Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia.
Takala-Harrison S., Jacob CG., Arze C., Cummings MP., Silva JC., Dondorp AM., Fukuda MM., Hien TT., Mayxay M., Noedl H., Nosten F., Kyaw MP., Nhien NTT., Imwong M., Bethell D., Se Y., Lon C., Tyner SD., Saunders DL., Ariey F., Mercereau-Puijalon O., Menard D., Newton PN., Khanthavong M., Hongvanthong B., Starzengruber P., Fuehrer H-P., Swoboda P., Khan WA., Phyo AP., Nyunt MM., Nyunt MH., Brown TS., Adams M., Pepin CS., Bailey J., Tan JC., Ferdig MT., Clark TG., Miotto O., MacInnis B., Kwiatkowski DP., White NJ., Ringwald P., Plowe CV.
BACKGROUND: The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia. METHODS: P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently. RESULTS: The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P = 1.97 × 10(-12)). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas. CONCLUSIONS: K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.