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。青蒿素为主的联合疗法(ACTs) 是疟疾的主要治疗药物，并将一种有效的短效青蒿素与一种长效伙伴相结合 毒品。ACTs迅速清除初始感染，同时提供治疗后防护期，减少 有再次感染的风险。在东南亚，青蒿素及其伴侣的耐药性大幅下降。 功效。在撒哈拉以南非洲，青蒿素耐药性尚未广泛确立，蒿甲醚-- Lumefantrine(AL)是最广泛使用的ACT。撒哈拉以南非洲的治疗面临的一个挑战是 疟疾和人类免疫缺陷病毒(艾滋病毒)感染的大量重叠。儿童发展和 抗逆转录病毒治疗显著改变AL暴露，这可能显著影响治疗结果和 有助于耐药选择。因此，我们进行了一项随机临床试验以评估其安全性。 以及5天(10剂量)与标准3天(6剂量)AL在改善药物暴露和治疗方面的有效性 对生活在乌干达高流行地区的艾滋病毒携带者和非艾滋病毒儿童的疗效。的潜在劣势 ACT方案是ACT成分半衰期的固有不匹配，导致延长的 亚治疗性鲁米芬“单一疗法”治疗后。在家长试验中，超过70%的儿童 在AL最初治疗的6周内出现反复出现的镜检可检测到的寄生虫血症。近期 使用更新的更灵敏的分子方法的研究发现了持续的亚显微寄生虫病 AL治疗后最多14天。因此，尽管增加AL暴露可能会提高疗效，但我们的 了解伙伴药物暴露、寄生虫动态和耐药选择之间的相互作用 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。治疗后的高新感染率 我们的研究为全面研究寄生虫在儿童中的动态及其影响提供了机会 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学研究在一个 随机临床试验，我建议评估持续寄生虫检测与治疗的关系 AL治疗后的结果、传播动力学和耐药性。我将进一步描述这一影响 对亚治疗伙伴药物水平的选择进行耐药。详细的寄生虫的组合 到目前为止，还没有进行菌株动力学、药物药代动力学和耐药性分析。我的 最重要的假设是，对药物暴露和寄生虫的影响有更详细的了解 耐药性选择的动态将使目前和未来的抗疟疾方案得到优化。 这项奖学金将为我提供分子生物学方面的高级实验和统计学背景。 和药理学，并将进一步发展为一名内科科学家，职业生涯在最前线 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.