Defining Antiretroviral Pharmacology Within HIV-1 Reservoirs of Males and Females

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT With this K23 Career Development Award, I will develop the skills necessary to reach my ultimate goal of becoming an independent investigator focused on assessing pharmacologic barriers to HIV cure. Career Development Plan: My long-term goal is to become an independently funded researcher with expertise in clinical pharmacology and pharmacokinetic (PK)-pharmacodynamic (PD) modeling to inform future HIV cure strategies. In the short-term during this K23 period, my goals are to investigate antiretroviral (ARV) drug exposure and viral dynamic relationships within HIV reservoirs and to prioritize exploration of sex differences within these relationships. In order to attain these goals, I will be mentored during this K23 award period by a group of experienced career scientists: Dr. Igho Ofotokun, an HIV translational clinician scientist with a focus on women's health, Dr. Edward Acosta, an HIV clinical pharmacologist, and Dr. Raymond Schinazi, a translational scientist in the arenas of novel drug development and HIV cure. Throughout this career award period, I will complete coursework and hands-on training in basic experimental pharmacology, longitudinal biostatistical analyses, PK-PD modeling, sex and gender sciences, HIV cure/eradication, and scientific communication. In combination with my previous foundation in the clinical care of HIV-infected persons, Master of Science in Clinical Research, and clinical/translational research, this training will uniquely position me for an independent career in the application of clinical pharmacology within HIV cure strategies. Research Plan: Emerging evidence indicates that sites outside of blood plasma, such as peripheral blood mononuclear cells (PBMCs) and gut-associated lymphoid tissue, remain reservoirs for HIV and play critical roles in viral persistence despite long-term potent combination antiretroviral therapy (cART). Suboptimal ARV drug concentrations within these reservoirs are thought to contribute to our inability to fully eradicate HIV. In addition, host factors such as sex have been found to impact ARV drug exposure within these sites and effect key outcomes such as time to virologic suppression. Our understanding of reservoir site pharmacology and the impact on sex is limited due to several barriers: 1) Difficulty in sampling reservoir sites intensively and 2) Scarcity of women enrolled in HIV clinical research studies. Optimal drug concentrations are ideally determined early in drug development by dose-ranging studies that require intensive blood plasma sampling; this methodology is impractical to employ within tissue sites. To mitigate these barriers, we propose to study the pharmacology of the integrase strand transfer inhibitor dolutegravir (DTG) within three body compartments: blood plasma, PBMCs, and rectal tissue using a novel integrated population pharmacokinetic-viral dynamic (PK-VD) modeling approach. This PK-VD modeling strategy generates concentration-response relationships with limited sampling and dosing simulations ideally suited to reservoir sites. Additionally, we will prioritize the exploration of sex differences by leveraging our extensive research infrastructure, including the clinical core of the Emory Center for AIDS Research (CFAR), the Atlanta Clinical and Translational Science Institute (ACTSI), and the motivated cohort of the Atlanta Women's Interagency HIV Study (WIHS). We hypothesize that integrated population PK-VD modeling will show that optimal drug doses needed to suppress HIV will be higher in PBMC and rectal tissue reservoirs compared to blood plasma and will be different between males and females. Our proposed aims are: 1) Compare descriptive data generated from our DTG PK-VD blood plasma model to existing dose-ranging study data for validation, 2) Extend the development of DTG PK-VD models to PBMC and rectal tissue reservoirs, and 3) Investigate sex differences in DTG PK-VD in all three body sites. To accomplish this, 20 ARV-naïve HIV-infected males and 20 ARV-naïve HIV infected females (total n = 40) will be enrolled in an 84 day (12 week) longitudinal study whereby blood plasma, PBMCs, and rectal tissue will be serially sampled during seven (7) study visits to measure DTG concentrations, HIV-1 RNA viral load, and 2-LTR unintegrated HIV DNA circles. From these data, integrated population PK-VD models will be constructed and dosing simulations used to determine optimal drug exposure needed to attain virologic suppression at all three sites within males and females. With support from a multi-disciplinary team of mentors, completion of this work will uniquely position me for an independent research career integrating pharmacologic interventions within HIV cure stratagems.