Andagalu Ben, Smith Edward, Durand Salomon, Valdivia Hugo O, Onyango Irene, Spring Michele, Pattaraporn Vanachayangkul, Baldeviano G Christian, Majid Elazia, Sriwichai Sabaithip, Cummings James, Tapia Lorena, Akala Hosea, Gosi Panita, Cabezas Cesar, Juma Dennis, Wongararunkochakorn Saowaluk, Sihuincha Moises, Chaisatit Chaiyaporn, Chebon-Bore Lorna, Kuntawunginn Worachet, Halbach Alaina, Kodchakorn Chanikarn, Thamnurak Chatchadaporn, Praditpol Chantida, Saingam Piyaporn, Edgel Kimberly A, Saunders David, Cheruiyot Agnes, Chuang Ilin, Milgotina Ekaterina, Fernandes Paula, Lescano Andres G, Boonyalai Nonlawat, Kamau Edwin, Forshey Brett M, Cinkovich Stephanie, Bethell Delia, Jongsakul Krisada, Fukuda Mark
U.S. Army Medical Research Directorate-Africa, Nairobi, Kenya.
Universidad Peruana Cayetano Heredia, Lima, Peru.
Int J Infect Dis. 2025 Jul 2;159:107971. doi: 10.1016/j.ijid.2025.107971.
Artemisinin-resistant Plasmodium falciparum challenges the effectiveness of all artemisinin-based combination therapies.
We conducted a clinical study in Peru, Kenya, and Thailand between June 2013 and November 2015 in subjects treated with three standard doses of artesunate followed by two doses of mefloquine. The primary endpoint was parasite clearance half-life (PC) during the 72-hour period of treatment. Secondary endpoints included clinical outcome at 42 days, detection of kelch13 (K13) mutations, pharmacokinetics, and pharmacodynamics.
The mean PC was higher in the Thai (4.1 hours) than Peruvian (2 hours) or Kenyan cohorts (2.2 hours) (P <0.0001). Higher PC was partially explained by K13 mutations in 13 (28%) of 46 Thai subjects, including World Health Organization (WHO) validated and candidate mutations. Twelve (26%) Thai cohort subjects had PC ≥5 hours with parasites from nine subjects carrying K13 mutations. There was an overall 42-day cure rate of 100% across all subjects.
This is the first concurrent evaluation of artemisinin resistance across three continents. The presence of 11% Thai subjects who satisfied WHO criteria for drug resistance establishes this area as endemic. Longer PC found in wild-type and candidate K13 mutant infections within the Thai cohort require further investigation to identify alternative mechanisms of resistance.
对青蒿素耐药的恶性疟原虫对所有以青蒿素为基础的联合疗法的有效性构成挑战。
2013年6月至2015年11月期间，我们在秘鲁、肯尼亚和泰国开展了一项临床研究，研究对象接受三剂标准剂量的青蒿琥酯治疗，随后再接受两剂甲氟喹治疗。主要终点是治疗72小时期间的疟原虫清除半衰期（PC）。次要终点包括42天时的临床结局、kelch13（K13）突变检测、药代动力学和药效学。
泰国队列（4.1小时）的平均PC高于秘鲁队列（2小时）或肯尼亚队列（2.2小时）（P<0.0001）。46名泰国受试者中有13名（28%）的K13突变部分解释了较高的PC，包括世界卫生组织（WHO）验证的和候选突变。12名（26%）泰国队列受试者的PC≥5小时，其疟原虫来自9名携带K13突变的受试者。所有受试者的42天总体治愈率为100%。
这是首次在三大洲同时对青蒿素耐药性进行评估。11%的泰国受试者符合WHO耐药标准，这表明该地区为青蒿素耐药性流行区。在泰国队列的野生型和候选K13突变体感染中发现的较长PC需要进一步研究，以确定耐药的其他机制。
