Improving Antiretroviral Management for HIV

描述(申请人提供)：该项目的目标是对HIV感染患者进行高质量的患者研究，重点回答有关抗逆转录病毒治疗的临床和发病机制问题，并评估改善抗逆转录病毒治疗临床管理的新策略和新出现的策略。该项目的中心假设是，精心规划和分析的研究不仅可以回答有关特定治疗组合的问题，还可以提供对治疗反应的发病机制的洞察，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员)将是该项目的中心目标。这些目标将通过与当地(UCSD AVRC)、全州(加利福尼亚协作治疗集团[CCTG])和国家(艾滋病临床试验集团[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的总首席调查员，我将能够继续通过积极参与CCTG的研究来促进初级调查人员的发展。主要研究主题是了解抗逆转录病毒暴露-反应关系及其对艾滋病毒发病和管理的影响。具体目标是： 1)通过评价TDF+ABC治疗失败的机制，探讨TDF+ABC治疗失败的机制 核苷血浆和细胞内暴露-反应关系。这项研究将使用一种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估)来评估TDF和ABC之间的相互作用。 2)明确抗逆转录病毒暴露-反应关系在艾滋病毒治疗中的作用。目的：评价治疗药物监测(TDM)对改善抗逆转录病毒治疗的管理和疗效的价值。目的2B：明确遗传差异(由单核苷酸多态的等位基因变异定义)对洛比那韦(Lopinavir)的暴露和反应的影响。

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.