Plasma and Genital HIV Dynamics in Women

女性血浆和生殖器艾滋病毒动态

• 批准号: 7919137
• 负责人: Michael N. Neely
• 金额: $ 5万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919137
• 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; 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博士是临床儿科助理教授，在传染病和临床药理学领域接受了专科培训。在过去的四年中，他一直在使用种群药代动力学（PK）建模来测量妇女，青少年和儿童对抗逆转录病毒疗法的依从性，并发现发现非核苷逆转录酶抑制剂（NNRTIS）可能与蛋白酶从蛋白酶脱落的蛋白酶蛋白酶蛋白酶蛋白酶脱蛋白（protease andease insease insease insease inite nnrtis）可能更相关。他的直接目的是使用先进的种群建模技术前瞻性地探索这一发现，以比较NNRTI或PI药效学（PD）对血浆中HIV复制的影响和女性生殖道的影响。他的长期目标是使用PK-PD建模来构建和回答治疗和科学问题，尤其是在妇女和儿童中。南加州大学非常适合这一目标，拥有临床调查的硕士课程，应用药代动力学实验室（LAPK），生物医学模拟资源（BMSR）以及3500多名HIV感染的患者，具有母性儿童青少年（MCA）诊所（MCA）临床诊所（MCA）诊所，专门针对HIV妇女和儿童和儿童和儿童和儿童的需求。 Neely博士将由Roger Jelliffe博士（LAPK）以及包括Andrea Kovacs博士（MCA）和David D'Argenio博士（BMSR）在内的顾问团队进行指导。研究：通过治疗分层的20名妇女，将在6个月的6个月内重复，配对的血液生成样品。血液和直接吸气的阴道液将通过LC-MS/MS分析药物浓度。 HIV RNA将通过等温核酸扩增在血液和宫颈拭子中进行定量。种群建模方法将用于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脱落的影响。相关性：该项目的数据将与几个重要的，未解决的临床问题有关，包括：1）有效地通过有效抑制生殖道中的病毒复制来预防艾滋病毒的性或产妇传播艾滋病毒？ 2）在维持血浆中抑制所必需的生殖道中抑制病毒复制吗？ 3）病毒动力学的短期模型是否可以用于预测对治疗的长期反应？ 4）女性应根据与男性不同的病毒/免疫学标准来启动抗逆转录病毒疗法吗？