Spread of artemisinin resistance in Plasmodium falciparum malaria

Abstract

Background: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies.

Methods: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined.

Results: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days.

Conclusions: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).

Figure 1. Location of Study Sites and Proportions of Patients with Artemisinin Resistance

Artemisinin resistance was defined by a parasite clearance half-life longer than 5 hours, with some Plasmodium falciparum isolates having kelch13 polymorphisms (at or beyond amino acid position 441).

Figure 2. Distribution of Parasite Clearance Half-Lives

Panel A shows the parasite clearance half-life according to study site (treatment groups have been pooled in all sites), and Panel B shows the location of P. falciparum kelch13 nonsynonymous polymorphisms. One circle represents one patient. Infections with mutations in the P. falciparum kelch13 are indicated by blue circles (wild-type or mutation before amino acid position 441), red circles (mutation after position 440), or black circles (at least part of kelch13 sequence is missing or heterozygous). Two patients had double mutations (n87k and k92n, and p441l and n725y); the site of the first mutation is shown.