TY - JOUR
T1 - Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study
AU - Imwong, Mallika
AU - Dhorda, Mehul
AU - Myo Tun, Kyaw
AU - Thu, Aung Myint
AU - Phyo, Aung Pyae
AU - Proux, Stephane
AU - Suwannasin, Kanokon
AU - Kunasol, Chanon
AU - Srisutham, Suttipat
AU - Duanguppama, Jureeporn
AU - Vongpromek, Ranitha
AU - Promnarate, Cholrawee
AU - Saejeng, Aungkana
AU - Khantikul, Nardlada
AU - Sugaram, Rungniran
AU - Thanapongpichat, Supinya
AU - Sawangjaroen, Nongyao
AU - Sutawong, Kreepol
AU - Han, Kay Thwe
AU - Htut, Ye
AU - Linn, Khin
AU - Win, Aye Aye
AU - Hlaing, Tin M.
AU - van der Pluijm, Rob W.
AU - Mayxay, Mayfong
AU - Pongvongsa, Tiengkham
AU - Phommasone, Koukeo
AU - Tripura, Rupam
AU - Peto, Thomas J.
AU - von Seidlein, Lorenz
AU - Nguon, Chea
AU - Lek, Dysoley
AU - Chan, Xin Hui S.
AU - Rekol, Huy
AU - Leang, Rithea
AU - Huch, Cheah
AU - Kwiatkowski, Dominic P.
AU - Miotto, Olivo
AU - Ashley, Elizabeth A.
AU - Kyaw, Myat Phone
AU - Pukrittayakamee, Sasithon
AU - Day, Nicholas P. J.
AU - Dondorp, Arjen M.
AU - Smithuis, Frank M.
AU - Nosten, Francois H.
AU - White, Nicholas J.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85088801479&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/S1473-3099(20)30228-0
DO - https://doi.org/10.1016/S1473-3099(20)30228-0
M3 - Article
C2 - 32679084
SN - 1473-3099
VL - 20
SP - 1470
EP - 1480
JO - Lancet infectious diseases
JF - Lancet infectious diseases
IS - 12
ER -