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

描述影响感染和未感染艾滋病毒儿童疟疾治疗的宿主、寄生虫和药理学因素

• 批准号: 10700089
• 负责人: SUNIL PARIKH
• 金额: $ 19.87万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-07 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10700089
• 关键词: Adolescent; Africa; Africa South of the Sahara; Aftercare; Antimalarials; Artemisinins; Asia; Biological Assay; Bite; Child; Childhood; Chronic; Combination Drug Therapy; Combined Modality Therapy; Data; Degradation Pathway; Detection; Dose; Drug Exposure; Drug Kinetics; Drug resistance; Early Diagnosis; Exhibits; Genomics; Genotype; Goals; HIV; Haplotypes; Heme; Immune response; Immunity; Immunosuppression; Individual; Infection; Intervention; Investigation; Lipids; Liver; Malaria; Measures; Microsatellite Repeats; Microscopic; Microscopy; Molecular; Morbidity - disease rate; Outcome; Parasite resistance; Parasitemia; Parasites; Parasitology; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Population; Predisposition; Pregnant Women; Prophylactic treatment; RNA; Recurrence; Regimen; Residual state; Resistance; Resolution; Ribosomal RNA; Risk; Risk Reduction; Rwanda; Safety; Sampling; Steroids; Techniques; Therapeutic; Time; Treatment Protocols; Uganda; Vulnerable Populations; antiretroviral therapy; artemether; asexual; benflumetol; biomarker identification; drug-sensitive; follow-up; immune activation; improved; improved outcome; in vivo; malaria infection; metabolomics; mortality; novel; pharmacodynamic model; pharmacologic; recurrent infection; response; risk selection; transcriptomics; transmission process; treatment optimization; treatment response

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.

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。基于青蒿素 组合疗法（ACT）结合了有效的短效性青蒿素和长效伴侣药物， Artemether-Lumefantrine（Al）是SSA中规定的抗疟药最广泛的。行为通过快速行动 减轻初始寄生虫负担（青蒿素），消除残留寄生虫（伴侣药物）和后 预防针对新感染（伴侣药物）的治疗，理论上结合疗法从理论上降低了 耐药的风险。 SSA还承担着全球艾滋病毒的最高负担，有超过240万儿童和 受HIV相关的免疫抑制和慢性HIV相关的免疫激活而受到挑战的青少年 尽管有效抗逆转录病毒疗法。我们和其他人表明，年轻人的浓度较低 在某些抗逆转录病毒治疗方案上，儿童，孕妇和艾滋病毒感染的个体。较低的药物 通过复发感染测量的水平与疗效显着降低相关。延长持续时间 Al疗法是改善预后的潜在方法。这促使我们评估了安全性，功效 5天（10剂）的药代动力学（PK）与患有和没有的儿童相比3天（6剂）AL 艾滋病毒生活在乌干达的高传播强度区域（Exalt试验）。按预期的是，扩展的方案 在患有和没有HIV的儿童中，明显改善了AL PK暴露。但是，虽然几乎所有的孩子都是 显微镜阴性在AL治疗的几天内，约有70％的儿童在显微镜下复发 在42天的随访中可检测到的寄生虫病。在此随访期间的真实寄生虫动态被隐藏 低于显微镜检测的阈值。我们试验的高度敏感的基于RNA的分子试验数据已有 在治疗后数周内发现了高持续的寄生虫RNA负担，其重要性尚不清楚。 但是，持续/经常性的寄生虫很可能会遇到伴侣的亚治疗水平 药物Lumefantrine（单一疗法），这可能会增加耐药性选择的风险。另外，非 在反复的疟疾感染和HIV相关的影响后，逐渐获得了灭菌免疫力 在OMICS时代，尚未探索对这些反应的免疫抑制和慢性免疫激活。 因此，尽管崇高的目标是改善患有和没有艾滋病毒的儿童的治疗，但更严格 分子和OMIC调查将使我们到1）更好地了解这种干预对 抗原功效，传播动力学和治疗后预防，2）确定固有的 PK不匹配的ACT药物半衰期可能是抗伴侣耐药性选择的有效力量，3） 确定宿主对疟疾的反应的关键方面，包括与艾滋病毒相关的疟疾的关键方面 儿童中分子的治疗反应。结果数据将允许优化行为 在这些脆弱的群体中。