Treatment of HIV-Associated Cognitive Impairment

描述（由申请人提供）：这是加州大学旧金山分校神经学家安娜-克莱尔·迈耶博士的K01奖申请。Meyer博士是一名年轻的研究人员，专注于在资源有限的环境下以患者为导向的神经系统传染病临床研究。Meyer博士将通过以下领域的课程、教程和实践经验获得额外的研究培训：将热带医学、神经生理学、神经心理学和神经病毒学的最新研究和实验室方法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卫生方面的额外培训。有了这个奖项，她将获得教学培训和指导临床研究经验，她需要建立自己作为一个独立的研究人员，并成功地竞争R01基金。这项K01奖将使Meyer博士能够采取下一步措施实现她的长期职业目标：成为一名领先的研究人员，开发、评估和实施创新的、具有成本效益的干预措施，以诊断和治疗撒哈拉以南非洲等资源有限的环境中的神经系统疾病。环境：为了支持她的职业目标和研究计划，Meyer博士组建了一个由高级临床研究人员组成的多学科指导委员会，他们将在国际合作中提供有关hiv相关神经认知障碍的临床、流行病学和转化研究方面的额外专业知识。她的主要导师是理查德·w·普莱斯博士，她的共同导师是理查德·w·普莱斯博士。格雷琴·伯贝克和克雷格·科恩。她的发展中国家导师将是Elizabeth Bukusi博士。她所在的加州大学旧金山分校（UCSF）被认为是美国首屈一指的健康科学、培训和研究中心之一，在生物医学研究方面享有盛誉。神经内科是一个领先的学术中心，致力于卓越的病人护理、教育和研究。HIV神经学研究项目开展HIV对神经系统影响的临床和基础科学研究，包括与临床HIV、病毒学和免疫学项目的积极合作。她的国际合作网站，家庭艾滋病护理和教育服务（FACES），是一个位于肯尼亚的艾滋病毒/艾滋病护理和治疗项目。FACES目前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累计招募了96,821名患者，其中37,310名患者接受了ART治疗。FACES临床站点以前有研究经验。此外，FACES站点配备了训练有素的临床医生和辅助人员，并具有完成本研究所需的基础设施和监督。研究计划：我们估计艾滋病毒相关的神经认知障碍（HAND）可能影响肯尼亚尼扬扎省近18.8万人，撒哈拉以南非洲550万人，全球825万人。HAND与抗逆转录病毒治疗（ART）依从性差和死亡率较高有关。联合抗逆转录病毒治疗是迄今为止治疗HAND最有效的方法，一些研究表明，对中枢神经系统（CNS）有较高渗透的抗逆转录病毒治疗可改善神经系统预后。然而，这些研究有重要的局限性，因此没有足够的证据推荐具有高中枢神经系统穿透有效性（CPE）的ART治疗HAND。本应用程序的目的是确定是否重要的是治疗艾滋病毒感染者的神经认知障碍与抗逆转录病毒治疗与高CPE。由于肯尼亚抗逆转录病毒治疗的选择有限，我们将能够直接比较特定抗逆转录病毒治疗方案的效果，从而避免先前研究的局限性。中心假设是，在HAND患者中，与低CPE的ART相比，高CPE的ART可改善神经系统预后。我们将招募一个前瞻性观察队列，包括200名hiv感染的抗逆转录病毒治疗的未接受ART治疗的成人hiv相关认知障碍患者。目的1：为了确定具有不同中枢神经系统药代动力学的常见ART方案对肯尼亚西部未接受ART治疗的HIV感染认知障碍成人的神经心理表现的影响。在为期48周的随访期间，我们将确定四种ART方案对三种NP测量的影响：综合评分、QNPZ-4和使用常见诊断标准的损害水平。目的2：确定具有不同中枢神经药代动力学的常见抗逆转录病毒治疗方案对肯尼亚西部患有认知障碍的抗逆转录病毒感染成人脑脊液（CSF）病毒复制和炎症的影响。在100个个体的亚样本中，我们将确定抗逆转录病毒治疗方案对：(1)CSF HIV-1 RNA的影响；(2) CSF：血浆HIV-1 RNA比值；(3)脑脊液白细胞计数；(4)脑脊液新蝶呤。我们还将为未来的合作研究创建一个独特的样本库。目的3：为了确定是否对神经心理测试组有练习效果，我们将对100名我们之前研究过的未感染艾滋病毒的人重新使用NP组。在一项随机对照试验中，这些特定的目标合乎逻辑地建立了R01，以确定ART对认知受损个体的综合系统和神经系统结局的影响。

DESCRIPTION (provided by applicant): 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- naove 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-naove 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-naove 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. PUBLIC HEALTH RELEVANCE: A better understanding of which antiretroviral therapies lead to the greatest improvements in cognition among individuals with HIV-associated neurocognitive disorders could help physicians better tailor antiretroviral therapy. Ultimately, this could lead to improved cognition, functional status and health for individuals with HIV-associated neurocognitive disorders.