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

项目摘要 尽管青蒿素联合疗法(ACTs)是治疗糖尿病最重要的药物 简单疟疾的治疗，基本问题尚未得到回答，包括哪些 药物选择和剂量最适合感染艾滋病毒和未感染艾滋病毒的儿童。在我们的第一笔资金中 周期，我们集中在蒿甲醚-鲁米芬作为乌干达最常用的处方药 并产生了显著的结果，显示了鲁米芬的药代动力学(PK)暴露， 对于预防新感染最重要的化合物，其范围可达10倍，具体取决于 艾滋病毒感染儿童正在接受的艾滋病毒抗逆转录病毒(ART)治疗。同样，青蒿素也是 也受到了影响，基于efavirenz的抗逆转录病毒药物显著降低了青蒿素和 卢米芬特灵。不同艺术的对比效果导致了显著的差异 疟疾的临床结果。此外，我们研究了未感染艾滋病毒的儿童，了解到 体重不足的儿童也容易受到重要的PK和药效学(PD， 暴露-反应)区别。对于我们的复兴，我们将专注于三个目标。首先，我们会 艾滋病病毒感染者延长剂量蒿甲醚-鲁米芬方案的PK/PD测定 儿童服用基于efavirenz的ART，旨在改善PK暴露和治疗 这种ACT方案的疗效。第二，我们将扩大我们的研究范围，首次调查， 另一种一线ACT双氢青蒿素-哌喹在艾滋病毒感染儿童中的PK，世卫组织 都在一线艺术上。第三，我们将确定具体分类的影响 营养不良对蒿甲醚-鲁米芬和双氢青蒿素-哌喹PK/PD的影响 未感染艾滋病毒的幼儿，并直接比较体重不足或发育迟缓的儿童 (乌干达最常见的两种营养不良形式)对生长指数正常的儿童。 我们的首要目标仍然是为幼儿提供最佳治疗指南。 在非洲。感染艾滋病毒和未感染艾滋病毒的儿童将参加密集的PK学习，因为 以及用于人口PK研究的额外儿童，以加强与 临床结果。至于我们的第一个融资周期，这项提议将利用尚未偿还的 乌干达托罗罗提供的基础设施，将受益于高度互补性的 Aweka博士和Parikh博士的专业知识，他们将继续担任联合PI。

Project Abstract Although the artemisinin-combination therapies (ACTs) are the most important drugs for the treatment of uncomplicated malaria, fundamental questions are unanswered including which ACT choice and dose is best for HIV-infected and HIV-uninfected children. In our first funding cycle we focused on artemether-lumefantrine as the most commonly prescribed ACT in Uganda and generated striking results that showed the pharmacokinetic (PK) exposure of lumefantrine, the compound most important for preventing new infections, can range by 10-fold depending on which HIV antiretroviral (ART) an HIV-infected child is receiving. Likewise, the artemisinins were also impacted, with efavirenz-based ART dramatically reducing both the artemisinins and lumefantrine. The contrasting effects seen with various ART led to significant differences in malaria clinical outcomes. Moreover, we studied HIV-uninfected children and learned that underweight children are also susceptible to important PK and pharmacodynamic (PD, exposure-response) distinctions. For our renewal we will focus on three aims. First we will determine the PK/PD of an extended artemether-lumefantrine dosing regimen in HIV-infected children on efavirenz-based ART that is designed to improve the PK exposure and treatment efficacy of this ACT regimen. Second, we will extend our studies to investigate, for the first time, the PK of another first line ACT, dihydroartemisinin-piperaquine, in HIV-infected children, who are on first-line ART. Third, we will determine the impact of specific classifications of malnutrition on the PK/PD of artemether-lumefantrine and dihydroartemisinin-piperaquine in HIV-uninfected young children and directly compare children who are underweight or stunted (the two most common forms of malnutrition in Uganda) to children with normal growth indices. Our overarching goal continues to be to inform the best treatment guidelines for young children in Africa. HIV-infected and HIV-uninfected children will be enrolled for intensive PK studies, as well as additional children for population PK studies to enhance association analyses with clinical outcomes. As for our first funding cycle, this proposal will leverage the outstanding infrastructure available in Tororo, Uganda and will benefit from the highly complementary expertise of Drs. Aweeka and Parikh who will continue to serve as joint-PIs.