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。非洲境内的治疗选择有所改善，治疗疟疾的青蒿素类复方疗法越来越多，治疗艾滋病毒的抗逆转录病毒疗法也有更多的机会。由于对旧药物的广泛耐药性，青蒿素综合疗法对治疗疟疾至关重要。青蒿素综合疗法具有复杂的药理学作用，通过细胞色素p450途径进行活化和/或代谢，易受生理差异和与青蒿素综合疗法的药物相互作用的影响。然而，治疗指南在很大程度上源于成人研究，忽略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ACT在儿童或孕妇中可能剂量不足，并且与显著的药物相互作用和毒性增加有关，特别是在HIV感染和伴随ART的情况下，中性粒细胞减少症。适当的剂量对于提高治疗效果和最大限度地减少耐药性和毒性风险至关重要。美国国立卫生研究院资助的试验比较了基于ART的治疗策略，以降低艾滋病毒感染儿童和孕妇的疟疾发病率（PROMOTE）目前正在乌干达的托罗罗进行，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），这是在ART背景下最广泛采用的ACT，以优化疟疾和艾滋病毒的治疗。具体目的是：1）在HIV感染儿童中评价ART和年龄对蒿甲醚-本芴醇（AL）药代动力学和药效学的影响; 2）在HIV感染孕妇中评价ART和妊娠对蒿甲醚-本芴醇PK和PD的影响; 3）确定标准剂量后的ART和AL暴露是否可预测患有HIV和疟疾合并感染的儿童和孕妇的中性粒细胞减少症。接受蛋白酶抑制剂（PI）或非核苷类逆转录酶抑制剂（NNRTI）ART治疗的HIV感染儿童和孕妇将从PROMOTE共同入组，并在疟疾治疗期间接受AL的强化PK评价。基于PI的方案包括洛匹那韦/利托那韦，基于NNRTI的方案包括奈韦拉平或依法韦仑。将结果与同样居住在Tororo的未感染HIV儿童的密集PK评价进行比较。为了评估药物暴露与临床结局之间的相关性，纵向人群PK/PD研究将确定AL暴露的变化是否影响疟疾治疗疗效，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，儿童和孕妇是特别易受疟疾和艾滋病毒感染重叠流行病影响的人群。我们的目标是描述这些人群中一线抗疟治疗的药代动力学特征，并将这些参数与治疗结果和药物不良事件相关联。研究结果应导致具体的蒿甲醚-苯芴醇剂量指南的基础上，年龄，怀孕，并使用伴随抗逆转录病毒治疗的艾滋病毒感染人群。

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.