Spread of artemisinin resistance in Plasmodium falciparum malaria.
Spread of artemisinin resistance in Plasmodium falciparum malaria.
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DOI：
10.1056/nejmoa1314981
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发表时间：
2014-07-31
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影响因子：
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通讯作者：
Tracking Resistance to Artemisinin Collaboration (TRAC)
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作者：
Ashley EA;Dhorda M;Fairhurst RM;Amaratunga C;Lim P;Suon S;Sreng S;Anderson JM;Mao S;Sam B;Sopha C;Chuor CM;Nguon C;Sovannaroth S;Pukrittayakamee S;Jittamala P;Chotivanich K;Chutasmit K;Suchatsoonthorn C;Runcharoen R;Hien TT;Thuy-Nhien NT;Thanh NV;Phu NH;Htut Y;Han KT;Aye KH;Mokuolu OA;Olaosebikan RR;Folaranmi OO;Mayxay M;Khanthavong M;Hongvanthong B;Newton PN;Onyamboko MA;Fanello CI;Tshefu AK;Mishra N;Valecha N;Phyo AP;Nosten F;Yi P;Tripura R;Borrmann S;Bashraheil M;Peshu J;Faiz MA;Ghose A;Hossain MA;Samad R;Rahman MR;Hasan MM;Islam A;Miotto O;Amato R;MacInnis B;Stalker J;Kwiatkowski DP;Bozdech Z;Jeeyapant A;Cheah PY;Sakulthaew T;Chalk J;Intharabut B;Silamut K;Lee SJ;Vihokhern B;Kunasol C;Imwong M;Tarning J;Taylor WJ;Yeung S;Woodrow CJ;Flegg JA;Das D;Smith J;Venkatesan M;Plowe CV;Stepniewska K;Guerin PJ;Dondorp AM;Day NP;White NJ;Tracking Resistance to Artemisinin Collaboration (TRAC)
恶性疟原虫对青蒿素的抗药性已在东南亚出现，目前对控制和消除疟疾构成威胁。绘制耐药性的地理范围对于规划遏制和消除战略至关重要。在2011年5月至2013年4月期间，我们在10个国家（7个在亚洲，3个在非洲）的15个地点招募了1241名患有急性、无并发症恶性疟疾的成人和儿童参加开放标签试验。患者口服青蒿琥酯，每日剂量为每公斤体重2毫克或每公斤4毫克，持续3天，然后进行为期3天的标准青蒿素联合治疗。每6小时测量一次外周血样本中的寄生虫计数，并确定寄生虫清除半衰期。寄生虫清除半衰期中位数从刚果民主共和国的1.9小时到泰国-柬埔寨边境的7.0小时不等。在从越南南部到缅甸中部的整个东南亚大陆，检测到了与13号染色体上恶性疟原虫kelch蛋白基因“螺旋桨”区域（kelch 13）的单点突变密切相关的缓慢清除感染（寄生虫清除半衰期>5小时）。治疗前和治疗后配子体血症的发生率在寄生虫清除缓慢的患者中更高，表明传播的可能性更大。在以青蒿素为基础的联合疗法失败的柬埔寨西部，6天疗程的抗疟治疗与42天的97.7%治愈率（95%置信区间，90.9至99.4）相关。青蒿素对恶性疟原虫的耐药性目前在东南亚大陆普遍存在，与kelch 13突变有关。目前，在标准的3天治疗无效的地区，延长青蒿素综合疗法疗程是有效的。（由英国资助。国际发展部等; ClinicalTrials.gov号码，NCT 01350856。）
Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand–Cambodia border. Slowly clearing in fections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the “propeller” region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.)