K13-propeller mutations in Plasmodium falciparum populations in malaria endemic regions of Vietnam from 2009 to 2016

Abstract

The spread of artemisinin resistant P. falciparum compromises the therapeutic efficacy of artemisinin combination therapies (ACT) and is considered the greatest threat to current global initiatives to control and eliminate malaria. This is particularly relevant for Vietnam, where dihydroartemisinin-piperaquine (DP) is the recommended ACT for P. falciparum The propeller domain gene of K13, a molecular marker of artemisinin resistance, was sequenced successfully in 1060 P. falciparum isolates collected at 3 malaria hotspots in Vietnam between 2009 and 2016. Eight K13 propeller mutations (Thr474Ile, Tyr493His, Arg539Thr, Ile543Thr, Pro553Leu, Val568Gly, Pro574Leu and Cys580Tyr) were found, including several that have been validated as artemisinin resistant markers. The prevalences of K13 mutations were 29% (222/767), 6% (11/188) and 43% (45/105) in in Binh Phuoc, Ninh Thuan and Gia Lai respectively. Cys580Tyr became the dominant genotype in recent years comprising 79.1% (34/43) of isolates in Binh Phuoc and 63% (17/27) in Gia Lai Province. K13 mutations were associated with reduced ring stage susceptibility to dihydroartemisinin (DHA) in-vitro and prolonged parasite clearance in-vivo. An analysis of haplotypes flanking K13 suggested the presence of multiple strains with Cys580Tyr, rather than a single strain expanding across the three sites

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