Study of zidovudine addition in HIV-associated neurocognitive disorders

齐多夫定加用治疗 HIV 相关神经认知障碍的研究

• 批准号: 8542402
• 负责人: Albert Anderson
• 金额: $ 17.99万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-10 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542402
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Anti-Retroviral Agents; Area; Award; Basic Science; Biological Markers; Biometry; Brain; Caring; Cerebrospinal Fluid; Chronic; Clinical Research; Clinical Trials; Cognitive; Dementia; Development; Diagnosis; Disease; Future; Generic Drugs; Goals; Gold; Grant; HIV; HIV diagnosis; HIV encephalitis; Highly Active Antiretroviral Therapy; Immune system; Impairment; Incidence; Individual; Insurance; Interdisciplinary Study; Interferon-alpha; Interferons; International; Knowledge; Lead; Lymphocyte Activation; Master' s Degree; Medical; Mentors; Mission; Modeling; Modification; Morbidity - disease rate; National Institute of Mental Health; Neuraxis; Neurocognition; Neurocognitive; Neuropathogenesis; Neuropsychological Tests; Neuropsychology; Neurosciences; Pathogenesis; Patients; Performance; Peripheral; Pharmaceutical Preparations; Placebos; Poverty; Prevalence; Principal Investigator; Public Health; Publishing; Quality of life; Randomized; Regimen; Research; Research Design; Research Personnel; Research Proposals; Residual state; Resources; Risk; Risk Factors; Role; Sampling; Severities; Short-Term Memory; Site-Directed Mutagenesis; Source; Specimen; Standardization; T-Lymphocyte; Testing; Therapeutic Intervention; Therapeutic Studies; Time; Translational Research; Unemployment; United States; Viral; Virus Diseases; Work; Zidovudine; antiretroviral therapy; base; career development; clinical care; clinically significant; cytokine; diagnosis standard; disability; experience; hazard; health related quality of life; health science research; immune activation; improved; meetings; member; mild cognitive impairment; monocyte; mortality; mouse model; neuropsychological; novel therapeutic intervention; public health relevance; repository; research and development; responsible research conduct; standard of care; systems research; validation studies; virus pathogenesis

DESCRIPTION (provided by applicant): This proposed K-23 grant resubmission will provide for the career development of a junior principal investigator who aims to become a leader in human immunodeficiency virus (HIV) clinical research with a focus on the central nervous system (CNS) involvement of HIV. The CNS complications of HIV continue to be a major source of morbidity and mortality. The prevalence of HIV-associated neurocognitive disorder (HAND) is increasing. The presence of HAND is a risk factor for work disability, poor quality of life, and mortality. The proposed research plan addresses three of the most important areas of HIV central nervous system (CNS) research: the possibility that certain antiretroviral medications differentially affect cognitive improvement in HAND, the role of specific cerebrospinal fluid (CSF) biomarkers as indicators of HAND activity, and the incompletely defined role of monocyte and lymphocyte activation in HIV neuropathogenesis. The proposed research is highly relevant to NIMH missions, which include the development of novel therapeutic approaches to mitigate the CNS complications of HIV. The research will take place in an urban HIV center where many of the patients have limited resources due to poverty and lack of medical insurance. Zidovudine is an antiretroviral medication that is now in generic form in the United States, is among the most effective antiretrovirals in penetrating the CNS, and is historically the best studied antiretrovirl for HIV-associated dementia. The investigator's primary hypothesis is that the addition of zidovudine in antiretroviral-na¿ve subjects with HAND will result in significantly greater neurocognitive improvement and biomarkers over the course of 48 weeks. This will be tested in a small clinical study in which subjects will receive a standard of care antiretroviral regimen plu either zidovudine or placebo. If the study shows superior improvement in neurocognition and/or biomarkers for subjects randomized to zidovudine, the team will pursue larger studies of zidovudine addition for individuals with HAND. The secondary aims of the proposal pertain to the hypothesis that biomarkers are a reflection of HAND and that cytokines and peripheral immune activation independently contribute to HAND and may be targets for modification with future therapies. The research team aims to estimate normal CSF biomarker values based on an established large repository of samples. They have shown that certain biomarkers correlate with HAND severity and improve during treatment. One aim would be to test a composite score of eight biomarkers alongside standardized neuropsychological testing. If a promising correlation is demonstrated, the biomarker score would be tested in larger studies as a correlate of HAND. The research team has also demonstrated in previous work that CSF IFN-alpha levels inversely correlate with neuropsychological scores in subjects with HAND. They have also shown that in a mouse model of HIV encephalitis, treatment with IFN-alpha blockade was associated with a benefit in working memory and decreased pathological markers in the brain. The proposed clinical study will allow the team to build on these findings. The team hypothesizes that individuals with residual neurocognitive impairment despite effective antiretroviral therapy will have higher residual CSF IFN-alpha levels. This would form the basis for clinical studies of IFN-alpha modifying therapy that the research team has developed for individuals with HAND. Another secondary aim is to examine the role of peripheral monocyte and lymphocyte activation in HAND. It is clear that peripheral lymphocyte activation contributes to overall AIDS pathogenesis. However, it is not known if lymphocyte activation independently contributes to HAND. Current evidence suggests that peripheral monocyte activation represents one of the initial steps in the establishment of the HIV reservoir in the brain. However, it is unclear whether peripheral monocyte activation is more modifiable with certain antiretroviral medications. This study will examine whether subjects with HAND randomized to zidovudine, which has demonstrated antiretroviral activity within monocytes, have less peripheral monocyte activation. If the proposed study indicates that HAND severity is related to peripheral immune activation and that the beneficial effect of certain antiretroviral agents may be related to modification of immune activation, this would lead to future studies of therapies that directly target immune activation for the amelioration of HAND or as a means to interrupt the establishment of the HIV reservoir in the brain, which represents one of the barriers to HIV eradication. The principal investigator for this proposal has assembled a diverse mentoring team with experts from HIV clinical research, neurosciences, and HIV basic research. These mentors each bring important strengths to the multidisciplinary research plan and have agreed to meet regularly with the principal investigator in order to provide guidance in research and career development. The principal investigator has significant experience in HIV clinical care and research. In addition to his medical degree, he holds a masters degree in health sciences research. He is based at one of the largest centers for HIV care in the United States. As part of the research proposal, he will also receive formal coursework in neuro-HIV/AIDS research, clinical trials, neuropsychology, biostatistics, and the responsible conduct of research. He will regularly attend international HIV research meetings in which he will present his research. Overall, this career development project will allow the principal investigator to pursue the goal o becoming an established investigator and leader in HIV CNS research.

