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

• 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
• 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

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(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混合感染的复杂影响。随着以青蒿素为基础的疟疾联合疗法(ACTs)的可获得性增加，以及艾滋病毒抗逆转录病毒疗法(ART)的使用范围扩大，非洲境内的治疗选择有所改善。由于对旧药的广泛抗药性，ACTs对疟疾的治疗至关重要。ACTs表现出复杂的药理作用，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药物与ARTS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，忽略了年龄或怀孕对药物处置的影响。越来越多的证据，包括我们小组的研究表明，ACTs在儿童或孕妇中可能剂量不足，并与艾滋病毒感染和伴随的ART环境中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症。适当的剂量是提高治疗效果和最大限度减少耐药性和毒性风险的关键。美国国立卫生研究院资助的比较基于抗逆转录病毒疗法的治疗策略以减少感染艾滋病毒的儿童和孕妇疟疾发病率的试验(PROCESS)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。这项建议将补充、促进和研究蒿甲醚-鲁米芬净(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，以优化疟疾和艾滋病毒的治疗。其具体目的是：1)评估ART和年龄对艾滋病毒感染儿童中蒿甲醚-鲁米芬(AL)药代动力学和药效学的影响；2)评估ART和妊娠对艾滋病毒感染孕妇中蒿甲醚-鲁米芬的PK和PD的影响；3)确定在标准剂量后暴露于ART和AL是否可以预测感染艾滋病毒和疟疾的儿童和孕妇的中性粒细胞减少症。感染了HIV的儿童和孕妇，接受了蛋白酶抑制剂(PI)或基于非核苷类逆转录酶抑制剂(NNRTI)的ART治疗，将与Promote联合登记，并在疟疾治疗期间接受密集的AL PK评估。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法韦伦。结果将与同样居住在托罗罗的未感染艾滋病毒的儿童的密集PK评估进行比较。为了评估药物暴露和临床结果之间的关系，纵向人群PK/PD研究将确定AL暴露的变化是否影响疟疾治疗效果，以及AL和ART暴露是否与在艾滋病毒和疟疾合并感染的个人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。 与公共卫生相关：儿童和孕妇是撒哈拉以南非洲疟疾和艾滋病毒感染重叠流行的特别脆弱人群。我们的目标是描述这些人群中一线抗疟疾治疗的药代动力学特征，并将这些参数与治疗结果和不良药物事件相关联。这些发现应该导致在HIV感染人群中根据年龄、怀孕和与抗逆转录病毒治疗相伴随的使用来制定特定的蒿甲醚-鲁米芬剂量指南。