Rifampicin Malabsorption in HIV+ Patients: Mechanisms and Recovery after HAART

描述(由申请人提供)：这项K23提案的总体目标是培训Christopher Vinnard，医学博士，公共卫生硕士，MSCE，作为艾滋病毒研究的独立调查员，特别强调艾滋病毒相关结核病(TB)的治疗和结果。职业发展计划包括药物计量学的培训，这是一个结合了定量临床药理学、系统生物学、统计学、计算和非参数数学专业知识的跨学科领域。会议将由德克萨斯大学西南分校的抗结核病药理学专家杰弗里·雅各布森博士和塔万达·甘博博士进行正式指导。德雷克塞尔大学医学院提供了一个非常丰富的环境，可以接触到合作者、教育资源和设施，这将促进Vinnard博士的专业发展。研究的重点将是艾滋病毒感染和关键的抗结核病药物利福平的吸收之间的相互作用。这项建议的目的是为候选人提供全面的指导和指导计划，以促进作为临床研究人员的独立性，并阐明固有的肠道功能障碍在艾滋病毒感染患者利福平吸收不良中的作用。具体目标1是通过将药代动力学研究与肠道功能、屏障完整性和全身免疫激活相结合，确定固有肠道功能障碍与利福平吸收的关系。该项目将作为受资助的R21项目“艾滋病毒/结核病中的免疫激活和异烟肼代谢”(PI：BISSON)的子研究，该项目将在博茨瓦纳哈博罗内招募艾滋病毒/结核病患者。具体目标2是研究抗逆转录病毒治疗对利福平吸收能力恢复(如果有的话)的影响。如果抗逆转录病毒治疗不能带来显著改善 在利福平吸收方面，未来的研究将评估旨在优化肠道吸收功能的新型辅助疗法。该项目将在Ducom传染病和艾滋病毒医学部的临床研究设施中进行，为Vinnard博士提供在他的家庭机构领导抗结核病疗法的纵向药代动力学研究的培训经验。在这个项目完成后，候选人将很好地被培训为一名独立的调查员，具有作为药物计量学专家的专业知识。鉴于这项提案的范围，对艾滋病毒感染患者利福平吸收调节的新机制的发现将为未来的研究奠定基础，这些研究将使Vinnard博士从接受指导进入这个为期5年的职业发展奖的独立阶段。在本奖项期间，Vinnard博士还将在雅各布森博士和甘博博士的指导下，继续加强他的国际合作，包括继续与比森博士和宾夕法尼亚大学博茨瓦纳分校项目合作。这些针对艾滋病毒感染者抗结核疗法的研究有可能改变全世界艾滋病毒/结核病患者的治疗方法。

DESCRIPTION (provided by applicant): The overall goal of this K23 proposal is to train Christopher Vinnard, MD, MPH, MSCE for a career as an independent investigator in HIV research, with a specific emphasis on the treatment and outcomes of HIV- associated tuberculosis (TB). The career development plan includes training in pharmacometrics, an interdisciplinary field that combines expertise in quantitative clinical pharmacology, systems biology, statistics, computing, and non-parametric mathematics. There will be formal mentoring by Dr. Jeffrey Jacobson and Dr. Tawanda Gumbo at UT Southwestern, an expert in anti-TB pharmacology. Drexel University College of Medicine offers a remarkably rich environment, with access to collaborators, educational resources, and facilities that will foster Dr. Vinnard's professional development. Research will focus on the interaction between HIV infection and the absorption of rifampicin, a key anti-TB drug. The goals of this proposal are to provide the candidate with a comprehensive mentoring and didactic program to facilitate independence as a clinical researcher, and to elucidate the role of intrinsic gut dysfunction in rifampicin malabsorption among HIV-infected patients. Specific Aim 1 is to define the relationship of intrinsic gut dysfunction with rifampicin absorption, by linking pharmacokinetic studies with measures of intestinal function, barrier integrity, and systemic immune activation. This project will be performed as a sub-study of the funded R21 "Immune Activation and Isoniazid Metabolism in HIV/TB" (PI: Bisson), which will enroll HIV/TB patients in Gaborone, Botswana. Specific Aim 2 is to investigate the effect of antiretroviral therapy on the recovery (if any) of rifampicin absorptive capacity. If antiretroviral therapy does not lead to significant improvements in rifampicin absorption, future investigations would evaluate novel adjunctive therapies aimed at optimizing the gut's absorptive function. This project will be performed in the clinical researc facilities of the Division of Infectious Diseases & HIV Medicine at DUCOM, providing Dr. Vinnard with the training experience of leading a longitudinal pharmacokinetic study of anti-TB therapies within his home institution. After the completion of this project, the candidate will be well traind as an independent investigator with expertise as a pharmacometrician. Given the scope of the proposal, the discovery of novel mechanisms for the regulation of rifampicin absorption in HIV-infected patients will provide the foundation for future investigations that will transition Dr. Vinnard from the mentored to the independent phase of this 5-year career development award. Dr. Vinnard also will continue to build his international collaborations during the course of this award period, with guidance from Dr. Jacobson and Dr. Gumbo, including continued collaboration with Dr. Bisson and the UPenn Botswana program. These studies of anti-TB therapies in HIV-infected patients have the potential to transform the treatment of HIV/TB patients throughout the world.