Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study

Lancet Infect Dis. 2019 Sep;19(9):952-961. doi: 10.1016/S1473-3099(19)30391-3. Epub 2019 Jul 22.

Abstract

Background: The 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.

Methods: 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. 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.

Findings: 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. 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.

Interpretation: Dihydroartemisinin-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.

Funding: UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, and National Institutes of Health.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antimalarials / therapeutic use*
  • Artemisinins / therapeutic use*
  • Cambodia
  • Drug Resistance, Multiple / genetics*
  • Drug Therapy, Combination
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Malaria, Falciparum / drug therapy*
  • Male
  • Mefloquine / therapeutic use
  • Membrane Transport Proteins / genetics
  • Middle Aged
  • Mutation
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / genetics*
  • Prospective Studies
  • Protozoan Proteins / genetics
  • Quinolines / therapeutic use*
  • Thailand
  • Treatment Failure
  • Vietnam
  • Young Adult

Substances

  • Antimalarials
  • Artemisinins
  • Membrane Transport Proteins
  • PfCRT protein, Plasmodium falciparum
  • Protozoan Proteins
  • Quinolines
  • artenimol
  • piperaquine
  • Mefloquine

Associated data

  • ClinicalTrials.gov/NCT02453308