Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial.
Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial.
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DOI：
10.1016/s0140-6736(20)30552-3
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发表时间：
2020-04-25
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通讯作者：
Tracking Resistance to Artemisinin Collaboration
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van der Pluijm RW;Tripura R;Hoglund RM;Pyae Phyo A;Lek D;Ul Islam A;Anvikar AR;Satpathi P;Satpathi S;Behera PK;Tripura A;Baidya S;Onyamboko M;Chau NH;Sovann Y;Suon S;Sreng S;Mao S;Oun S;Yen S;Amaratunga C;Chutasmit K;Saelow C;Runcharern R;Kaewmok W;Hoa NT;Thanh NV;Hanboonkunupakarn B;Callery JJ;Mohanty AK;Heaton J;Thant M;Gantait K;Ghosh T;Amato R;Pearson RD;Jacob CG;Gonçalves S;Mukaka M;Waithira N;Woodrow CJ;Grobusch MP;van Vugt M;Fairhurst RM;Cheah PY;Peto TJ;von Seidlein L;Dhorda M;Maude RJ;Winterberg M;Thuy-Nhien NT;Kwiatkowski DP;Imwong M;Jittamala P;Lin K;Hlaing TM;Chotivanich K;Huy R;Fanello C;Ashley E;Mayxay M;Newton PN;Hien TT;Valecha N;Smithuis F;Pukrittayakamee S;Faiz A;Miotto O;Tarning J;Day NPJ;White NJ;Dondorp AM;Tracking Resistance to Artemisinin Collaboration
恶性疟原虫对青蒿素和伙伴药物的抗药性是控制和消除疟疾的主要威胁。以青蒿素为基础的三联疗法，将现有的共同配制的青蒿素为基础的三联疗法联合收割机与第二种伙伴药物相结合，这种药物会慢慢消除，可能提供有效的治疗，并推迟抗疟药物耐药性的出现。在这项多中心、开放标签、随机试验中，我们在8个国家的18家医院和诊所招募了无并发症恶性疟原虫疟疾患者。符合条件的患者年龄为2-65岁，患有急性、无并发症的恶性疟原虫疟疾单独或与非恶性疟原虫种类混合，体温为37·5°C或更高，或在过去24小时内有发热史。根据患者所在地，采用区组随机化方法将患者随机（1：1）分配至两种治疗之一：在泰国、柬埔寨、越南和缅甸，患者被分配至双氢青蒿素-哌喹或双氢青蒿素-哌喹加甲氟喹;在柬埔寨的三个研究中心，患者被分配至青蒿琥酯-甲氟喹或双氢青蒿素-哌喹加甲氟喹;在老挝、缅甸、孟加拉国、印度和刚果民主共和国，他们被分配给蒿甲醚-本芴醇或蒿甲醚-本芴醇加阿莫地喹。所有药物均经口给药，剂量因药物组合和部位而异。患者每周随访42天。主要终点是疗效，定义为42天PCR校正的充分临床和寄生虫学应答。主要分析是通过意向性治疗进行的，对所有随机分配接受治疗的患者进行了研究药物安全性和耐受性的详细评估。本研究在ClinicalTrials.gov注册，NCT 02453308，并已完成。在2015年8月7日至2018年2月8日期间，1100名患者接受了双氢青蒿素-哌喹（183 [17%]），双氢青蒿素-哌喹加甲氟喹（269 [24%]），青蒿琥酯-甲氟喹（73 [7%]），蒿甲醚-苯芴醇（289 [26%]）或蒿甲醚-苯芴醇加阿莫地喹（286 [26%]）。中位年龄为23岁（IQR 13 - 34），1100例患者中有854例（78%）为男性。在柬埔寨、泰国和越南，双氢青蒿素-哌喹加甲氟喹后42天PCR校正的疗效为98%（149/152; 95% CI 94 - 100），双氢青蒿素-哌喹后为48%（67/141; 95% CI 39 - 56;风险差异51%，95% CI 42 - 59; p<0.0001）。在缅甸的三个地点，双氢青蒿素-哌喹加甲氟喹的疗效为91%（42/46; 95% CI 79 - 98），而双氢青蒿素-哌喹后的疗效为100%（42/42; 95% CI 92 - 100）（风险差异9%，95% CI 1 - 17; p= 0.12）。在柬埔寨的3个研究中心，双氢青蒿素-哌喹加甲氟喹的42天PCR校正疗效（96% [68/71; 95% CI 88 - 99]）不劣于青蒿琥酯-甲氟喹（95% [69/73; 95% CI 87 - 99]）（风险差异1%; 95% CI −6 - 8; p= 1.00）。蒿甲醚-本芴醇加阿莫地喹的42天总体PCR校正疗效（98% [281/286; 95%CI 97 - 99]）与蒿甲醚-本芴醇相似（97% [279/289; 95%CI 94 - 98];风险差异2%，95%CI −1 - 4; p= 0.30）。两种TACT均耐受良好，但双氢青蒿素-哌喹加甲氟喹组（30/794例[3.8%]）的早期呕吐（1小时内）比双氢青蒿素-哌喹组（8/543例[1.5%]; p= 0.012）更常见。蒿甲醚-本芴醇+阿莫地喹（1703例中的22例[1.3%]）和蒿甲醚-本芴醇（1721例中的11例[0.6%]）后呕吐不常见。在蒿甲醚-本芴醇中添加阿莫地喹可延长心电图校正的QT间期（与基线相比，52小时平均增加8.8 ms [SD 18.6] vs 0.9 ms [16.1]; p<0.01），但在双氢青蒿素-哌喹中加入甲氟喹（双氢青蒿素-哌喹平均增加22.1 ms [SD 19.2]，双氢青蒿素-哌喹加甲氟喹平均增加20.8 ms [SD 17.8]; p= 0.50）。双氢青蒿素-哌喹加甲氟喹和蒿甲醚-苯芴醇加阿莫地喹TACT是治疗无并发症恶性疟原虫疟疾的有效、耐受性良好和安全的治疗方法，包括在青蒿素和ACT伙伴耐药地区。英国国际发展部、威康信托基金会、比尔和梅林达盖茨基金会、英国医学研究理事会和美国国立卫生研究院。
Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance. In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2–65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either dihydroartemisinin–piperaquine or dihydroartemisinin–piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate–mefloquine or dihydroartemisinin–piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether–lumefantrine or artemether–lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete. Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either dihydroartemisinin–piperaquine (183 [17%]), dihydroartemisinin–piperaquine plus mefloquine (269 [24%]), artesunate–mefloquine (73 [7%]), artemether–lumefantrine (289 [26%]), or artemether–lumefantrine plus amodiaquine (286 [26%]). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after dihydroartemisinin–piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after dihydroartemisinin–piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p<0·0001). Efficacy of dihydroartemisinin–piperaquine plus mefloquine in the three sites in Myanmar was 91% (42 of 46; 95% CI 79 to 98) versus 100% (42 of 42; 95% CI 92 to 100) after dihydroartemisinin–piperaquine (risk difference 9%, 95% CI 1 to 17; p=0·12). The 42-day PCR corrected efficacy of dihydroartemisinin–piperaquine plus mefloquine (96% [68 of 71; 95% CI 88 to 99]) was non-inferior to that of artesunate–mefloquine (95% [69 of 73; 95% CI 87 to 99]) in three sites in Cambodia (risk difference 1%; 95% CI −6 to 8; p=1·00). The overall 42-day PCR-corrected efficacy of artemether–lumefantrine plus amodiaquine (98% [281 of 286; 95% CI 97 to 99]) was similar to that of artemether–lumefantrine (97% [279 of 289; 95% CI 94 to 98]; risk difference 2%, 95% CI −1 to 4; p=0·30). Both TACTs were well tolerated, although early vomiting (within 1 h) was more frequent after dihydroartemisinin–piperaquine plus mefloquine (30 [3·8%] of 794) than after dihydroartemisinin–piperaquine (eight [1·5%] of 543; p=0·012). Vomiting after artemether–lumefantrine plus amodiaquine (22 [1·3%] of 1703) and artemether–lumefantrine (11 [0·6%] of 1721) was infrequent. Adding amodiaquine to artemether–lumefantrine extended the electrocardiogram corrected QT interval (mean increase at 52 h compared with baseline of 8·8 ms [SD 18·6] vs 0·9 ms [16·1]; p<0·01) but adding mefloquine to dihydroartemisinin–piperaquine did not (mean increase of 22·1 ms [SD 19·2] for dihydroartemisinin–piperaquine vs 20·8 ms [SD 17·8] for dihydroartemisinin–piperaquine plus mefloquine; p=0·50). Dihydroartemisinin–piperaquine plus mefloquine and artemether–lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance. UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.