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

抗疟治疗和耐药性选择背景下的高分辨率疟疾寄生虫和药物动力学

基本信息

批准号：
10484397
负责人：
Justin Goodwin
金额：
$ 3.09万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10484397
关键词：
Adolescent Africa Africa South of the Sahara Aftercare Anti-Retroviral Agents Antimalarials Artemisinins Biological Assay Bite Blood Cessation of life Child Child Development Clinical Combination Drug Therapy Combined Modality Therapy Coupled Data Detection Development Disadvantaged Doctor of Philosophy Dose Drug Exposure Drug Kinetics Drug resistance Early Diagnosis Equilibrium Fellowship Future Genetic study Genotype Goals HIV HIV Infections HIV antiretroviral Haplotypes Health Individual Infection Intervention Investigation Liver Malaria Measures Microsatellite Repeats Microscopic Microscopy Molecular Molecular Biology Molecular Genetics Monitor Morbidity - disease rate Mutation Nature Parasite resistance Parasitemia Parasites Parents Pathogenesis Pharmaceutical Preparations Pharmacodynamics Pharmacology Physicians Population Predisposition Pregnant Women Prevention Prophylactic treatment RNA Randomized Randomized Clinical Trials Recurrence Regimen Relapse Research Residual state Resistance Resolution Risk Safety Sampling Scientist Southeastern Asia Techniques Therapeutic Training Treatment Efficacy Treatment Protocols Treatment outcome Uganda Ursidae Family Virus Diseases antiretroviral therapy artemether asexual base benflumetol career co-infection deep sequencing density design drug-sensitive efavirenz follow-up global health improved in vivo infectious disease treatment mortality pharmacodynamic model recurrent infection therapy resistant transmission process treatment optimization

项目摘要

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.

疟疾是全球发病率和死亡率的主要原因。是疟疾的主要治疗方法，将有效的短效青蒿素与长效伙伴相结合 ACT 药物可快速清除初始感染，同时提供治疗后预防期，从而减少感染。在东南亚，青蒿素及其伙伴的耐药性显着降低了 ACT。在撒哈拉以南非洲地区，青蒿素耐药性尚未广泛确立，蒿甲醚- lumefantrine (AL) 是撒哈拉以南非洲地区最广泛使用的 ACT 治疗面临的挑战。疟疾和人类免疫缺陷病毒（HIV）感染有很大重叠。抗逆转录病毒治疗显着改变 AL 暴露，从而显着影响治疗结果和因此，我们进行了一项随机临床试验来评估安全性。 5 天（10 剂量）与标准 3 天（6 剂量）AL 改善药物暴露和治疗效果的比较对生活在乌干达高流行地区的感染和未感染艾滋病毒的儿童的疗效潜在的缺点。 ACT 方案是 ACT 成分半衰期固有的不匹配，导致治疗时间延长在家长试验中，超过 70% 的儿童接受治疗后使用苯芴醇“单一疗法”。 AL 最近初始治疗后 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、更灵敏的分子方法的研究已检测到持续的亚显微寄生虫血症 AL 治疗后最多 14 天，因此，尽管增加 AL 暴露可能会提高疗效，但我们的研究结果显示，了解伙伴药物暴露、寄生虫动力学和高耐药性选择之间的相互作用缺乏多克隆感染的传播环境和疟疾发病机制和 ACT 药物暴露。进一步受到艾滋病毒感染和抗逆转录病毒治疗的影响，治疗后新发感染率很高。我们的研究提供了全面研究儿童寄生虫动态及其影响的机会使用最先进的分子和遗传学研究来了解艾滋病毒感染对这些动态的影响。随机临床试验，我建议评估持续性寄生虫检测与治疗的关系 AL 治疗后的结果、传播动态和耐药性我将进一步描述其影响。亚治疗伙伴药物水平对耐药性选择的影响详细寄生虫的组合。迄今为止尚未进行菌株动力学、药物药代动力学和耐药性分析。总体假设是，更详细地了解药物暴露和寄生虫的影响耐药性选择的动态变化将有助于优化当前和未来的抗疟方案。该奖学金将为我提供分子生物学方面的高级实验和统计背景和药理学，并将进一步促进我作为一名医学科学家的发展，并在职业生涯的最前沿全球卫生背景下的传染病治疗和预防。