Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia

Shannon Takala-Harrison*, Christopher G. Jacob, Cesar Arze, Michael P. Cummings, Joana C. Silva, Arjen M. Dondorp, Mark M. Fukuda, Tran Tinh Hien, Mayfong Mayxay, Harald Noedl, Francois Nosten, Myat P. Kyaw, Nguyen Thanh Thuy Nhien, Mallika Imwong, Delia Bethell, Youry Se, Chanthap Lon, Stuart D. Tyner, David L. Saunders, Frederic ArieyOdile Mercereau-Puijalon, Didier Menard, Paul N. Newton, Maniphone Khanthavong, Bouasy Hongvanthong, Peter Starzengruber, Hans Peter Fuehrer, Paul Swoboda, Wasif A. Khan, Aung Pyae Phyo, Myaing M. Nyunt, Myat H. Nyunt, Tyler S. Brown, Matthew Adams, Christopher S. Pepin, Jason Bailey, John C. Tan, Michael T. Ferdig, Taane G. Clark, Olivo Miotto, Bronwyn MacInnis, Dominic P. Kwiatkowski, Nicholas J. White, Pascal Ringwald, Christopher V. Plowe

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

324 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)670-679
Number of pages10
JournalJournal of Infectious Diseases
Volume211
Issue number5
DOIs
StatePublished - 1 Mar 2015
Externally publishedYes

Keywords

  • Artemisinin resistance
  • Kelch
  • Malaria
  • Plasmodium falciparum
  • Southeast Asia

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