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

项目摘要 虽然青蒿素联合疗法（ACT）是最重要的药物， 治疗无并发症的疟疾，基本问题是没有答案的，包括 ACT的选择和剂量最适合艾滋病毒感染和未感染艾滋病毒的儿童。在我们的第一笔资金中 在一个周期中，我们将蒿甲醚-苯芴醇作为乌干达最常用的ACT处方药 并产生了惊人的结果，显示本芴醇的药代动力学（PK）暴露， 对于预防新感染最重要的化合物，根据不同的情况， 艾滋病毒感染儿童正在接受的艾滋病毒抗逆转录病毒治疗。同样，青蒿素也是 也受到影响，以依法韦仑为基础的ART大大减少了青蒿素和 苯芴醇各种ART所观察到的对比效果导致了在以下方面的显着差异 疟疾临床结果。此外，我们研究了未感染艾滋病毒的儿童，并了解到， 体重不足的儿童也易受重要的PK和药效学（PD， 区分）。对于我们的更新，我们将专注于三个目标。首先我们将 确定HIV感染者中延长的蒿甲醚-苯芴醇给药方案的PK/PD 儿童接受以依法韦仑为基础的ART，旨在改善PK暴露和治疗 ACT方案的有效性。第二，我们将扩大我们的研究，首次调查， 另一种一线ACT双氢青蒿素-哌喹在HIV感染儿童中的PK， 第三，我们将确定特定分类的影响， 营养不良对蒿甲醚-本芴醇和双氢青蒿素-哌喹PK/PD的影响 未感染艾滋病毒的幼儿和直接比较体重不足或发育不良的儿童 (the乌干达最常见的两种形式的营养不良）的儿童与正常生长指数。 我们的首要目标仍然是为幼儿提供最佳治疗指南 在非洲将入组HIV感染和未感染HIV的儿童进行密集PK研究， 以及用于群体PK研究的其他儿童，以加强与以下疾病的相关性分析 临床结果。至于我们的第一个供资周期，这项建议将利用未偿还的 乌干达托罗罗现有的基础设施，并将受益于高度互补的 Aweeka博士和Parikh博士将继续担任联合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.