Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study

Abstract

Background: Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand-Myanmar (Burma) border.

Methods: In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms.

Findings: 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5-2·7) in 2001, to 3·7 h (3·6-3·8) in 2010, compared with a mean of 5·5 h (5·2-5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010.

Interpretation: Genetically determined artemisinin resistance in P falciparum emerged along the Thailand-Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2-6 years.

Funding: The Wellcome Trust and National Institutes of Health.

Figure 1

Parasite clearance half-life of Plasmodium falciparum on the Thailand–Myanmar border over 10 years We plotted untransformed parasite clearance half-lives over time for all malaria infections with a good fit to a linear model (R²>0.8). Data from western Cambodia gathered between June, 2007, and November, 2010, are shown for comparison, compressed as if they had been obtained in a single year. The dotted red line shows a threshold value of 6·2 h, used to differentiate between fast-clearing and slow-clearing infections. The dotted blue boxes show the periods for which bloodspots were available. These two time windows form the basis of the genetic analysis.

Figure 2

Change in parasite clearance half-life of Plasmodium falciparum 2001–10 (A) Geometric means of parasite clearance half-life in patients with hyperparasitaemia on the Thailand–Myanmar border. *Subset of infections treated with artesunate monotherapy (ART) for more than 48 h, for which 48 h clearance rates and parasite clearance half-lives were calculated. Error bars are 95% CIs and above them is the number of patients. (B) Proportion of patients with very slow clearance (parasite clearance half-life≥6·2 h). Error bars are binomial 95% CIs. Colour scheme is as per A.

Figure 3

Effect of parasite genotype on parasite clearance rates Clearance half-lives in patients infected with parasites bearing identical 93-locus genotypes. Red dotted line marks the 6·2 h threshold used to categorise slow-clearing parasites. The arrows show slow clearance parasite genotypes gathered in November, 2003. *Ranked by mean parasite clearance half-life.