Plasma and Genital HIV Dynamics in Women

描述(由候选人提供)：候选人：Neely博士是临床儿科学助理教授，接受过传染病和临床药理学方面的分专业培训。在过去的4年里，他一直在使用群体药代动力学(PK)模型来衡量妇女、青少年和儿童对抗逆转录病毒治疗的依从性，并发现非核苷类逆转录酶抑制剂(NNRTI)可能比蛋白酶抑制剂(PI)更容易导致HIV RNA从宫颈脱落。他的近期目标是使用先进的人口建模技术前瞻性地探索这一发现，以比较NNRTI或PI药效学(PD)对艾滋病毒在血浆和女性生殖道中复制的影响。他的长期目标是发展一个卓越的研究中心，使用PK-PD模型来提出和回答治疗和科学问题，特别是在妇女和儿童中。南加州大学非常适合这一目标，拥有临床研究硕士项目、应用药代动力学实验室(LAPK)、生物医学模拟资源(BMSR)和3500多名艾滋病毒感染患者，母婴青少年(MCA)诊所专门关注艾滋病毒感染妇女和儿童的需求。尼利博士将由罗杰·耶利夫博士(LAPK)以及包括安德里亚·科瓦奇博士(MCA)和大卫·达吉尼奥博士(BMSR)在内的顾问团队指导。研究：重复的、配对的血液和生殖器样本将在6个月内从20名女性身上获得，并按治疗进行分层。血液和直接吸入的阴道液将用LC-MS/MS分析药物浓度。血液和宫颈拭子中的HIV RNA将通过等温核酸扩增进行定量。人口建模方法将被用来表征血浆和阴道液中的药物PK，并比较PD对血浆和宫颈HIV RNA随时间的释放的影响。相关性：这个项目的数据将与几个重要的、尚未回答的临床问题相关，包括：1)某些药物是否通过有效抑制生殖道中的病毒复制而更有效地预防艾滋病毒的性传播或母婴传播？2)是否有必要抑制生殖道中的病毒复制以维持血浆中的抑制？3)病毒动力学的短期模型能否用于预测治疗的长期反应？4)女性是否应该根据不同于男性的病毒学/免疫学标准开始抗逆转录病毒治疗？

DESCRIPTION (provided by candidate): Candidate: Dr. Neely is an Assistant Professor of Clinical Pediatrics with subspecialty training in infectious diseases and clinical pharmacology. For the last 4 years he has been using population pharmacokinetic (PK) modeling to measure adherence to antiretroviral therapy by women, adolescents, and children, as well as finding that non-nucleoside reverse transcriptase inhibitors (NNRTIs) may be more associated with shedding of HIV RNA from the cervix than are protease inhibitors (PIs). His immediate aims are to prospectively explore this finding using advanced population modeling techniques to compare NNRTI or PI pharmacodynamic (PD) effects on HIV replication in plasma and the female genital tract. His long-term objective is to develop a research center of excellence, using PK-PD modeling to pose and answer therapeutic and scientific questions, particularly in women and children. The University of Southern California is ideally suited for this goal, having a Master's program in Clinical Investigation, the Laboratory of Applied Pharmacokinetics (LAPK), the Biomedical Simulations Resource (BMSR), and over 3500 HIV-infected patients, with the Maternal Child Adolescent (MCA) clinic focused specifically on the needs of HIV- infected women and children. Dr. Neely will be mentored by Dr. Roger Jelliffe (LAPK), as well as a team of advisors including Dr. Andrea Kovacs (MCA) and Dr. David D'Argenio (BMSR). Research: Repeated, paired blood-genital samples will be obtained over a 6-month period from 20 women, stratified by treatment. Blood and directly aspirated vaginal fluid will be analyzed by LC-MS/MS for drug concentrations. HIV RNA will be quantified in blood and cervical swabs by isothermal nucleic acid amplification. Population modeling methods will be used to characterize drug PK in plasma and vaginal fluid and to compare the PD effects on plasma and cervical HIV RNA shedding over time. Relevance: Data from this project will be pertinent to several important, unanswered clinical questions, including: 1) Are some agents more effective in preventing sexual or maternal-to-child transmission of HIV by effectively suppressing viral replication in the genital tract? 2) Is suppression of viral replication in the genital tract necessary to maintain suppression in plasma? 3) Can short-term models of viral dynamics be used to predict long-term responses to therapy? 4) Should women initiate antiretroviral therapy according to different virologic/immunologic criteria than for men?