Treatment of HIV-Associated Cognitive Impairment

HIV 相关认知障碍的治疗

• 批准号: 8704774
• 负责人: Ana-Claire Lew Meyer
• 金额: $ 13.52万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2016-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704774
• 关键词: AIDS Dementia Complex; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adherence; Adult; Adverse effects; Affect; Africa South of the Sahara; Aftercare; Ambulatory Care; Anti-Retroviral Agents; Area; Award; Basic Science; Biomedical Research; Brain; California; Caring; Cerebrospinal Fluid; Clinical; Clinical Investigator; Clinical Research; Clinical Sciences; Clinical Trials; Cognition; Cohort Studies; Collaborations; Communicable Diseases; Control Groups; Data; Developing Countries; Diagnosis; Diagnostic; Disease; Drug Kinetics; Education; Effectiveness; Enrollment; Environment; Epidemiology; Familiarity; Family; Funding; Future; Goals; HIV; HIV-1; Health; Health Sciences; Home environment; Immunology; Impaired cognition; Impairment; Incidence; Individual; Infection; Inflammation; Institution; International; Kenya; Laboratory Research; Lead; Measures; Mentored Research Scientist Development Award; Mentors; Methods; Neopterin; Nervous system structure; Neuraxis; Neurocognitive; Neurologic; Neurological outcome; Neurologist; Neurology; Neuropsychological Tests; Neuropsychology; Neurovirology; Observational Study; Patient Care; Patients; Penetration; Performance; Pharmaceutical Preparations; Physicians; Plasma; Prevalence; Price; Province; Proxy; RNA; Randomized Controlled Trials; Regimen; Reporting; Research; Research Infrastructure; Research Personnel; Research Training; Resources; Risk; Sampling; San Francisco; Services; Site; Testing; Training; Translational Research; Treatment Effectiveness; Tropical Medicine; Universities; Viral; Work; abstracting; antiretroviral therapy; base; career; clinical research site; cohort; cost effective; design; effective intervention; effective therapy; experience; follow-up; functional status; global health; implementation science; improved; innovation; mortality; multidisciplinary; neurophysiology; neuropsychological; patient oriented; programs; prospective; psychologic; repository; research study; treatment program; virology

Project Summary/Abstract: The Candidate: This is an application for a K01 award for Dr. Ana-Claire Meyer, a neurologist at the University of California, San Francisco. Dr. Meyer is establishing herself as a young investigator focused on patient-oriented clinical research on infectious diseases of the nervous system in resource-limited settings. Dr. Meyer will obtain additional research training through coursework, tutorials and practical experience in the following areas: applying state-of-the-art research and laboratory methods in tropical medicine, neurophysiology, neuropsychology and neurovirology to global health settings; designing and implementing clinical trials; and additional training in implementation science and global health. With this award, she will obtain the didactic training and mentored clinical research experience she needs to establish herself as an independent researcher and successfully compete for R01 funding. This K01 award will enable Dr. Meyer to take the next steps to achieve her long-term career goal: to become a leading researcher developing, evaluating, and implementing innovative and cost-effective interventions to diagnose and treat neurologic conditions in resource limited settings such as sub-Saharan Africa. The Environment: To support her career objectives and research plan, Dr. Meyer has assembled a multidisciplinary mentoring committee comprised of senior clinical investigators who will provide added expertise in conducting clinical, epidemiological, and translational research on HIV-associated neurocognitive disorders within an international collaborative. Her primary mentor is Dr. Richard W. Price, and her co-mentors are Drs. Gretchen Birbeck and Craig Cohen. Her developing country mentor will be Dr. Elizabeth Bukusi. Her home institution, the University of California San Francisco (UCSF), is considered one of the nation's premier health sciences, training, and research centers and has a well-established reputation in biomedical research. The Department of Neurology is a leading academic center dedicated to excellence in patient care, education and research. The HIV Neurology Research Program conducts clinical and basic science research on the effects of HIV on the nervous system and includes active collaborations with clinical HIV, virology and immunology programs. Her international collaborative site, Family AIDS Care and Education Services (FACES), is an HIV/AIDS care and treatment program based in Kenya. FACES currently provides HIV care in 83 facilities in Nyanza Province and Nairobi. As of December 31, 2010, FACES had 96,821 patients cumulatively enrolled with 37,310 patients on ART. FACES clinical sites have previous experience with research studies. In addition, FACES sites are staffed by well-trained clinicians and ancillary staff and have the necessary infrastructure and oversight to complete this study. Research Plan: We estimate that HIV-associated neurocognitive disorders (HAND) may affect nearly 188,000 individuals in Nyanza Province, Kenya, 5.5 million across sub-Saharan Africa, and 8.25 million worldwide. HAND has been associated with poor adherence to antiretroviral therapy (ART) and with higher mortality. Combination ART is the most effective treatment for HAND to date and some studies have suggested that ART with higher penetration into the central nervous system (CNS) lead to improved neurologic outcomes. However, these studies have important limitations and thus there is insufficient evidence to recommend ART with high CNS penetration effectiveness (CPE) for the treatment of HAND. The objective of this application is to determine whether it is important to treat HIV-infected individuals with neurocognitive disorders with ART with high CPE. Because of limited ART choices in Kenya, we will be able to directly compare the effects of specific ART regimens thus avoiding the limitations of prior studies. The central hypothesis is that, among individuals with HAND, ART with high CPE lead to improved neurologic outcomes as compared to ART with low CPE. We will enroll a prospective observational cohort of 200 HIV-infected ART- na¿ve adults with HIV-associated cognitive impairment. Aim 1: To determine the effect of common ART regimens with different CNS pharmacokinetics on the neuro-psychological performance of ART-na¿ve HIV infected adults with cognitive impairment in western Kenya Over a follow-up period of 48 weeks, we will determine the effect of four ART regimens on three NP measures: a composite score, the QNPZ-4, and level of impairment using common diagnostic criteria. Aim 2: To determine the effect of common ART regimens with different CNS pharmacokinetics on viral replication and inflammation in the cerebrospinal fluid (CSF) of ART-na¿ve HIV infected adults with cognitive impairment in western Kenya In a sub-sample of 100 individuals, we will determine the effect of ART regimens on: (1) CSF HIV-1 RNA; (2) CSF:plasma HIV-1 RNA ratio; (3) CSF WBC count; (4) CSF neopterin. We will also create a unique repository of samples for future collaborative studies. Aim 3: To determine whether there is a practice effect on the neuropsychological test battery We will re-administer our NP battery to 100 HIV un-infected individuals who we have previously studied. These specific aims logically build toward an R01 to determine the effect of ART on combined systemic and neurologic outcomes in cognitively impaired individuals in a randomized controlled trial.

