High-resolution malaria parasite and drug dynamics in the context of antimalarial treatment and drug resistance selection

疟疾是全球发病率和死亡率的主要原因。基于青蒿素的联合疗法（ACT） 是疟疾的主要治疗方法，联合收割机将强效短效青蒿素与长效伙伴结合在一起 药ACTs可迅速清除初始感染，同时提供治疗后预防期， 再次感染的风险。在东南亚，青蒿素及其伙伴药物耐药性大幅降低了ACT 功效在撒哈拉以南非洲，青蒿素耐药性尚未广泛建立，蒿甲醚- 本芴醇（AL）是最广泛处方的ACT。撒哈拉以南非洲治疗的一个挑战是 疟疾和人体免疫缺陷病毒（艾滋病毒）感染大量重叠。儿童发展和 抗逆转录病毒治疗可显著改变AL暴露，这可显著影响治疗结果， 有助于抗药性的选择。因此，我们进行了一项随机临床试验，以评估安全性 和5天（10剂）与标准3天（6剂）AL相比改善药物暴露和治疗的疗效 在乌干达艾滋病高发地区的艾滋病毒感染和未感染儿童中的疗效。的潜在缺点 ACT方案是ACT组分半衰期的固有不匹配，导致ACT治疗持续时间延长。 治疗后亚治疗性本芴醇“单一疗法”。在父母试验中，超过70%的孩子 在AL初始治疗6周内出现复发性显微镜可检测到的寄生虫血症。 使用更新更敏感的分子方法的研究已经检测到持续的亚显微寄生虫血症 治疗后14天。因此，虽然增加AL暴露可能会提高疗效，但我们的研究结果表明， 了解伴侣药物暴露，寄生虫动态和高耐药选择的相互作用， 缺乏多克隆感染的传播环境。疟疾发病机制和ACT药物暴露是 进一步受到艾滋病毒感染和抗逆转录病毒治疗的影响。治疗后新感染率高 我们的研究提供了全面研究儿童寄生虫动态的机会， 艾滋病毒感染对这些动态的影响。使用最先进的分子和遗传研究， 通过一项随机临床试验，我建议评估持续寄生虫检测与治疗的关系 结果、传播动力学和AL治疗后的耐药性。我将进一步描述 亚治疗水平的伴侣药物对耐药性的选择。详细的寄生虫 菌株动力学、药物药代动力学和耐药性分析至今尚未进行。我 总体假设是，更详细地了解药物暴露和寄生虫的影响， 抗药性选择的动态将使目前和今后的抗疟治疗方案得以优化。 这个奖学金将为我提供一个先进的实验和分子生物学的统计背景 和药理学，并将进一步发展我作为一个医生，科学家与职业生涯的最前沿， 在全球卫生背景下的传染病治疗和预防。

Malaria is a leading cause of morbidity and mortality globally. Artemisinin-based combination therapies (ACTs) are the primary treatment for malaria and combine a potent short-acting artemisinin with a longer-acting partner drug. ACTs rapidly clear the initial infection while providing a post-treatment prophylactic period that reduces the risk of reinfection. In Southeast Asia, artemisinin and partner drug resistance has dramatically decreased ACT efficacy. In sub-Saharan Africa, where artemisinin resistance has not been widely established, artemether- lumefantrine (AL) is the most widely prescribed ACT. A challenge to treatment in sub-Saharan Africa is the substantial overlap of malaria and human immunodeficiency virus (HIV) infections. Child development and antiretroviral therapy significantly alter AL exposure, which can significantly impact treatment outcomes and contribute to drug resistance selection. Therefore, we conducted a randomized clinical trial to evaluate the safety and efficacy of 5-day (10-dose) versus standard 3-day (6-dose) AL to improve drug exposure and therapeutic efficacy in children with and without HIV living in a high endemic region of Uganda. A potential disadvantage of ACT regimens is the inherent mismatch in ACT component half-lives, resulting in an extended period of subtherapeutic lumefantrine “monotherapy” following treatment. In the parent trial, over 70% of children developed recurrent microscopically detectable parasitemia within 6 weeks of initial treatment with AL. Recent studies using newer more sensitive molecular approaches have detected persistent submicroscopic parasitemia up to 14 days after AL treatment. Thus, although increasing AL exposure may improve efficacy, our understanding of the interplay of partner drug exposure, parasite dynamics, and drug resistance selection in high transmission settings with multiclonal infections is lacking. Malaria pathogenesis and ACT drug exposure are further influenced by HIV infection and antiretroviral therapy. The high rate of new infections following treatment in our study provides the opportunity to comprehensively study parasite dynamics in children, and the impact that HIV infection has on those dynamics. Using state of the art molecular and genetic studies conducted in a randomized clinical trial, I propose to assess the relationship of persistent parasite detection to treatment outcomes, transmission dynamics, and drug resistance after AL treatment. I will further characterize the influence of sub-therapeutic partner drug levels on the selection of drug resistance. The combination of detailed parasite strain dynamics, drug pharmacokinetics, and drug resistance analysis has not been conducted to date. My overarching hypothesis is that a more detailed understanding of the influence of drug exposure and parasite dynamics on drug resistance selection will enable the optimization of current and future antimalarial regimens. This fellowship will provide me with an advanced experimental and statistical background in molecular biology and pharmacology, and will further my development as a physician-scientist with a career at the forefront of infectious disease treatment and prevention in a global health context.