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Title: Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study
Authors: Rob W. van der Pluijm
Mallika Imwong
Nguyen Hoang Chau
Nhu Thi Hoa
Nguyen Thanh Thuy-Nhien
Ngo Viet Thanh
Podjanee Jittamala
Borimas Hanboonkunupakarn
Kitipumi Chutasmit
Chalermpon Saelow
Ratchadaporn Runjarern
Weerayuth Kaewmok
Rupam Tripura
Thomas J. Peto
Sovann Yok
Seila Suon
Sokunthea Sreng
Sivanna Mao
Savuth Oun
Sovannary Yen
Chanaki Amaratunga
Dysoley Lek
Rekol Huy
Mehul Dhorda
Kesinee Chotivanich
Elizabeth A. Ashley
Mavuto Mukaka
Naomi Waithira
Phaik Yeong Cheah
Richard J. Maude
Roberto Amato
Richard D. Pearson
Sónia Gonçalves
Christopher G. Jacob
William L. Hamilton
Rick M. Fairhurst
Joel Tarning
Markus Winterberg
Dominic P. Kwiatkowski
Sasithon Pukrittayakamee
Tran Tinh Hien
Nicholas PJ Day
Olivo Miotto
Nicholas J. White
Arjen M. Dondorp
Harvard T.H. Chan School of Public Health
University of Oxford
National Institute of Allergy and Infectious Diseases
Mahidol University
Nuffield Department of Clinical Medicine
Wellcome Sanger Institute
Pailin Provincial Health Department
Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU)
Khun Han Hospital
Phusing Hospital
World Wide Antimalarial Resistance Network (WWARN)-Asia Regional Centre
Ratanakiri Referral Hospital
Sampov Meas Referral Hospital
Royal Institute of Thailand
National Institute of Public Health
National Center for Parasitology, Entomology and Malaria Control
Keywords: Medicine
Issue Date: 1-Sep-2019
Citation: The Lancet Infectious Diseases. Vol.19, No.9 (2019), 952-961
Abstract: © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4·0 license 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, 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.
ISSN: 14744457
Appears in Collections:Scopus 2019

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