Antimalarial Pharmacology in HIV Coinfected Children and Pregnant Women in Uganda

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合并感染的复杂影响。非洲的治疗选择得到改善，以青蒿素为基础的疟疾联合疗法（ACTs）的可得性增加，艾滋病毒抗逆转录病毒疗法（ART）的可及性扩大。由于对旧药物的广泛耐药性，以青蒿素为基础的联合疗法对治疗疟疾至关重要。ACTs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，并且易受生理差异和药物-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，忽视了年龄或妊娠对药物处置的影响。越来越多的证据，包括我们小组的研究，表明在儿童或孕妇中，以青蒿素为基础的联合治疗可能剂量不足，并且在艾滋病毒感染和合并抗逆转录病毒治疗的情况下，与显著的药物相互作用和毒性增加有关，特别是中性粒细胞减少。适当的剂量是提高治疗效果和减少耐药和毒性风险的关键。由美国国立卫生研究院资助的试验目前正在乌干达托罗罗进行，该地区疟疾传播率和艾滋病毒感染率很高，试验比较了基于抗逆转录病毒治疗的降低艾滋病毒感染儿童和孕妇疟疾发病率的治疗策略。该提案将补充促进和研究在抗逆转录病毒治疗背景下最广泛使用的青蒿素-氨苯曲明（AL）的药代动力学（PK）和药效学（PD），以优化疟疾和艾滋病毒的治疗。具体目的是：1)评价ART治疗和年龄对hiv感染儿童蒿甲醚-氨芳碱（AL）药代动力学和药效学的影响；2)评价抗逆转录病毒治疗和妊娠对hiv感染孕妇甲醚-氨苯曲明药物PK和PD的影响；3)确定标准剂量下ART和AL暴露是否可预测HIV和疟疾合并感染的儿童和孕妇中性粒细胞减少症。接受蛋白酶抑制剂（PI）或基于非核苷逆转录酶抑制剂（NNRTI）的抗逆转录病毒治疗的艾滋病毒感染儿童和孕妇将从PROMOTE联合入组，并在疟疾治疗期间对AL进行密集的PK评估。以pi为基础的方案包括洛匹那韦/利托那韦，以nnrti为基础的方案包括奈韦拉平或依非韦伦。结果将与对同样居住在托罗罗的未感染艾滋病毒儿童进行的强化PK评估进行比较。为了评估药物暴露与临床结果之间的关系，纵向人群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率相关。拟议的药理学研究将为非洲最广泛采用的联合疗法和抗逆转录病毒治疗方案的未来给药指南提供信息。

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.