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Title: Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study
Authors: Mallika Imwong
Mehul Dhorda
Kyaw Myo Tun
Aung Myint Thu
Aung Pyae Phyo
Stephane Proux
Kanokon Suwannasin
Chanon Kunasol
Suttipat Srisutham
Jureeporn Duanguppama
Ranitha Vongpromek
Cholrawee Promnarate
Aungkana Saejeng
Nardlada Khantikul
Rungniran Sugaram
Supinya Thanapongpichat
Nongyao Sawangjaroen
Kreepol Sutawong
Kay Thwe Han
Ye Htut
Khin Linn
Aye Aye Win
Tin M. Hlaing
Rob W. van der Pluijm
Mayfong Mayxay
Tiengkham Pongvongsa
Koukeo Phommasone
Rupam Tripura
Thomas J. Peto
Lorenz von Seidlein
Chea Nguon
Dysoley Lek
Xin Hui S. Chan
Huy Rekol
Rithea Leang
Cheah Huch
Dominic P. Kwiatkowski
Olivo Miotto
Elizabeth A. Ashley
Myat Phone Kyaw
Sasithon Pukrittayakamee
Nicholas P.J. Day
Arjen M. Dondorp
Frank M. Smithuis
Francois H. Nosten
Nicholas J. White
Shoklo Malaria Research Unit
Thailand Ministry of Public Health
Mahosot Hospital, Lao
Mahidol University
Nuffield Department of Medicine
Prince of Songkla University
Wellcome Sanger Institute
University of Oxford Medical Sciences Division
Myanmar Health Network Organization
University of Health Sciences
Myanmar Oxford Clinical Research Unit
University of Medicine 1
Ministry of Health and Sports
Medical Action Myanmar
Defence Services Medical Academy
Buntharik Hospital
Defence Services Medical Research Centre
Savannakhet Provincial Health Department
Royal Society of Thailand
Worldwide Antimalarial Resistance Network
National Center for Parasitology, Entomology and Malaria Control
Office of Disease Prevention and Control
Keywords: Medicine
Issue Date: 1-Jan-2020
Citation: The Lancet Infectious Diseases. (2020)
Abstract: © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: The Greater Mekong subregion is a recurrent source of antimalarial drug resistance in Plasmodium falciparum malaria. This study aimed to characterise the extent and spread of resistance across this entire region between 2007 and 2018. Methods: P falciparum isolates from Myanmar, Thailand, Laos, and Cambodia were obtained from clinical trials and epidemiological studies done between Jan 1, 2007, and Dec 31, 2018, and were genotyped for molecular markers (pfkelch, pfcrt, pfplasmepsin2, and pfmdr1) of antimalarial drug resistance. Genetic relatedness was assessed using microsatellite and single nucleotide polymorphism typing of flanking sequences around target genes. Findings: 10 632 isolates were genotyped. A single long pfkelch Cys580Tyr haplotype (from −50 kb to +31·5 kb) conferring artemisinin resistance (PfPailin) now dominates across the eastern Greater Mekong subregion. Piperaquine resistance associated with pfplasmepsin2 gene amplification and mutations in pfcrt downstream of the Lys76Thr chloroquine resistance locus has also developed. On the Thailand–Myanmar border a different pfkelch Cys580Tyr lineage rose to high frequencies before it was eliminated. Elsewhere in Myanmar the Cys580Tyr allele remains widespread at low allele frequencies. Meanwhile a single artemisinin-resistant pfkelch Phe446Ile haplotype has spread across Myanmar. Despite intense use of dihydroartemisinin–piperaquine in Kayin state, eastern Myanmar, both in treatment and mass drug administrations, no selection of piperaquine resistance markers was observed. pfmdr1 amplification, a marker of resistance to mefloquine, remains at low prevalence across the entire region. Interpretation: Artemisinin resistance in P falciparum is now prevalent across the Greater Mekong subregion. In the eastern Greater Mekong subregion a multidrug resistant P falciparum lineage (PfPailin) dominates. In Myanmar a long pfkelch Phe446Ile haplotype has spread widely but, by contrast with the eastern Greater Mekong subregion, there is no indication of artemisinin combination therapy (ACT) partner drug resistance from genotyping known markers, and no evidence of spread of ACT resistant P falciparum from the east to the west. There is still a window of opportunity to prevent global spread of ACT resistance. Funding: Thailand Science Research and Innovation, Initiative 5%, Expertise France, Wellcome Trust.
ISSN: 14744457
Appears in Collections:Scopus 2020

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