Protective Efficacy and Safety of Three Antimalarial Regimens for the Prevention of Malaria in Young Ugandan Children: A Randomized Controlled Trial

BackgroundChemoprevention offers a promising strategy for prevention of malaria in African children. However, the optimal chemoprevention drug and dosing strategy is unclear in areas of year-round transmission and resistance to many antimalarial drugs. To compare three available regimens, we conducted an open-label randomized controlled trial of chemoprevention in Ugandan children.Methods and FindingsThis study was conducted between June 28, 2010, and September 25, 2013. 400 infants were enrolled and 393 randomized at 6 mo of age to no chemoprevention, monthly sulfadoxine-pyrimethamine (SP), daily trimethoprim-sulfamethoxazole (TS), or monthly dihydroartemisinin-piperaquine (DP). Study drugs were administered at home without supervision. Piperaquine (PQ) levels were used as a measure of compliance in the DP arm. Participants were given insecticide-treated bednets, and caregivers were encouraged to bring their child to a study clinic whenever they were ill. Chemoprevention was stopped at 24 mo of age, and participants followed-up an additional year. Primary outcome was the incidence of malaria during the intervention period. During the intervention, the incidence of malaria in the no chemoprevention arm was 6.95 episodes per person-year at risk. Protective efficacy was 58% (95% CI, 45%–67%, pp = 0.01) for TS, and 7% for SP (95% CI, −19% to 28%, p = 0.57). PQ levels were below the detection limit 52% of the time when malaria was diagnosed in the DP arm, suggesting non-adherence. There were no differences between the study arms in the incidence of serious adverse events during the intervention and the incidence of malaria during the 1-y period after the intervention was stopped.ConclusionsFor preventing malaria in children living in an area of high transmission intensity, monthly DP was the most efficacious and safe, although adherence may pose a problem. Monthly SP and daily TS may not be appropriate in areas with high transmission intensity and frequent resistance to antifolates.Trial registrationwww.ClinicalTrials.govNCT00948896Please see later in the article for the Editors' Summary研究背景 化学预防（chemoprevention）为非洲儿童疟疾预防提供了颇具前景的策略。然而，在全年存在疟疾传播且对多种抗疟药物产生耐药性的地区，最优的化学预防药物与给药方案仍不明确。为对比三种现有方案，我们在乌干达儿童中开展了一项开放标签随机对照化学预防试验。 研究方法与结果 本研究于2010年6月28日至2013年9月25日期间开展。共纳入400名婴儿，其中393名在6月龄时被随机分配至无化学预防组、每月磺胺多辛-乙胺嘧啶（sulfadoxine-pyrimethamine, SP）组、每日甲氧苄啶-磺胺甲恶唑（trimethoprim-sulfamethoxazole, TS）组，以及每月双氢青蒿素-哌喹（dihydroartemisinin-piperaquine, DP）组。研究药物于家中无监督下给药。在DP组中，以哌喹（piperaquine, PQ）血药浓度作为依从性的评估指标。所有受试者均获得经杀虫剂处理的蚊帐，并告知其监护人在儿童患病时及时带其前往研究诊所就诊。化学预防于受试者24月龄时终止，后续再对受试者进行为期1年的随访。本研究的主要结局为干预期间的疟疾发病率。 干预期间，无化学预防组的疟疾发病率为每人年6.95例。TS组的保护效力为58%（95%置信区间：45%~67%，pp = 0.01），SP组为7%（95%置信区间：-19%~28%，p = 0.57）。在DP组中，当确诊疟疾时，52%的样本哌喹血药浓度低于检测限，提示存在依从性不佳的情况。干预期间各组严重不良事件发生率，以及干预终止后1年随访期内的疟疾发病率均无显著差异。 研究结论 对于生活在高传播强度地区的儿童，每月DP方案在疟疾预防方面最为有效且安全，不过依从性或为潜在问题。在高传播强度且频繁出现抗叶酸类药物耐药的地区，每月SP方案与每日TS方案或并不适用。 试验注册：www.ClinicalTrials.gov NCT00948896。详见本文后续的编辑总结。