resistance to antimalarial drugs came from western Cambodia in 2013. Here, we analyse genetic changes in the P falciparum population of western Cambodia in the 6 years before those reports.MethodsWe analysed genome sequence data on 1492 P falciparum samples from 11 locations across southeast Asia, including 464 samples collected in western Cambodia between 2007 and 2013. Different epidemiological origins of resistance were identified by haplotypic analysis of the kelch13 artemisinin resistance locus and the plasmepsin 2–3 piperaquine resistance locus.FindingsWe identified more than 30 independent origins of artemisinin resistance, of which the KEL1 lineage accounted for 140 (91%) of 154 parasites resistant to dihydroartemisinin–piperaquine. In 2008, KEL1 combined with PLA1, the major lineage associated with piperaquine resistance. By 2013, the KEL1/PLA1 co-lineage had reached a frequency of 63% (24/38) in western Cambodia and had spread to northern Cambodia.InterpretationThe KEL1/PLA1 co-lineage emerged in the same year that dihydroartemisinin–piperaquine became the first-line antimalarial drug in western Cambodia and spread rapidly thereafter, displacing other artemisinin-resistant parasite lineages. These findings have important implications for management of the global health risk associated with the current outbreak of multidrug-resistant malaria in southeast Asia.FundingWellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, UK Department for International Development, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases.
Highlights
The first-line treatment for Plasmodium falciparum malaria is artemisinin combination therapy.[1]
In 2008, it became apparent that P falciparum was becoming resistant to artemisinin in western Cambodia, and over the few years resistance was observed in other parts of Cambodia, as well as in Thailand, Vietnam, Myanmar, and Laos.[4,5,6]
We found that 91% of parasites resistant to dihydroartemisinin–piperaquine were of the KEL1/PLA1 co-lineage, suggesting that they arose from a common epidemiological origin, and that this co-lineage is probably the same lineage observed in other countries by Imwong and colleagues
Summary
The first-line treatment for Plasmodium falciparum malaria is artemisinin combination therapy.[1] Artemisinin and its derivatives are potent and fast-acting antimalarial drugs, but they are short acting.[2] The rationale behind artemisinin combination therapy is to combine artemisinin with a longer-acting partner drug to ensure that all parasites are killed and to prevent the emergence of resistance.[3]. In 2008, it became apparent that P falciparum was becoming resistant to artemisinin in western Cambodia, and over the few years resistance was observed in other parts of Cambodia, as well as in Thailand, Vietnam, Myanmar, and Laos.[4,5,6] this finding caused widespread concern, there were some mitigating factors. Partner drugs of artemisinin combination therapy were able to clear parasites despite the slower response of parasites to artemisinin; artemisinin combination therapy remained effective as first-line antimalarial therapy
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