Abstract
SummaryBackgroundThe emergence and spread of resistance in Plasmodium falciparum malaria to artemisinin combination therapies in the Greater Mekong subregion poses a major threat to malaria control and elimination. The current study is part of a multi-country, open-label, randomised clinical trial (TRACII, 2015–18) evaluating the efficacy, safety, and tolerability of triple artemisinin combination therapies. A very high rate of treatment failure after treatment with dihydroartemisinin-piperaquine was observed in Thailand, Cambodia, and Vietnam. The immediate public health importance of our findings prompted us to report the efficacy data on dihydroartemisinin-piperaquine and its determinants ahead of the results of the overall trial, which will be published later this year.MethodsPatients aged between 2 and 65 years presenting with uncomplicated P falciparum or mixed species malaria at seven sites in Thailand, Cambodia, and Vietnam were randomly assigned to receive dihydroartemisinin-piperaquine with or without mefloquine, as part of the TRACII trial. The primary outcome was the PCR-corrected efficacy at day 42. Next-generation sequencing was used to assess the prevalence of molecular markers associated with artemisinin resistance (kelch13 mutations, in particular Cys580Tyr) and piperaquine resistance (plasmepsin-2 and plasmepsin-3 amplifications and crt mutations). This study is registered with ClinicalTrials.gov, number NCT02453308.FindingsBetween Sept 28, 2015, and Jan 18, 2018, 539 patients with acute P falciparum malaria were screened for eligibility, 292 were enrolled, and 140 received dihydroartemisinin-piperaquine. The overall Kaplan-Meier estimate of PCR-corrected efficacy of dihydroartemisinin-piperaquine at day 42 was 50·0% (95% CI 41·1–58·3). PCR-corrected efficacies for individual sites were 12·7% (2·2–33·0) in northeastern Thailand, 38·2% (15·9–60·5) in western Cambodia, 73·4% (57·0–84·3) in Ratanakiri (northeastern Cambodia), and 47·1% (33·5–59·6) in Binh Phuoc (southwestern Vietnam). Treatment failure was associated independently with plasmepsin2/3 amplification status and four mutations in the crt gene (Thr93Ser, His97Tyr, Phe145Ile, and Ile218Phe). Compared with the results of our previous TRACI trial in 2011–13, the prevalence of molecular markers of artemisinin resistance (kelch13 Cys580Tyr mutations) and piperaquine resistance (plasmepsin2/3 amplifications and crt mutations) has increased substantially in the Greater Mekong subregion in the past decade.InterpretationDihydroartemisinin-piperaquine is not treating malaria effectively across the eastern Greater Mekong subregion. A highly drug-resistant P falciparum co-lineage is evolving, acquiring new resistance mechanisms, and spreading. Accelerated elimination of P falciparum malaria in this region is needed urgently, to prevent further spread and avoid a potential global health emergency.FundingUK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, and National Institutes of Health.
Highlights
In the 1990s, widespread multidrug resistance to Plas-modium falciparum malaria throughout southeast Asia led to the introduction of highly effective artemisinin combination therapies (ACTs
Patients aged between 2 and 65 years presenting with uncomplicated P falciparum or mixed species malaria at seven sites in Thailand, Cambodia, and Vietnam were randomly assigned to receive dihydroartemisinin-piperaquine with or without mefloquine, as part of the TRACII trial
Between Sept 28, 2015, and Jan 18, 2018, 539 patients with acute P falciparum malaria were screened for eligibility, 292 were enrolled, and 140 received dihydroartemisinin-piperaquine
Summary
In the 1990s, widespread multidrug resistance to Plas-modium falciparum malaria throughout southeast Asia led to the introduction of highly effective artemisinin combination therapies (ACTs). In the 1990s, widespread multidrug resistance to Plas-modium falciparum malaria throughout southeast Asia led to the introduction of highly effective artemisinin combination therapies (ACTs)1 These drugs have since contributed substantially to the sharp decline in the global malaria disease burden and saved millions of lives.. More recent studies between 2012 and 2013 reported a PCR-corrected efficacy of 63·2% in Pursat and 98·4% in Ratanakiri, northeastern Cambodia, at day 63. A 2012–13 study in Ratanakiri, Pursat, and Preah Vihear in Cambodia found no correlation between treatment outcomes and day 7 piperaquine levels, and baseline parasite densities and patient age, but found that kelch gene mutations and high piperaquine in vitro 50% inhibitory concentrations were predictors of treatment failure. Imwong and colleagues in 2017 and Amato and colleagues in 2018 independently showed that a parasite co-lineage containing a kelch Cys580Tyr mutation and amplification of plasmepsin2/3 emerged in western Cambodia and spread across northeastern Thailand, northern and and spread of artemisinin resistance in southeast Asia. Artemisinin resistance in P falciparum has emerged and spread throughout the Greater Mekong subregion, and is characterised by slow in vivo parasite clearance resulting from reduced drug susceptibility of ring-stage parasites. Loss of artemisinin efficacy in ACTs has facilitated the re-emergence of mefloquine resistance on the ThailandMyanmar border and contributed to the emergence and spread of piperaquine resistance in P falciparum in Cambodia and southern Vietnam.
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