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。青蒿素类药物 联合疗法(ACT)结合了一种有效的短效青蒿素和一种长效伙伴药物， 蒿甲醚-鲁米芬(AL)是SSA中应用最广泛的抗疟药。ACTS通过快速的 减少初始寄生虫负担(青蒿素)，消除残留寄生虫(伙伴药物)，并在 针对新感染的治疗预防(伙伴药物)，理论上联合治疗可减少 有抗药性的风险。SSA还承担着全球最高的艾滋病毒负担，有超过240万儿童和 青少年同时面临艾滋病毒相关免疫抑制和慢性艾滋病毒相关免疫激活的挑战 尽管进行了有效的抗逆转录病毒治疗。我们和其他人已经表明，年轻人体内的铝浓度较低 儿童、孕妇和艾滋病毒联合感染者接受某些抗逆转录病毒治疗方案。低等药物 根据反复感染来衡量，这些水平与显著降低的疗效相关。延长持续时间 AL治疗是一种潜在的改善预后的方法。这促使我们评估该药的安全性、有效性、 5天(10剂量)与标准3天(6剂量)AL在儿童中的药代动力学(PK) 生活在乌干达高传播强度地区的艾滋病毒(高危试验)。正如预期的那样，延长的方案 显著改善感染和不感染艾滋病毒的儿童的AL PK暴露。然而，尽管几乎所有的孩子都是 镜检阴性在AL治疗后的几天内，约70%的儿童出现镜检复发 在42天的随访中检测到寄生虫血症。这一后续时期的真实寄生虫动态被隐藏起来 低于显微镜检测的门槛。我们试验中高度敏感的基于RNA的分子试点数据 治疗后数周内检测到高负荷的持久性寄生虫RNA，其意义尚不清楚。 然而，持续/复发的寄生虫很可能会遇到低于治疗水平的伴侣。 药物鲁米芬(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影响后，逐渐获得绝育免疫力 在组学时代，免疫抑制和慢性免疫激活对这些反应还没有被探索过。 因此，虽然EALT的目标是改善感染和不感染艾滋病毒的儿童的治疗，但更严格的 分子和基因组研究将使我们1)更好地了解这一干预措施对 抗疟疾疗效、传播动力学和治疗后预防，2)决定固有的 ACT药物半衰期的PK错配可能是伴侣耐药选择的重要因素。 确定宿主对疟疾的反应的关键方面，包括与艾滋病毒有关的关键方面 在儿童中有分子描述的治疗反应。所产生的数据将允许对ACTS进行优化 在这些弱势群体中。

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.