Improving Antiretroviral Management for HIV

描述（由申请人提供）：本项目的目标是对HIV感染患者进行高质量的以患者为导向的研究，重点是回答有关抗逆转录病毒治疗的临床和发病机制问题，并评估新的和新兴的策略，以改善抗逆转录病毒治疗的临床管理。该项目的中心假设是，精心计划和分析的研究不仅可以回答有关特定治疗组合的问题，而且还可以提供对治疗反应的发病机制的见解，并确定在临床上管理患者的策略。指导年轻的研究人员（M.P.H.学生，传染病研究员和初级教师）将是这个项目的中心目标。这些目标将通过与当地（UCSD AVRC）、全州（加州协作治疗组[CCTG]）和国家（艾滋病临床试验组[ACTG]）临床试验组织合作构思、设计、启动、实施和分析随机对照试验来实现。作为CCTG的总首席研究员，我将能够继续通过积极参与CCTG研究来促进初级研究者发展的传统。主要研究主题是了解抗逆转录病毒治疗反应的关系及其对艾滋病毒发病机制和管理的影响。具体目标是： 1)通过评估TDF + ABC治疗失败的机制， 核苷血浆和细胞内的免疫应答关系。本研究将采用独特的临床试验设计（交叉、短期病毒动力学的药代动力学评价）来评价TDF和ABC之间的相互作用。 2)明确抗逆转录病毒治疗中的免疫应答关系。目的2A：评价治疗药物监测（TDM）对改善抗逆转录病毒治疗管理和疗效的价值。目标2B：确定遗传差异（由单核苷酸多态性的等位基因变体定义）对抗逆转录病毒药物洛匹那韦暴露和应答的影响。

DESCRIPTION (provided by applicant): The goal of this project is to conduct high quality patient oriented research with HIV infected patients which focuses on answering clinical and pathogenesis based questions concerning antiretroviral therapy and evaluates new and emerging strategies to improve the clinical management of antiretroviral therapy. The central hypothesis of the project is that carefully planned and analyzed studies can not only answer questions about specific treatment combinations, but can also provide insight into the pathogenesis of treatment responses and define strategies to manage patients in the clinic. Mentoring young investigators (M.P.H. students, Infectious Disease fellows, and junior faculty) will be a central goal of this project. These goals will be accomplished by conceiving, designing, initiating, carrying out, and analyzing randomized controlled trials in collaboration with local (UCSD AVRC), statewide (California Collaborative Treatment Group [CCTG]), and national (AIDS Clinical Trials Group [ACTG]) clinical trials organizations. As the overall Principal Investigator of the CCTG, I will be able to continue the tradition of fostering the development of junior investigators through active participation in CCTG studies. The primary research theme is to understand the antiretroviral exposure-response relationship and its implications for the pathogenesis and management of HIV. The specific aims are: 1) To examine the mechanistic pathways leading to therapeutic failure of TDF + ABC by evaluating nucleoside plasma and intracellular exposure-response relationships. The study will use a unique clinical trial design (cross-over, pharmacokinetic evaluation of short-term viral dynamics) to evaluate the interaction between TDF and ABC. 2) To define the role of antiretroviral exposure-response relationships in HIV therapeutics. Aim 2A: To evaluate the value of therapeutic drug monitoring (TDM) to improve the management and outcome of antiretroviral therapy. Aim 2B: To define the impact of genetic differences (defined by allelic variants of single nucleoside polymorphisms) on exposure and response to lopinavir, the antiretroviral agent.