项目概要/摘要： 候选人：这是一份K 01奖的申请，申请者是安娜-克莱尔·迈耶博士，一位神经学家， 加州大学旧金山分校弗朗西斯科。Meyer博士正在成为一名年轻的调查员，专注于 在资源有限的情况下开展以病人为中心的神经系统传染病临床研究。博士 迈耶将获得额外的研究培训，通过课程，教程和实践经验，在 在热带医学中应用最先进的研究和实验室方法， 神经生理学、神经心理学和神经病毒学应用于全球卫生环境;设计和实施 临床试验;以及实施科学和全球健康方面的额外培训。凭借这个奖项，她将 获得她需要的教学培训和指导临床研究经验，以使自己成为一名 独立研究员，并成功地竞争R 01资金。这个K 01奖项将使迈耶博士， 采取下一步行动来实现她的长期职业目标：成为一名领先的研究人员， 评估和实施创新和具有成本效益的干预措施，以诊断和治疗神经系统疾病 在资源有限的情况下，如撒哈拉以南非洲。 环境：为了支持她的职业目标和研究计划，Meyer博士收集了一份 由高级临床研究者组成的多学科指导委员会， 在HIV相关神经认知方面进行临床、流行病学和转化研究的专业知识 在国际合作中。她的主要导师是Richard W.普莱斯和她的导师们 是格雷琴·伯贝克和克雷格·科恩医生她的发展中国家导师将是Elizabeth Bukusi博士。 她的家乡，加州旧金山弗朗西斯科（UCSF），被认为是一个 全国首屈一指的健康科学，培训和研究中心，并在 生物医学研究神经病学系是一个领先的学术中心，致力于卓越的， 患者护理、教育和研究。艾滋病毒神经学研究计划进行临床和基础 艾滋病毒对神经系统影响的科学研究，包括与临床 艾滋病毒、病毒学和免疫学项目。她的国际合作网站，家庭艾滋病护理和教育 FACES是一个设在肯尼亚的艾滋病毒/艾滋病护理和治疗方案。Faces目前提供 在尼扬扎省和内罗毕的83个设施提供艾滋病毒护理。截至2010年12月31日，FACES拥有96，821个 累积入组37，310例ART患者。FACES临床研究中心有既往经验 进行研究。此外，FACES研究中心配备了训练有素的临床医生和辅助人员， 有必要的基础设施和监督来完成这项研究。 研究计划：我们估计，艾滋病毒相关的神经认知障碍（HAND）可能会影响近 肯尼亚尼扬扎省有18.8万人，撒哈拉以南非洲有550万人， 国际吧HAND与抗逆转录病毒治疗（ART）依从性差相关， mortality.联合ART是迄今为止最有效的治疗HAND的方法，一些研究表明， 表明ART对中枢神经系统（CNS）的渗透性更高，可改善神经功能 结果。然而，这些研究有重要的局限性，因此没有足够的证据来证明 推荐具有高CNS渗透有效性（CPE）的ART用于治疗HAND。的目标 这项应用是为了确定是否重要的是治疗艾滋病毒感染者的神经认知 具有高CPE的ART疾病。由于肯尼亚的ART选择有限，我们将能够直接 比较特定ART方案的效果，从而避免先前研究的局限性。中央 假设是，在患有HAND个体中，具有高CPE的ART导致改善的神经学结果， 与低CPE的ART相比。我们将招募200名HIV感染ART的前瞻性观察队列， 患有艾滋病相关认知障碍的初治成人。 目的1：确定具有不同CNS药代动力学的常用ART方案对 肯尼亚西部未接受抗逆转录病毒治疗的HIV感染成年人的神经心理学表现 在48周的随访期内，我们将确定四种ART方案对三种NP指标的影响： 综合评分、QNPZ-4和使用常见诊断标准的损伤水平。 目的2：确定具有不同CNS药代动力学的常用ART方案对病毒感染的影响。 抗逆转录病毒治疗初治的HIV感染成人的脑脊液（CSF）中的复制和炎症 肯尼亚西部的减值 在100名个体的子样本中，我们将确定ART方案对以下方面的影响：（1）CSF HIV-1 RNA;（2） CSF：血浆HIV-1 RNA比率;（3）CSF WBC计数;（4）CSF新蝶呤。我们还将创建一个唯一的存储库 用于未来的合作研究。 目的3：确定神经心理成套测验是否存在练习效应 我们将重新管理我们的NP电池100艾滋病毒未感染的个人谁，我们以前研究。 这些具体目标在逻辑上建立在R 01的基础上，以确定ART对全身和全身性疾病的综合影响。 一项随机对照试验中认知受损个体的神经学结局。