Treatment of HIV-Associated Cognitive Impairment

项目摘要/摘要： 候选人：这是为安娜-克莱尔·迈耶博士申请K01奖的申请书，她是华盛顿大学的神经科医生 加州大学旧金山分校。迈耶博士将自己确立为一名年轻的研究人员，专注于 在资源有限的情况下，以患者为导向的神经系统传染病临床研究。Dr。 Meyer将通过课程作业、教程和在 以下领域：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在全球卫生环境中的应用；设计和实施 临床试验；以及实施科学和全球卫生方面的额外培训。有了这个奖项，她将 获得她所需的教学培训和临床研究指导经验，以确立自己的 独立研究人员，并成功争取R01资金。这一K01奖项将使迈耶博士能够 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， 评估和实施创新的、具有成本效益的干预措施来诊断和治疗神经病 在资源有限的情况下，如撒哈拉以南非洲的条件。 环境：为了支持她的职业目标和研究计划，迈耶博士组织了一份 由高级临床研究人员组成的多学科指导委员会将提供额外的 在HIV相关神经认知的临床、流行病学和翻译研究方面的专业知识 国际范围内的障碍合作。她的主要导师是理查德·W·普莱斯博士和她的合作导师 是格雷琴·伯贝克博士和克雷格·科恩博士。她的发展中国家导师将是伊丽莎白·布库西博士。 她的家乡加州大学旧金山分校(UCSF)被认为是 全国首屈一指的健康科学、培训和研究中心，在 生物医学研究。神经病学系是一个致力于卓越的学术中心 病人护理、教育和研究。艾滋病毒神经学研究计划进行临床和基础研究 关于艾滋病毒对神经系统影响的科学研究，包括与临床的积极合作 艾滋病毒、病毒学和免疫学项目。她的国际合作网站，家庭艾滋病关怀和教育 服务(FACES)是一项总部设在肯尼亚的艾滋病毒/艾滋病护理和治疗计划。Faces目前提供 在Nyanza省和内罗毕的83个设施中提供艾滋病毒护理。截至2010年12月31日，Facebook有96,821人 患者累计纳入37,310名接受ART治疗的患者。脸部临床站点有既往经验 通过研究研究。此外，Face网站的工作人员都是训练有素的临床医生和辅助人员，以及 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HIV相关的神经认知障碍(HAND)可能会影响到近 肯尼亚尼安萨省有18.8万人，撒哈拉以南非洲地区有550万人，825万人 全世界。HAND与抗逆转录病毒治疗(ART)的依从性较差有关，与较高的 死亡率。到目前为止，联合抗逆转录病毒治疗是治疗手部疾病最有效的方法，一些研究已经 提示ART对中枢神经系统(CNS)的渗透率较高，有助于改善神经学 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 推荐具有高中枢神经系统穿透效能(CPE)的ART治疗手部疾病。的目标是 这项应用是为了确定用神经认知疗法治疗艾滋病毒感染者是否重要。 伴有高CPE的ART障碍。由于肯尼亚的艺术选择有限，我们将能够直接 比较特定抗逆转录病毒疗法的效果，从而避免先前研究的局限性。中环 假说是，在有手的个体中，CPE高的ART可以改善神经学结果，因为 与CPE低的ART相比。我们将招募200名艾滋病病毒感染者的前瞻性观察队列- 目前尚无艾滋病相关认知障碍的成年人。 目的1：比较不同中枢神经系统药代动力学的常用抗逆转录病毒治疗方案对患者的影响。 肯尼亚西部地区艾滋病病毒感染者认知障碍成人的神经心理表现 在48周的随访期内，我们将确定四种ART方案对三种NP措施的效果： 综合评分，QNPZ-4，以及使用通用诊断标准的损害程度。 目的：观察不同中枢药物动力学的常用ART方案对病毒的影响。 人类免疫缺陷病毒感染成人认知障碍患者脑脊液中的复制和炎症 肯尼亚西部的损害 在一个100人的子样本中，我们将确定ART方案对：(1)脑脊液HIV-1RNA的影响；(2) 脑脊液：血浆HIV-1RNA比值；(3)脑脊液白细胞计数；(4)脑脊液新喋呤。我们还将创建一个唯一的存储库 为未来的合作研究提供样本。 目的3：确定神经心理测试组合是否有练习效果 我们将对我们之前研究过的100名未感染艾滋病毒的人重新管理我们的NP电池。 这些具体目标合乎逻辑地建立在R01上，以确定ART对系统性和系统性结合的影响 一项随机对照试验中认知受损个体的神经学结果。

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.