Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker

Abstract

Background: Emergence 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.

Methods: We 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.

Findings: Overall, 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.

Interpretation: Artemisinin 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.

Funding: Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation.

Figure 1

Location of sampling sites, sample sizes, and administrative states and regions of Myanmar, and a relief map of southeast Asia Red circles show numbers of patients in each region.

Figure 2

Primary aminoacid positions of K13 mutations identified in Myanmar and border regions

Figure 3

Local prevalence of individual K13 mutations by administrative state or region in Myanmar Only mutations found in at least nine isolates, or at least three states or regions, are shown.

Figure 4

Geographical extent of predicted artemisinin resistance as determined by the prevalence of K13 propeller mutations (>440 aminoacids) visualised by approaches using a Bayesian model (A, with uncertainty shown in B) and kriging interpolation (C, with uncertainty shown in D) In the main prevalence maps, colour shows total prevalence of relevant K13 mutations (median in A and mean in C). In the uncertainty maps, orange and red areas show the greatest uncertainty in Shan State (in the east) and the southern peninsula. In A the colour of the circles is proportional to the recorded K13-mutation prevalence at a particular site and the radius of the circle is proportional to the sample size of the study.