Infectious Diseases Research Collaboration, Kampala, Uganda.
Department of Medicine, Stanford University, Stanford, CA, USA.
Lancet Infect Dis. 2019 Sep;19(9):962-972. doi: 10.1016/S1473-3099(19)30299-3. Epub 2019 Jul 12.
Intermittent preventive treatment (IPT) of malaria with dihydroartemisinin-piperaquine is a promising strategy for malaria prevention in young African children. However, the optimal dosing strategy is unclear and conflicting evidence exists regarding the risk of malaria after cessation of chemoprevention. We aimed to compare two dosing strategies of IPT with dihydroartemisinin-piperaquine in young Ugandan children, and to evaluate the risk of malaria after cessation of IPT.
In this double-blind, randomised controlled phase 2 trial, women and their unborn children were recruited at Tororo District Hospital (Tororo, Uganda). Eligible participants were HIV-negative women aged 16 years or older with a viable pregnancy (gestational age 12-20 weeks). Women and their unborn children were randomly assigned (1:1:1:1) to one of four treatment groups, all receiving dihydroartemisinin-piperaquine, on the basis of the IPT intervention received by the woman during pregnancy: women every 8 weeks, children every 4 weeks; women every 4 weeks, children every 4 weeks; women every 8 weeks, children every 12 weeks; and women every 4 weeks, children every 12 weeks. Block randomisation was done by an independent investigator using a computer-generated randomisation list (permuted block sizes of six and 12). We analysed children on the basis of their random assignment to receive dihydroartemisinin-piperaquine (20 mg/160 mg tablets) once daily for 3 consecutive days every 4 weeks or 12 weeks. Children received study drugs from age 8 weeks to 24 months and were followed-up to age 36 months. Participants and investigators were masked to treatment allocation. The primary outcome was the incidence of symptomatic malaria during the intervention and following cessation of the intervention, adjusted for potential confounders. The primary outcome and safety were assessed in the modified intention-to-treat population, which included all children who reached 8 weeks of age and received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02163447.
Between Oct 21, 2014, and May 18, 2015, 191 children were born, of whom 183 reached 8 weeks of age and received at least one dose of study drug and thus were included in the primary analysis (96 children in the 4-week group and 87 in the 12-week group). During the intervention, the incidence of symptomatic malaria was significantly lower among children treated every 4 weeks than children treated every 12 weeks; three episodes occurred among children treated every 4 weeks (incidence 0·018 episodes per person-year) compared with 61 episodes among children treated every 12 weeks (incidence 0·39 episodes per person-year; adjusted incidence rate ratio [aIRR] 0·041, 95% CI 0·012-0·150, p<0·0001). After cessation of IPT, children who had previously received dihydroartemisinin-piperaquine every 4 weeks had a lower incidence of symptomatic malaria than children who were treated every 12 weeks; 62 episodes occurred among children previously treated every 4 weeks (incidence 0·73 episodes per person-year) compared with 83 episodes among children treated every 12 weeks (incidence 1·1 episodes per person-year; aIRR 0·62, 0·40-0·95, p=0·028). In the 4-week group, 94 (98%) of 96 children had adverse events versus 87 (100%) of 87 children in the 12-week group. The most commonly reported adverse event was cough in both treatment groups (94 [98%] in the 4-week group vs 87 [100%] in the 12-week group). 16 children had severe adverse events (seven [7%] children in the 4-week group vs nine [10%] children in the 12-week group). No severe adverse events were thought to be related to study drug administration. One death occurred during the intervention (age 8 weeks to 24 months), which was due to respiratory failure unrelated to malaria.
IPT with dihydroartemisinin-piperaquine given every 4 weeks was superior to treatment every 12 weeks for the prevention of malaria during childhood, and this protection was extended for up to 1 year after cessation of IPT.
Eunice Kennedy Shriver National Institute of Child Health and Human Development.
二氢青蒿素哌喹间歇性预防治疗（IPT）是预防年轻非洲儿童疟疾的一种很有前景的策略。然而，最佳的给药策略尚不清楚，并且在停止化学预防后疟疾的风险存在矛盾的证据。我们旨在比较两种二氢青蒿素哌喹 IPT 给药策略在年轻乌干达儿童中的效果，并评估停止 IPT 后疟疾的风险。
这是一项在托罗罗区医院（托罗罗，乌干达）进行的双盲、随机对照 2 期试验。招募了 HIV 阴性、年龄在 16 岁及以上、有存活妊娠（妊娠 12-20 周）的妇女及其未出生的孩子。根据妇女在怀孕期间接受的 IPT 干预措施，将符合条件的参与者随机分为四组中的一组：每 8 周一次的妇女，每 4 周一次的儿童；每 4 周一次的妇女，每 4 周一次的儿童；每 8 周一次的妇女，每 12 周一次的儿童；每 4 周一次的妇女，每 12 周一次的儿童。通过独立调查员使用计算机生成的随机分组列表（大小为 6 和 12 的随机分组）进行分层随机分组。我们根据他们接受二氢青蒿素哌喹（20mg/160mg 片剂）连续 3 天每天一次、每 4 周或 12 周的方案进行分析。儿童从 8 周龄开始接受研究药物治疗，直到 24 个月龄，并随访至 36 个月龄。参与者和调查员对治疗分配情况进行了屏蔽。主要结局是干预期间和停止干预后出现有症状疟疾的发生率，调整了潜在混杂因素。主要结局和安全性在包括所有达到 8 周龄并接受至少一剂研究药物的儿童的改良意向治疗人群中进行了评估。该试验在 ClinicalTrials.gov 注册，编号为 NCT02163447。
2014 年 10 月 21 日至 2015 年 5 月 18 日期间，共有 191 名儿童出生，其中 183 名达到 8 周龄并接受了至少一剂研究药物，因此纳入了主要分析（4 周组 96 名儿童，12 周组 87 名儿童）。在干预期间，每 4 周治疗的儿童与每 12 周治疗的儿童相比，出现有症状疟疾的发生率显著降低；每 4 周治疗的儿童中有 3 例（发病率为 0.018 例/人年），而每 12 周治疗的儿童中有 61 例（发病率为 0.39 例/人年；调整发病率比 [aIRR] 0.041，95%CI 0.012-0.150，p<0.0001）。停止 IPT 后，以前每 4 周接受二氢青蒿素哌喹治疗的儿童与以前每 12 周接受治疗的儿童相比，出现有症状疟疾的发生率较低；以前每 4 周治疗的儿童中有 62 例（发病率为 0.73 例/人年），而以前每 12 周治疗的儿童中有 83 例（发病率为 1.1 例/人年；aIRR 0.62，0.40-0.95，p=0.028）。在 4 周组中，94 名（98%）96 名儿童发生不良事件，而 12 周组中 87 名（100%）儿童发生不良事件。最常见的不良事件是两组均有咳嗽（4 周组 94 例[98%]，12 周组 87 例[100%]）。16 名儿童发生严重不良事件（4 周组 7 例[7%]，12 周组 9 例[10%]）。没有严重的不良事件被认为与研究药物的管理有关。1 例死亡发生在干预期间（8 周龄至 24 个月龄），与疟疾无关的呼吸衰竭有关。
每 4 周给予二氢青蒿素哌喹 IPT 优于每 12 周治疗儿童疟疾，并且这种保护作用可延长至停止 IPT 后 1 年。
美国国立卫生研究院儿童健康与人类发育研究所。
