Antimalarial Pharmacology in HIV Coinfected Children and Pregnant Women in Uganda

乌干达 HIV 合并感染儿童和孕妇的抗疟药理学

基本信息

批准号：
8071032
负责人：
FRANCESCA T. AWEEKA
金额：
$ 57.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-23 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8071032
关键词：
5 year old Adopted Adult Adverse event Affect Africa Africa South of the Sahara Age American Anemia Antimalarials Artemisinins Child Clinical Combined Modality Therapy Complement Complex Cytochrome P450 Development District Hospitals Dose Drug Exposure Drug Interactions Drug Kinetics Drug resistance Drug toxicity Enrollment Epidemic Evaluation Event Exhibits Exposure to Funding Future Goals Guidelines HIV HIV Infections Health Individual Infant Infection Lead Lopinavir/Ritonavir Low Birth Weight Infant Malaria Metabolism Morbidity - disease rate Neutropenia Nevirapine Outcome Parasites Pathway interactions Pharmaceutical Preparations Pharmacodynamics Pharmacology Physiological Population Pregnancy Pregnant Women Protease Inhibitor Recruitment Activity Recurrence Regimen Research Residual state Resistance Risk Spontaneous abortion Stavudine Time Toxic effect Treatment Efficacy Treatment Failure Treatment outcome Uganda United States National Institutes of Health Vulnerable Populations Zidovudine antiretroviral therapy artemether artemisinine base benflumetol efavirenz experience follow-up improved mortality non-nucleoside reverse transcriptase inhibitors nucleoside analog stem transmission process treatment strategy trial comparing

项目摘要

DESCRIPTION (provided by applicant): Malaria and HIV infection are two of the most important health challenges of our time. Children under 5 years of age and pregnant women are particularly vulnerable to the complicating effects of malaria and HIV co- infection. Treatment options within Africa have improved, with increasing availability of artemisinin-based combination therapies (ACTs) for malaria and expanded access to antiretroviral therapy (ART) for HIV. ACTs are critical for treatment of malaria due to widespread resistance to older drugs. ACTs exhibit complex pharmacology, undergo activation and/or metabolism via cytochrome p450 pathways and are susceptible to physiological differences and drug-drug interactions with ARTs. However, treatment guidelines have largely stemmed from adult studies, and have ignored the impact of age or pregnancy on drug disposition. Mounting evidence, including studies from our group, indicates that ACTs may be underdosed in children or pregnant women, and are associated with significant drug interactions and heightened toxicities, in particular neutropenia, in the setting of HIV infection and concomitant ART. Proper dosing is critical to improve treatment efficacy and minimize risk of drug resistance and toxicity. NIH-funded trials comparing ART-based treatment strategies for reducing malaria morbidity in HIV-infected children and pregnant women (PROMOTE) are currently underway in Tororo, Uganda, a region with high rates of malaria transmission and HIV infection. This proposal will complement PROMOTE and investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of artemether-lumefantrine (AL), the most widely adopted ACT, in the context of ART, to optimize treatment for malaria and HIV. The specific aims are 1) To evaluate the impact of ART and age on the pharmacokinetics and pharmacodynamics of artemether-lumefantrine (AL) in HIV-infected children; 2) To evaluate the impact of ART and pregnancy on the PK and PD of artemether-lumefantrine in HIV-infected pregnant women; 3) To determine if ART and AL exposure following standard dosing is predictive of neutropenia in children and pregnant women with HIV and malaria co-infection. HIV-infected children and pregnant women, treated with either protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART will be co- enrolled from PROMOTE, and undergo intensive PK evaluations for AL during treatment for malaria. PI-based regimens include lopinavir/ritonavir, and NNRTI-based regimens include either nevirapine or efavirenz. Results will be compared to intensive PK evaluations in HIV-uninfected children also residing in Tororo. To assess associations between drug exposure and clinical outcomes, longitudinal population PK/PD studies will determine if changes in AL exposure impact malaria treatment efficacy, and if AL and ART exposure correlates with high rates of neutropenia observed in HIV and malaria co-infected individuals. The proposed pharmacology studies will inform future dosing guidelines for the most widely adopted ACT and ART regimens in Africa. PUBLIC HEALTH RELEVANCE: Children and pregnant women represent particularly vulnerable populations to the overlapping epidemics of malaria and HIV infection in sub-Saharan Africa. We aim to characterize the pharmacokinetics of first-line antimalarial therapies in these groups, and correlate these parameters with treatment outcomes and adverse drug events. Findings should lead to specific artemether-lumefantrine dosing guidelines based on age, pregnancy, and use with concomitant antiretroviral therapy in HIV-infected populations.

