Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study.
Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study.
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DOI：
10.1016/s1473-3099(20)30228-0
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
White NJ
中科院分区：
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作者：
Imwong M;Dhorda M;Myo Tun K;Thu AM;Phyo AP;Proux S;Suwannasin K;Kunasol C;Srisutham S;Duanguppama J;Vongpromek R;Promnarate C;Saejeng A;Khantikul N;Sugaram R;Thanapongpichat S;Sawangjaroen N;Sutawong K;Han KT;Htut Y;Linn K;Win AA;Hlaing TM;van der Pluijm RW;Mayxay M;Pongvongsa T;Phommasone K;Tripura R;Peto TJ;von Seidlein L;Nguon C;Lek D;Chan XHS;Rekol H;Leang R;Huch C;Kwiatkowski DP;Miotto O;Ashley EA;Kyaw MP;Pukrittayakamee S;Day NPJ;Dondorp AM;Smithuis FM;Nosten FH;White NJ
大湄公河次区域是恶性疟原虫疟疾抗疟药物耐药性的反复出现的来源。这项研究旨在确定2007年至2018年期间整个地区的耐药性程度和传播范围。来自缅甸，泰国，老挝和柬埔寨的恶性疟原虫分离株来自2007年1月1日至2018年12月31日期间进行的临床试验和流行病学研究，并对抗疟药物耐药性的分子标记物（pfkelch，pfcrt，pfplasmepsin 2和pfmdr 1）进行基因分型。利用微卫星和靶基因侧翼序列的单核苷酸多态性分型来评估遗传相关性。对10632株分离株进行了基因分型。 一个单一的长pfkelch Cys 580 Tyr单倍型（从-50 kb到+31 statist 5 kb）赋予青蒿素抗性（PfPailin）现在在大湄公河东部次区域占主导地位。还出现了与pfplasmepsin 2基因扩增和Lys 76 Thr氯喹耐药基因座下游pfcrt突变相关的哌喹耐药。在泰国-缅甸边境，另一个pfkelch Cys 580 Tyr谱系在被消除之前上升到高频率。在缅甸的其他地方，Cys 580 Tyr等位基因仍然以低等位基因频率广泛分布。与此同时，一种单一的青蒿素耐药pfkelch Phe 446 Ile单倍型已经在缅甸蔓延。尽管在缅甸东部的卡因大量使用双氢青蒿素-哌喹进行治疗和大规模给药，但未观察到哌喹耐药标志物的选择。pfmdr 1扩增是甲氟喹耐药性的标志，在整个区域的流行率仍然很低。恶性疟原虫对青蒿素的耐药性目前在大湄公河次区域普遍存在。在大湄公河次区域东部，多重耐药恶性疟原虫谱系（PfPailin）占主导地位。在缅甸，一个长的pfkelch Phe 446 Ile单倍型已经广泛传播，但与东部大湄公河次区域相比，没有迹象表明青蒿素联合疗法（ACT）的合作伙伴药物耐药性的基因分型已知标记，也没有证据表明ACT耐药恶性疟原虫从东部传播到西部。仍然有机会防止ACT耐药性在全球蔓延。泰国科学研究和创新，倡议5%，法国专业知识，惠康信托。
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. 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. 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. 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. Thailand Science Research and Innovation, Initiative 5%, Expertise France, Wellcome Trust.