Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study.
Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study.
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柬埔寨恶性疟原虫疟疾中的双氢青蒿素-哌喹抗药性：一项多地点前瞻性队列研究。
DOI：
10.1016/s1473-3099(15)00487-9
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
Fairhurst RM
中科院分区：
文献类型：
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作者：
Amaratunga C;Lim P;Suon S;Sreng S;Mao S;Sopha C;Sam B;Dek D;Try V;Amato R;Blessborn D;Song L;Tullo GS;Fay MP;Anderson JM;Tarning J;Fairhurst RM
恶性疟原虫对青蒿素的抗药性有可能降低青蒿素综合疗法的疗效，从而损害全球消除疟疾的努力。柬埔寨目前的一线青蒿素综合疗法-双氢青蒿素-哌喹最近的治疗失败表明，该国可能正在出现哌喹耐药性。我们探讨了青蒿素耐药性和双氢青蒿素-哌喹治疗失败之间的关系，并试图确认柬埔寨存在哌喹耐药性恶性疟原虫感染。在这项前瞻性队列研究中，我们招募了柬埔寨三个省（菩萨、柏威夏和腊塔纳基里）2-65岁的无并发症恶性疟原虫疟疾患者。参与者被给予标准的3天疗程的双氢青蒿素-哌喹。测量外周血寄生虫密度，直到寄生虫清除，然后每周一次，直至63天。主要结局为63天内复发恶性疟原虫寄生虫血症。我们测量了基线、第7天和复发当天的哌喹血浆浓度。我们评估了寄生虫分离株耐药性的表型和基因型标记。该研究在ClinicalTrials.gov注册，编号NCT 01736319。在2012年9月4日至2013年12月31日期间，我们招募了241名参与者。在青蒿素耐药性根深蒂固的Pursat，81名患者中有37名（46%）寄生虫复发。在出现青蒿素耐药性的柏威夏，63名患者中有10人（16%）复发，在青蒿素耐药性罕见的腊塔纳基里，60名患者中有1人（2%）复发。与非复发患者相比，复发恶性疟原虫感染患者更可能在基线时检测到哌喹血浆浓度，但在年龄、初始寄生虫密度或7天哌喹血浆浓度方面无显著差异。复发的寄生虫有较高的kelch 13突变的患病率，较高的哌喹50%抑制浓度（IC 50）值，和较低的甲氟喹IC 50值;没有多个pfmdr 1拷贝，甲氟喹耐药的遗传标记。双氢青蒿素-哌喹失效是由青蒿素和哌喹耐药性引起的，通常发生在私营部门使用双氢青蒿素-哌喹的地方。在柬埔寨，青蒿琥酯加甲氟喹可能是治疗双氢青蒿素-哌喹失效的可行选择，在双氢青蒿素-哌喹失效常见的地区，青蒿琥酯加甲氟喹可能是更有效的一线青蒿素综合疗法。在青蒿素和青蒿素综合疗法耐药性普遍的地区，需要使用单次低剂量伯氨喹消除循环中的配子体。国家过敏和传染病研究所。
Artemisinin resistance in Plasmodium falciparum threatens to reduce the efficacy of artemisinin combination therapies (ACTs), thus compromising global efforts to eliminate malaria. Recent treatment failures with dihydroartemisinin-piperaquine, the current first-line ACT in Cambodia, suggest that piperaquine resistance may be emerging in this country. We explored the relation between artemisinin resistance and dihydroartemisinin–piperaquine failures, and sought to confirm the presence of piperaquine-resistant P falciparum infections in Cambodia. In this prospective cohort study, we enrolled patients aged 2–65 years with uncomplicated P falciparum malaria in three Cambodian provinces: Pursat, Preah Vihear, and Ratanakiri. Participants were given standard 3-day courses of dihydroartemisinin–piperaquine. Peripheral blood parasite densities were measured until parasites cleared and then weekly to 63 days. The primary outcome was recrudescent P falciparum parasitaemia within 63 days. We measured piperaquine plasma concentrations at baseline, 7 days, and day of recrudescence. We assessed phenotypic and genotypic markers of drug resistance in parasite isolates. The study is registered with ClinicalTrials.gov, number NCT01736319. Between Sept 4, 2012, and Dec 31, 2013, we enrolled 241 participants. In Pursat, where artemisinin resistance is entrenched, 37 (46%) of 81 patients had parasite recrudescence. In Preah Vihear, where artemisinin resistance is emerging, ten (16%) of 63 patients had recrudescence and in Ratanakiri, where artemisinin resistance is rare, one (2%) of 60 patients did. Patients with recrudescent P falciparum infections were more likely to have detectable piperaquine plasma concentrations at baseline compared with non-recrudescent patients, but did not differ significantly in age, initial parasite density, or piperaquine plasma concentrations at 7 days. Recrudescent parasites had a higher prevalence of kelch13 mutations, higher piperaquine 50% inhibitory concentration (IC50) values, and lower mefloquine IC50 values; none had multiple pfmdr1 copies, a genetic marker of mefloquine resistance. Dihydroartemisinin–piperaquine failures are caused by both artemisinin and piperaquine resistance, and commonly occur in places where dihydroartemisinin–piperaquine has been used in the private sector. In Cambodia, artesunate plus mefloquine may be a viable option to treat dihydroartemisinin–piperaquine failures, and a more effective first-line ACT in areas where dihydroartemisinin–piperaquine failures are common. The use of single low-dose primaquine to eliminate circulating gametocytes is needed in areas where artemisinin and ACT resistance is prevalent. National Institute of Allergy and Infectious Diseases.