Delineating host, parasite and pharmacologic factors impacting the treatment of malaria in children with and without HIV

项目摘要 疟疾是撒哈拉以南非洲（SSA）全球发病率和死亡率的主要原因。青蒿素 联合疗法（ACT）将一种强效短效青蒿素和一种长效伙伴药物结合起来， 蒿甲醚-苯芴醇（AL）是撒哈拉以南非洲最广泛的抗疟药物。青蒿素综合疗法通过快速 减少初始寄生虫负担（青蒿素），消除残留寄生虫（伙伴药物）， 治疗预防新发感染（伙伴药物），联合治疗理论上可减少 耐药风险。撒南非洲也是全世界艾滋病毒负担最重的地区，有240多万儿童， 受HIV相关免疫抑制和慢性HIV相关免疫激活双重挑战的青少年 尽管抗逆转录病毒治疗有效。我们和其他人已经表明，在年轻人中，AL浓度较低， 儿童、孕妇和接受某些抗逆转录病毒治疗方案的艾滋病毒合并感染者。降低药品 水平与显著降低的疗效相关，如复发性感染所测量的。延长期限 AL治疗是改善预后的潜在方法。这促使我们评估安全性，有效性， 在有和无以下情况的儿童中，5天（10剂）与标准3天（6剂）AL的药代动力学（PK） 艾滋病毒生活在乌干达的高传播强度地区（EXALT试验）。正如预期的那样， 显著改善了有和无HIV儿童的AL PK暴露。然而，尽管几乎所有的孩子都 在AL治疗的几天内，显微镜检查呈阴性，约70%的儿童在显微镜下出现复发 在42天的随访中可检测到寄生虫血症。在这一后续阶段，真正的寄生虫动态是隐藏的 低于显微镜检测的阈值。来自我们试验的高度敏感的基于RNA的分子试验数据， 在治疗后数周内检测到持续性寄生虫RNA的高负荷，其意义尚不清楚。 然而，持续性/复发性寄生虫可能会遇到亚治疗水平的伴侣， 药物苯芴醇（单一疗法），这可能会增加耐药选择的风险。此外，非- 在反复感染疟疾和艾滋病毒相关疾病的影响下， 免疫抑制和慢性免疫激活对这些应答的影响在组学时代尚未被探索。 因此，虽然EXALT的目标是改善艾滋病毒感染和未感染儿童的治疗，但更严格的 分子和组学研究将使我们能够1）更好地了解这种干预的真正影响， 抗疟疗效、传播动力学和治疗后预防，2）确定是否固有的 ACT药物半衰期的PK不匹配可能是伴侣耐药选择的有力因素，以及3） 确定宿主对疟疾的反应的关键方面，包括艾滋病毒背景下的反应， 在儿童中进行分子描述的治疗反应。由此产生的数据将有助于优化青蒿素综合疗法 这些弱势群体。

Project Summary Malaria is a leading cause of global morbidity and mortality in sub-Saharan Africa (SSA). Artemisinin-based combination therapies (ACTs) combine a potent short-acting artemisinin and a longer-acting partner drug, with artemether-lumefantrine (AL) as the most widely prescribed antimalarial in SSA. ACTs act through the rapid reduction of initial parasite burden (artemisinin), elimination of residual parasites (partner drug), and post- treatment prophylaxis against new infections (partner drug), with combination therapy theoretically reducing the risk of drug resistance. SSA also bears the highest burden of HIV worldwide, with over 2.4 million children and adolescents challenged by both HIV-related immunosuppression and chronic HIV-related immune activation despite effective antiretroviral therapy. We and others have shown that AL concentrations are lower in young children, pregnant women, and HIV-coinfected individuals on certain antiretroviral therapy regimens. Lower drug levels correlated with significantly reduced efficacy, as measured by recurrent infection. Extending the duration of AL therapy is a potential approach to improve outcomes. This prompted us to evaluate the safety, efficacy, and pharmacokinetics (PK) of 5-day (10-dose) versus standard 3-day (6-dose) AL in children with and without HIV living in a high transmission intensity region of Uganda (EXALT trial). As intended, the extended regimen significantly improved AL PK exposure in children with and without HIV. However, while nearly all children were microscopy-negative within a few days of AL therapy, ~70% of children developed recurrent microscopically detectable parasitemia over 42-day follow-up. The true parasite dynamics over this follow-up period are hidden below the threshold of microscopic detection. Highly sensitive RNA-based molecular pilot data from our trial has detected a high burden of persistent parasite RNA for weeks after treatment, the significance of which is unclear. However, it is likely that persistent/recurrent parasites are likely to encounter subtherapeutic levels of partner drug lumefantrine (monotherapy), which may increase the risk of drug resistance selection. In addition, non- sterilizing immunity is gradually acquired following repeated malaria infections and the impact of HIV-related immunosuppression and chronic immune activation on these responses has not been explored in the omics era. Thus, while the goal of EXALT was to improve treatment in children with and without HIV, a more rigorous molecular and omic investigation will allow us to 1) better understand the true impact of this intervention on antimalarial efficacy, transmission dynamics, and post-treatment prophylaxis, 2) determine whether the inherent PK mismatch of ACT drug half-lives may serve as a potent force for partner drug resistance selection, and 3) identify key aspects of the host response to malaria, including those in the setting of HIV, that are associated with molecularly-delineated treatment responses in children. Resulting data will allow for optimization of ACTs in these vulnerable groups.