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

描述（由申请人提供）：本K23提案的总体目标是培训Christopher Vinnard，MD，MPH，MSCE作为HIV研究的独立研究者，特别强调HIV相关结核病（TB）的治疗和结局。职业发展计划包括药物计量学培训，这是一个跨学科领域，结合了定量临床药理学，系统生物学，统计学，计算和非参数数学的专业知识。将有正式的指导博士杰弗里雅各布森和博士塔万达甘博在UT西南，在抗结核病药理学专家。德雷克塞尔大学医学院提供了一个非常丰富的环境，与合作者，教育资源和设施，将促进博士。研究的重点将是艾滋病毒感染和利福平（一种关键的抗结核药物）吸收之间的相互作用。该提案的目标是为候选人提供全面的指导和教学计划，以促进作为临床研究人员的独立性，并阐明内在肠道功能障碍在HIV感染患者中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的测量相联系，确定内在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“HIV/TB中的免疫激活和异烟肼代谢”（PI：Bisson）的子研究进行，该研究将在博茨瓦纳哈博罗内招募HIV/TB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（如有）的影响。如果抗逆转录病毒疗法不能显著改善 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的连续疗法。该项目将在DUCOM传染病和HIV医学部的临床研究机构进行，为Vinnard博士提供在其所在机构领导抗结核治疗纵向药代动力学研究的培训经验。在完成这个项目后，候选人将作为一个独立的研究者，具有药物计量学的专业知识。鉴于该提案的范围，发现新的机制来调节利福平在艾滋病毒感染患者中的吸收将为未来的研究提供基础，这些研究将使Vinnard博士从指导阶段过渡到这个5年职业发展奖的独立阶段。Vinnard博士还将在Jacobson博士和Gumbo博士的指导下，在此期间继续建立他的国际合作，包括与Bisson博士和UPenn博茨瓦纳项目的继续合作。这些关于艾滋病毒感染者抗结核治疗的研究有可能改变全世界艾滋病毒/结核病患者的治疗。

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.