Abstract
SummaryBackgroundEmergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations.MethodsWe did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar.FindingsOverall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations.InterpretationArtemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided.FundingWellcome Trust–Mahidol University–Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation.
Highlights
Artemisinin-based combination treatments are the mainstay of treatment for Plasmodium falciparum malaria globally, but artemisinin resistance, evidenced by delayed parasite clearance after artemisinin treatment, is prevalent across an expanding area of southeast Asia.[1,2,3,4,5,6,7]
Various K13propeller mutations have been documented in population surveys in the region, and when phenotypes are available in numbers sufficient enough to achieve statistical power, the most prevalent mutations are associated with delayed parasite clearance after artemisinin treatment[4,5,7,18] and reduced in-vitro responses.[19,20]
Studies of population genetics have described P falciparum founder populations that share an underlying predisposed genetic background[40] rising to fairly high levels; each population is linked to specific K13 mutations[41] and has high levels of artemisinin resistance both in vivo and in vitro.[19]
Summary
Artemisinin-based combination treatments are the mainstay of treatment for Plasmodium falciparum malaria globally, but artemisinin resistance, evidenced by delayed parasite clearance after artemisinin treatment, is prevalent across an expanding area of southeast Asia.[1,2,3,4,5,6,7] Artemisinin resistance is characterised by reduced susceptibility of the ring stage of parasite development[8,9] and is clearly associated with increasing rates of failure of artemisinin-based combination treatments in Cambodia[10,11,12,13] and Thailand.[14]Mutations that change the primary aminoacid sequence of the so-called propeller region of the kelch motifcontaining gene, known as K13, have been identified as a key causal determinant of artemisinin resistance in southeast Asia,[4,15,16] acting through upregulation of unfolded protein response pathways.[17]. Artemisinin-based combination treatments are the mainstay of treatment for Plasmodium falciparum malaria globally, but artemisinin resistance, evidenced by delayed parasite clearance after artemisinin treatment, is prevalent across an expanding area of southeast Asia.[1,2,3,4,5,6,7] Artemisinin resistance is characterised by reduced susceptibility of the ring stage of parasite development[8,9] and is clearly associated with increasing rates of failure of artemisinin-based combination treatments in Cambodia[10,11,12,13] and Thailand.[14]. Discovery of a molecular marker of artemisinin resistance before global spread provides a unique opportunity for Lancet Infect Dis 2015; 15: 415–21
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