描述（由申请人提供）：疟疾和艾滋病毒感染是我们这个时代最重要的两个健康挑战。 5 岁以下儿童和孕妇特别容易受到疟疾和艾滋病毒双重感染的复杂影响。随着基于青蒿素的疟疾联合疗法 (ACT) 的可用性不断增加，以及艾滋病毒抗逆转录病毒疗法 (ART) 的普及，非洲的治疗选择有所改善。由于人们对旧药物普遍存在耐药性，联合疗法对于治疗疟疾至关重要。 ACT 表现出复杂的药理学，通过细胞色素 p450 途径进行激活和/或代谢，并且容易受到生理差异和与 ART 的药物相互作用的影响。然而，治疗指南很大程度上源于成人研究，并忽略了年龄或怀孕对药物处置的影响。包括我们小组的研究在内的越来越多的证据表明，在儿童或孕妇中，ACT 可能剂量不足，并且与显着的药物相互作用和毒性增加有关，特别是在 HIV 感染和同时接受 ART 的情况下，会导致中性粒细胞减少症。正确的剂量对于提高治疗效果并最大程度地降低耐药性和毒性风险至关重要。美国国立卫生研究院 (NIH) 资助的试验目前正在乌干达托罗罗进行，该试验比较基于抗逆转录病毒疗法的治疗策略，以降低感染艾滋病毒的儿童和孕妇的疟疾发病率 (PROMOTE)，该地区疟疾传播和艾滋病毒感染率较高。该提案将补充 PROMOTE 并研究蒿甲醚-本芴醇 (AL) 的药代动力学 (PK) 和药效学 (PD)，这是 ART 背景下最广泛采用的 ACT，以优化疟疾和 HIV 的治疗。具体目标是 1) 评估 ART 和年龄对 HIV 感染儿童中蒿甲醚-本芴醇 (AL) 药代动力学和药效学的影响； 2) 评价ART和妊娠对HIV感染孕妇中蒿甲醚-本芴醇的PK和PD的影响； 3) 确定标准剂量后暴露于 ART 和 AL 是否可预测 HIV 和疟疾双重感染的儿童和孕妇出现中性粒细胞减少症。接受基于蛋白酶抑制剂 (PI) 或非核苷逆转录酶抑制剂 (NNRTI) 的 ART 治疗的 HIV 感染儿童和孕妇将从 PROMOTE 中共同入组，并在疟疾治疗期间接受针对 AL 的强化 PK 评估。基于 PI 的治疗方案包括洛匹那韦/利托那韦，基于 NNRTI 的治疗方案包括奈韦拉平或依非韦伦。结果将与同样居住在托罗罗的未感染艾滋病毒儿童的强化 PK 评估进行比较。为了评估药物暴露与临床结果之间的关联，纵向群体 PK/PD 研究将确定 AL 暴露的变化是否会影响疟疾治疗效果，以及 AL 和 ART 暴露是否与 HIV 和疟疾合并感染个体中观察到的高中性粒细胞减少症发生率相关。拟议的药理学研究将为非洲最广泛采用的 ACT 和 ART 方案的未来剂量指南提供信息。公共卫生相关性：在撒哈拉以南非洲地区，儿童和孕妇是疟疾和艾滋病毒感染重叠流行病的特别脆弱人群。我们的目标是表征这些群体中一线抗疟疗法的药代动力学，并将这些参数与治疗结果和药物不良事件相关联。研究结果应根据艾滋病毒感染人群的年龄、妊娠情况以及联合抗逆转录病毒治疗的情况制定具体的蒿甲醚-本芴醇剂量指南。