Abstract
SummaryBackgroundThe 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.MethodsP 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.Findings10 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.InterpretationArtemisinin 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.FundingThailand Science Research and Innovation, Initiative 5%, Expertise France, Wellcome Trust.
Highlights
The emergence and uncontrolled spread of artemisininresistant Plasmodium falciparum parasites in the Greater Mekong subregion in the past 13 years represents a serious potential threat to malaria control in the Indian subcontinent and Africa
Mutations in the gene encoding a Kelch protein on P falciparum chromosome 13 are strongly associated with artemisinin resistance,[7] resulting in reduced ring stage susceptibility and slow parasite clearance. pfplasmepsin[2,3] (PF3D7_1408000) amplification and mutations in the P falciparum chloroquine resistance transporter downstream of the 4-aminoquinoline resistance locus have both been associated with piperaquine resistance.[5,8,9,10,11] pfmdr[1] (PF3D7_0523000) amplification is a well established marker of mefloquine resistance,[4,12] which contributes to reduced lumefantrine suscepti bility in southeast Asia.[13]
Study design and participants As part of studies[3,11,15,16,17,18,19,20,21,22,23,24,25] on the epidemiology, treatment, and targeted elimination of artemisinin-resistant malaria done between Jan 1, 2007, and Dec 31, 2018, across the Greater Mekong subregion, venous blood samples, filter paper blood spots, and completed rapid diagnostic test strips were collected from patients presenting with microscopy or rapid test-confirmed uncomplicated falciparum malaria and from healthy participants in surveys of villages where targeted malaria elimination activities were planned
Summary
The emergence and uncontrolled spread of artemisininresistant Plasmodium falciparum parasites in the Greater Mekong subregion in the past 13 years represents a serious potential threat to malaria control in the Indian subcontinent and Africa. Mutations in the gene encoding a Kelch protein (pfkelch; PF3D7_1343700) on P falciparum chromosome 13 are strongly associated with artemisinin resistance,[7] resulting in reduced ring stage susceptibility and slow parasite clearance. Pfplasmepsin[2,3] (PF3D7_1408000) amplification and mutations in the P falciparum chloroquine resistance transporter (pfcrt; PF3D7_0709000) downstream of the 4-aminoquinoline resistance locus (positions 72–76 with Lys76Thr) have both been associated with piperaquine resistance.[5,8,9,10,11] pfmdr[1] (PF3D7_0523000) amplification is a well established marker of mefloquine resistance,[4,12] which contributes to reduced lumefantrine suscepti bility in southeast Asia.[13] We aimed to assess these www.thelancet.com/infection Vol 20 December 2020. 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
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