Plasma and Genital HIV Dynamics in Women

女性血浆和生殖器艾滋病毒动态

• 批准号: 7904762
• 负责人: Michael N. Neely
• 金额: $ 9.5万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904762
• 关键词: 16 year old; Adherence; Adolescent; Anti-Retroviral Agents; Aspirate substance; Atazanavir; Behavior; Blood; CD4 Lymphocyte Count; California; Centers of Research Excellence; Cervical; Cervix Uteri; Child; Clinic; Clinical; Clinical Pharmacology; Clinical Trials; Communicable Diseases; Computer Simulation; Computer software; Counseling; Data; Discrimination; Dose; Drug Kinetics; Drug resistance; Enrollment; Female; Genital system; Goals; HIV; Immunologics; Individual; Individual Differences; Infection; K-Series Research Career Programs; Laboratories; Mass Spectrum Analysis; Measures; Mentors; Methods; Modeling; Nucleic Acids; Participant; Patients; Pediatrics; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Plasma; Population; Population Study; Prevalence; Prevention; Protease Inhibitor; RNA; Regimen; Research; Research Personnel; Resources; Risk; Ritonavir; Sampling; Specimen; Swab; Techniques; Testing; Therapeutic; Time; Training; Treatment Protocols; Universities; Vertical Disease Transmission; Viral; Viral Load result; Virus Shedding; Visit; Woman; antiretroviral therapy; base; efavirenz; genital secretion; men; non-nucleoside reverse transcriptase inhibitors; novel; pharmacodynamic model; pharmacokinetic model; prevent; professor; programs; prophylactic; response; sex; simulation; transmission process; vaginal fluid

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?

描述（由候选人提供）：候选人：Neely博士是临床儿科学助理教授，接受过感染性疾病和临床药理学的亚专业培训。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）更与宫颈HIV RNA的脱落相关。他的近期目标是使用先进的群体建模技术前瞻性地探索这一发现，以比较NNRTI或PI对血浆和女性生殖道中HIV复制的药效学（PD）作用。他的长期目标是发展一个卓越的研究中心，使用PK-PD模型提出和回答治疗和科学问题，特别是在妇女和儿童。南加州大学非常适合这一目标，拥有临床研究硕士课程，应用药代动力学实验室（LAPK），生物医学模拟资源（BMSR）和超过3500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·杰利夫博士（LAPK）以及包括安德烈·科瓦奇博士（MCA）和大卫·德米利奥博士（BMSR）在内的顾问团队指导。研究：将在6个月内从20名女性中获得重复的配对血液生殖器样本，按治疗分层。将通过LC-MS/MS分析血液和直接抽吸的阴道液的药物浓度。将通过等温核酸扩增对血液和宫颈拭子中的HIV RNA进行定量。将使用群体建模方法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随时间脱落的影响。相关性：该项目的数据将与几个重要的、尚未回答的临床问题有关，包括：1）是否有些药物通过有效抑制生殖道中的病毒复制，在预防性传播或母婴传播艾滋病毒方面更有效？2)抑制生殖道中的病毒复制是否是维持血浆中抑制所必需的？3)短期病毒动力学模型能否用于预测治疗的长期反应？4)女性是否应该根据与男性不同的病毒学/免疫学标准开始抗逆转录病毒治疗？