Optimizing ACT use for African children in the setting of HIV and malnutrition

摘要 双氢青蒿素-哌喹(DP)是一种以青蒿素为基础的联合疗法，是最重要的药物之一。 用于治疗简单疟疾的药物，但确保其最佳效果的根本问题仍然存在 在我们最脆弱的人群，特别是儿童，以及在相互作用的抗逆转录病毒的背景下使用 治疗。多洛替格雷(DTG)，根据最新的艾滋病毒治疗指南，现在是艾滋病毒治疗的一线选择， 从未在伴随DP的环境中对儿童进行过研究，它对DP药代动力学的影响是 未知，而Lopinavir/ritonavir(LPV/r，另一种HIV治疗方法)已知可增加最大哌喹 但儿童心脏毒性的大小和相关风险仍不清楚。我们计划 扩大我们目前的拨款，使我们能够研究DTG和DP之间的潜在相互作用，以及更多 仔细和安全地评估LPV/r和DP之间的潜在有害相互作用。这项管理工作 补充剂正在请求支持，以允许将DTG作为将在 评估。具体地说，我们正在请求支持扩大对儿童的控制，以包括更广泛的 年龄范围，这是必要的年龄匹配的儿童谁管理的DTG。此外，本副刊 正在请求支持，以允许进行两个阶段的研究设计，使我们能够完成对 LPV/r/和DP之间可能的相互作用(即LPV/r预计会增加哌喹的浓度，从而 与QT间期延长有关)。这两个请求是在以下方面提供基础设施支持 乌干达。综上所述，我们的研究结果有可能显著影响治疗指南 通过这项关于DP在儿童中的药代动力学和药效学的决定性研究 这些抗逆转录病毒疗法的背景。我们的主要目标是提供优化的DP给药策略 孩子们。

Abstract Dihydroartemisinin-piperaquine (DP), an artemisinin-based combination therapy, is one of the most important drugs for the treatment of uncomplicated malaria, yet fundamental questions remain for assuring its optimal use in our most vulnerable populations, especially for children, and in the context of interacting antiretroviral therapies. Dolutegravir (DTG), now a first-line HIV treatment option per the updated HIV treatment guidelines, has never been studied in children in the setting of concomitant DP and its impact on DP pharmacokinetics is unknown, while lopinavir/ritonavir (LPV/r, another HIV treatment), is known to increase maximum piperaquine concentrations but the magnitude and associated risk of cardiotoxicity in children is still unclear. We plan to expand our current grant to allow us to study potential interactions between DTG and DP and to also more carefully, and safely, evaluate the potentially detrimental interaction between LPV/r and DP. This administrative supplement is requesting support to allow the study of DTG as one of three antiretrovirals that will be under evaluation. Specifically we are requesting support for the expansion of control children to include a broader age range which is necessary to age-match children who are managed on DTG. Additionally, this supplement is requesting support to permit a two phase study design that will allow us to complete a safe evaluation of the likely interaction between LPV/r / and DP (i.e. LPV/r is expected to increase piperaquine concentrations which has been associated with QTc prolongation). These two requests are to provide infrastructure support in Uganda. In summary, the results of our study has the potential to significantly impact treatment guidelines for HIV and malaria in children through this definitive study of pharmacokinetics and pharmacodynamics of DP in the setting of these antiretroviral therapies. Our overaching goal is to inform optimized DP dosing strategies for children.