Department of Clinical Pharmacy, University of California, San Francisco, San Francisco, CA, USA.
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
Nat Commun. 2021 Nov 18;12(1):6714. doi: 10.1038/s41467-021-27051-8.
Intermittent preventive treatment (IPT) with dihydroartemisinin-piperaquine (DP) is highly protective against malaria in children, but is not standard in malaria-endemic countries. Optimal DP dosing regimens will maximize efficacy and reduce toxicity and resistance selection. We analyze piperaquine (PPQ) concentrations (n = 4573), malaria incidence data (n = 326), and P. falciparum drug resistance markers from a trial of children randomized to IPT with DP every 12 weeks (n = 184) or every 4 weeks (n = 96) from 2 to 24 months of age (NCT02163447). We use nonlinear mixed effects modeling to establish malaria protective PPQ levels and risk factors for suboptimal protection. Compared to DP every 12 weeks, DP every 4 weeks is associated with 95% protective efficacy (95% CI: 84-99%). A PPQ level of 15.4 ng/mL reduces the malaria hazard by 95%. Malnutrition reduces PPQ exposure. In simulations, we show that DP every 4 weeks is optimal across a range of transmission intensities, and age-based dosing improves malaria protection in young or malnourished children.
间歇性预防治疗（IPT）使用双氢青蒿素-哌喹（DP）对儿童疟疾具有高度保护作用，但在疟疾流行国家并非标准治疗方法。最佳 DP 剂量方案将最大限度地提高疗效，降低毒性和耐药性选择风险。我们分析了来自一项试验的数据，该试验将儿童随机分为每 12 周（n=184）或每 4 周（n=96）接受 IPT 治疗的 DP 方案，随访时间为 2 至 24 个月（NCT02163447）。结果共纳入了 4573 名儿童的哌喹（PPQ）浓度（n=4573）、疟疾发病率数据（n=326）和恶性疟原虫耐药标志物。我们使用非线性混合效应模型确定疟疾保护性 PPQ 水平和保护效果不理想的风险因素。与每 12 周 DP 相比，每 4 周 DP 相关的疟疾保护率为 95%（95%CI：84-99%）。PPQ 水平为 15.4ng/mL 可将疟疾风险降低 95%。营养不良会降低 PPQ 暴露水平。在模拟中，我们发现 DP 每 4 周的方案在不同传播强度下均为最佳方案，且基于年龄的剂量方案可提高年轻或营养不良儿童的疟疾保护效果。
