Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study - 26/11/20

Doi : 10.1016/S1473-3099(20)30228-0

Mallika Imwong, ProfPhD ^a,^b,⁎ , Mehul Dhorda, PhD ^b,^d, Kyaw Myo Tun, MD ^e, Aung Myint Thu, MD ^f, Aung Pyae Phyo, PhD ^f,^g, Stephane Proux, MSc ^f, Kanokon Suwannasin, BSc ^b, Chanon Kunasol, MSc ^b, Suttipat Srisutham, PhD ^b, Jureeporn Duanguppama, MSc ^b, Ranitha Vongpromek, MSc ^d, Cholrawee Promnarate, MSc ^d, Aungkana Saejeng, PhD ^h, Nardlada Khantikul, PhD ⁱ, Rungniran Sugaram, MSc ^h, Supinya Thanapongpichat, PhD ^j, Nongyao Sawangjaroen, PhD ^k, Kreepol Sutawong, MSc ^l, Kay Thwe Han, MMedSc ^m, Ye Htut, BS ^m, Khin Linn, MD ^m, Aye Aye Win, BS ⁿ, Tin M Hlaing, ProfDrPH ^o, Rob W van der Pluijm, MD ^b,^p, Mayfong Mayxay, MD ^q,^r, Tiengkham Pongvongsa, PhD ^s, Koukeo Phommasone, MD ^r, Rupam Tripura, MD ^b,^p, Thomas J Peto, PhD ^b,^p, Lorenz von Seidlein, MD ^b,^p, Chea Nguon, MD ^t, Dysoley Lek, MD ^t, Xin Hui S Chan, MRCP ^b,^p, Huy Rekol, MD ^t, Rithea Leang, PhD ^t, Cheah Huch, MD ^t, Dominic P Kwiatkowski, ProfFRS ^u,^v, Olivo Miotto, ProfPhD ^b,^u,^v, Elizabeth A Ashley, BS ^p,^r, Myat Phone Kyaw, PhD ^w, Sasithon Pukrittayakamee, ProfDPhil ^b,^c,^x, Nicholas P J Day, ProfFMedSci ^b,^p, Arjen M Dondorp, ProfMD ^b,^p, Frank M Smithuis, MD ^g,^p,^y, Francois H Nosten, ProfMD ^f,^p, Nicholas J White, ProfFRS ^b,^p

^a Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

^b Mahidol–Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

^c Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

^d Worldwide Antimalarial Resistance Network, Bangkok, Thailand

^e Department of Preventive and Social Medicine, Defence Services Medical Academy, Yangon, Myanmar

^f Shoklo Malaria Research Unit, Mahidol–Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand

^g Myanmar Oxford Clinical Research Unit, Yangon, Myanmar

^h Bureau of Vector-borne Diseases, Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand

ⁱ Office of Disease Prevention and Control Region 1, Chiang Mai, Thailand

^j Faculty of Medical Technology, Prince of Songkla University, Songkhla, Thailand

^k Department of Microbiology, Faculty of Science, Prince of Songkla University, Songkhla, Thailand

^l Buntharik Hospital, Amphoe Buntharik, Ubon Ratchathani, Thailand

^m Department of Medical Research, Ministry of Health and Sports, Yangon, Myanmar

ⁿ Department of Tropical and Infectious Diseases, University of Medicine 1, Yangon, Myanmar

^o Defence Services Medical Research Centre, Naypyitaw, Myanmar

^p Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK

^q Institute of Research and Education Development, University of Health Sciences, Ministry of Health, Vientiane, Laos

^r Lao–Oxford–Mahosot Hospital–Wellcome Trust Research Unit, Vientiane, Laos

^s Savannakhet Provincial Health Department, Phonsavangnuea village, Kaysone-Phomvihan district, Savannakhet, Laos

^t National Center for Parasitology, Entomology, and Malaria Control, Phnom Penh, Cambodia

^u Wellcome Sanger Institute, Hinxton, UK

^v Medical Research Council Centre for Genomics and Global Health, Big Data Institute, University of Oxford, Oxford, UK

^w Department of Medical Research, Myanmar Health Network Organization, Yangon, Myanmar

^x The Royal Society of Thailand, Dusit, Bangkok, Thailand

^y Medical Action Myanmar, Yangon, Myanmar

^* Correspondence to: Prof Mallika Imwong, Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand Department of Molecular Tropical Medicine and Genetics Faculty of Tropical Medicine Mahidol University Bangkok 10400 Thailand

Summary

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.

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Vol 20 - N° 12

P. 1470-1480 - décembre 2020 Retour au numéro

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Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study - 26/11/20

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