Effectiveness and safety of high dose primaquine and tafenoquine in Plasmodium vivax patients (EFFORT)

Background Shorter courses of primaquine and single dose tafenoquine have potential to improve effectiveness in preventing recurrent Plasmodium vivax infection, but there are limited data on their comparative effectiveness when provided unsupervised. The aim of the study was to assess the effectiveness and safety of these new treatment options. Methods We conducted a multi-centre, open-label individually randomised controlled superiority trial in Ethiopia, Pakistan, Indonesia and Cambodia. Adult patients with uncomplicated P. vivax infection and glucose-6-phosphate dehydrogenase (G6PD) activity of 70% or greater were eligible for enrolment. Patients were treated with blood schizontocidal drugs (chloroquine in Ethiopia and Pakistan, dihydroartemisinin-piperaquine in Indonesia and artesunate-pyronaridine in Cambodia) and randomly assigned (1:1:1) to receive 7 days of unsupervised high-dose primaquine (total dose 7mg/kg), single dose tafenoquine (300mg) or 14 days low-dose primaquine (total dose 3.5mg/kg). Randomisation was stratified by site, by an independent statistician using randomly permuted blocks of varying sizes. The primary endpoint, assessed in a modified intention to treat population, was the cumulative incidence of any P. vivax parasitaemia within 6 months compared between the primaquine arms, secondary endpoints included comparison with the tafenoquine arm. The study was registered at ClinicalTrials.gov (NCT04411836). Findings Between April 2021 and September 2024, a total of 960 patients were enrolled in equal proportion (320 patients per arm). The cumulative incidence of P. vivax recurrence at 6 months was 13·0% (97.55% CI 9·0-18·5) in the 7-day-high-dose primaquine arm and 18·5% (97.55% CI 13·8-24·6) in the 14-day-low-dose primaquine arm (Hazard Ratio (HR) =0·66; 97.55% CI 0·40-1·09, p=0·063). The corresponding incidence in the tafenoquine arm was 12·6% (97.55% CI 8·8-18·0); HR=0·64 (97.55% CI 0·39-1·05, p=0·041) compared to the 14-day-low-dose primaquine arm. Of the adverse events occurring before day 42, 43% (24/56) were reported as drug related in the 7-day-high-dose primaquine arm, compared to 22% (16/72) in the tafenoquine arm and 34% (13/38) in the 14-day-low-dose primaquine arm. Two drug related serious adverse events occurred in the 7-day-high-dose primaquine arm. Interpretation Both unsupervised 7-day-high-dose primaquine and tafenoquine were well tolerated in G6PD normal patients and had a lower risk of P. vivax recurrence compared to 14-day-low-dose primaquine, albeit with uncertain magnitude. Our findings support the effectiveness and operational feasibility of shorter radical cure regimens across diverse malaria-endemic settings.

背景 短疗程伯氨喹（primaquine）与单剂量他非诺喹（tafenoquine）在预防间日疟原虫（Plasmodium vivax）复发感染方面具有提升疗效的潜力，但在非监督给药情况下，二者的对比有效性数据仍十分有限。本研究旨在评估上述新型治疗方案的有效性与安全性。
方法 本研究在埃塞俄比亚、巴基斯坦、印度尼西亚及柬埔寨开展一项多中心、开放标签个体随机对照优效性试验。纳入标准为确诊单纯性间日疟原虫感染且葡萄糖-6-磷酸脱氢酶（glucose-6-phosphate dehydrogenase, G6PD）活性≥70%的成年患者。所有受试者先接受血液裂殖体杀灭药（blood schizontocidal drugs）治疗：埃塞俄比亚与巴基斯坦组予氯喹（chloroquine），印度尼西亚组予双氢青蒿素哌喹（dihydroartemisinin-piperaquine），柬埔寨组予青蒿琥酯咯萘啶（artesunate-pyronaridine）；随后按1:1:1的比例随机分配至3组，分别接受7天非监督给药的高剂量伯氨喹（总剂量7mg/kg）、单剂量他非诺喹（300mg），或14天非监督给药的低剂量伯氨喹（总剂量3.5mg/kg）。随机分组由独立统计师采用可变长度随机区组设计按研究中心进行分层。本研究的主要终点为在改良意向治疗人群中评估6个月内任意间日疟原虫血症的累积发生率，并对比两个伯氨喹给药组的差异；次要终点则包括与他非诺喹组的疗效对比。本研究已在ClinicalTrials.gov注册（注册号：NCT04411836）。
结果 2021年4月至2024年9月期间，本研究共纳入960例受试者，各组分配比例均等（每组320例）。7天高剂量伯氨喹组6个月间日疟复发累积发生率为13.0%（97.5%置信区间：9.0~18.5），14天低剂量伯氨喹组为18.5%（97.5%置信区间：13.8~24.6），两组风险比（HR）为0.66（97.5%置信区间：0.40~1.09，P=0.063）。他非诺喹组的对应复发率为12.6%（97.5%置信区间：8.8~18.0），与14天低剂量伯氨喹组相比，HR为0.64（97.5%置信区间：0.39~1.05，P=0.041）。针对给药前42天发生的不良事件，7天高剂量伯氨喹组中有43%（24/56）被判定为药物相关不良事件，他非诺喹组为22%（16/72），14天低剂量伯氨喹组为34%（13/38）。7天高剂量伯氨喹组共发生2例药物相关严重不良事件。
解读 对于G6PD活性正常的患者，非监督给药的7天高剂量伯氨喹与单剂量他非诺喹均具有良好的耐受性，且与14天低剂量伯氨喹相比，二者的间日疟复发风险更低，尽管该差异的具体程度仍有待明确。本研究结果证实，短疗程根治方案在不同疟疾流行地区均具有有效性与临床可操作性。