Chaorattanakawee Suwanna, Lon Chanthap, Jongsakul Krisada, Gawee Jariyanart, Sok Somethy, Sundrakes Siratchana, Kong Nareth, Thamnurak Chatchadaporn, Chann Soklyda, Chattrakarn Sorayut, Praditpol Chantida, Buathong Nillawan, Uthaimongkol Nichapat, Smith Philip, Sirisopana Narongrid, Huy Rekol, Prom Satharath, Fukuda Mark M, Bethell Delia, Walsh Douglas S, Lanteri Charlotte, Saunders David
US Army Medical Component-Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS), Bangkok, Thailand.
Department of Parasitology and Entomology, Faculty of Public Health, Mahidol University, Bangkok, Thailand.
Malar J. 2016 Oct 21;15(1):519. doi: 10.1186/s12936-016-1569-y.
The recent dramatic decline in dihydroartemisinin-piperaquine (DHA-PPQ) efficacy in northwestern Cambodia has raised concerns about the rapid spread of piperaquine resistance just as DHA-PPQ is being introduced as first-line therapy in neighbouring countries.
Ex vivo parasite susceptibilities were tracked to determine the rate of progression of DHA, PPQ and mefloquine (MQ) resistance from sentinel sites on the Thai-Cambodian and Thai-Myanmar borders from 2010 to 2015. Immediate ex vivo (IEV) histidine-rich protein 2 (HRP-2) assays were used on fresh patient Plasmodium falciparum isolates to determine drug susceptibility profiles.
IEV HRP-2 assays detected the precipitous emergence of PPQ resistance in Cambodia beginning in 2013 when 40 % of isolates had an IC greater than the upper limit of prior years, and this rate doubled to 80 % by 2015. In contrast, Thai-Myanmar isolates from 2013 to 14 remained PPQ-sensitive, while northeastern Thai isolates appeared to have an intermediate resistance profile. The opposite trend was observed for MQ where Cambodian isolates appeared to have a modest increase in overall sensitivity during the same period, with IC declining to median levels comparable to those found in Thailand. A significant association between increased PPQ IC and IC among Cambodian isolates with DHA-PPQ treatment failure was observed. Nearly all Cambodian and Thai isolates were deemed artemisinin resistant with a >1 % survival rate for DHA in the ring-stage assay (RSA), though there was no correlation among isolates to indicate cross-resistance between PPQ and artemisinins.
Clinical DHA-PPQ failures appear to be associated with declines in the long-acting partner drug PPQ, though sensitivity appears to remain largely intact for now in western Thailand. Rapid progression of PPQ resistance associated with DHA-PPQ treatment failures in northern Cambodia limits drugs of choice in this region, and urgently requires alternative therapy. The temporary re-introduction of artesunate AS-MQ is the current response to PPQ resistance in this area, due to inverse MQ and PPQ resistance patterns. This will require careful monitoring for re-emergence of MQ resistance, and possible simultaneous resistance to all three drugs (AS, MQ and PPQ).
近期在柬埔寨西北部，双氢青蒿素-哌喹（DHA-PPQ）疗效急剧下降，这引发了人们对哌喹耐药性迅速传播的担忧，而此时DHA-PPQ正在邻国被引入作为一线治疗药物。
追踪体外寄生虫敏感性，以确定2010年至2015年泰国-柬埔寨边境和泰国-缅甸边境哨点的DHA、PPQ和甲氟喹（MQ）耐药性进展速度。对新鲜的恶性疟原虫患者分离株进行即时体外（IEV）富含组氨酸蛋白2（HRP-2）检测，以确定药物敏感性谱。
IEV HRP-2检测发现，自2013年起柬埔寨出现了哌喹耐药性急剧上升的情况，当时40%的分离株的IC高于前几年的上限，到2015年这一比例翻了一番，达到80%。相比之下，2013年至2014年泰国-缅甸的分离株对PPQ仍敏感，而泰国东北部的分离株似乎具有中等耐药性特征。对于MQ则观察到相反的趋势，同期柬埔寨分离株的总体敏感性似乎有适度增加，IC降至与泰国相当的中位水平。在柬埔寨接受DHA-PPQ治疗失败的分离株中，观察到PPQ的IC增加与DHA的IC之间存在显著关联。几乎所有柬埔寨和泰国的分离株在环状体阶段试验（RSA）中对DHA的存活率>1%，被认为对青蒿素有耐药性，尽管分离株之间没有相关性表明PPQ与青蒿素之间存在交叉耐药性。
临床DHA-PPQ治疗失败似乎与长效搭档药物PPQ的疗效下降有关，尽管目前泰国西部的敏感性似乎在很大程度上仍保持完好。柬埔寨北部与DHA-PPQ治疗失败相关的PPQ耐药性迅速发展，限制了该地区的首选药物，迫切需要替代疗法。由于MQ和PPQ的耐药性模式相反，目前该地区针对PPQ耐药性的应对措施是重新临时引入青蒿琥酯-甲氟喹（AS-MQ）。这将需要仔细监测MQ耐药性的再次出现，以及可能同时出现对所有三种药物（AS、MQ和PPQ）的耐药性。