描述(由申请人提供)：这项拟议的K-23补助金重新提交将提供一名初级首席研究员的职业发展，他的目标是成为人类免疫缺陷病毒(HIV)临床研究的领导者，重点是艾滋病毒参与中枢神经系统(CNS)。艾滋病毒的中枢神经系统并发症仍然是发病率和死亡率的主要来源。艾滋病毒相关神经认知障碍(HAND)的患病率正在上升。手的存在是导致工作残疾、生活质量差和死亡的风险因素。拟议的研究计划涉及艾滋病毒中枢神经系统(CNS)研究的三个最重要的领域：某些抗逆转录病毒药物对手部认知改善的不同影响的可能性，特定脑脊液(CSF)的作用 作为手活动指标的生物标志物，以及单核细胞和淋巴细胞激活在艾滋病毒神经发病中的未完全确定的作用。拟议的研究与NIMH任务高度相关，其中包括开发新的治疗方法来减轻艾滋病毒的中枢神经系统并发症。这项研究将在一个城市艾滋病毒中心进行，那里的许多患者由于贫困和缺乏医疗保险而资源有限。齐多夫定是一种抗逆转录病毒药物，目前在美国是仿制药，是穿透中枢神经系统最有效的抗逆转录病毒药物之一，历史上是治疗艾滋病毒相关痴呆的研究最好的抗逆转录病毒药物。研究人员的主要假设是，在48周的过程中，在抗逆转录病毒阴性的受试者中加入齐多夫定将显著改善神经认知和生物标记物。这将在一项小型临床研究中进行测试，在该研究中，受试者将接受标准的抗逆转录病毒治疗方案，外加齐多夫定或安慰剂。如果这项研究显示随机服用齐多夫定的受试者在神经认知和/或生物标记物方面有显著改善，研究小组将对手部患者进行更大规模的齐多夫定补充研究。该提案的次要目标涉及这样的假设，即生物标记物是手部的反映，细胞因子和外周免疫激活独立地对手部做出贡献，并可能成为未来治疗的修改目标。该研究小组的目标是基于建立的大型样本库来估计正常的脑脊液生物标记物的值。他们已经表明，某些生物标记物与手的严重程度相关，并在治疗过程中有所改善。其中一个目标是测试八个生物标记物的综合得分，以及标准化的神经心理测试。如果有希望的相关性被证明，生物标记物得分将在更大的研究中作为手的相关性进行测试。研究小组还在之前的工作中证明，在手部疾病的受试者中，脑脊液中的干扰素-α水平与神经心理评分呈负相关。他们还表明，在艾滋病毒脑炎的小鼠模型中，使用干扰素-α阻断治疗与改善工作记忆和降低大脑中的病理标记物有关。拟议的临床研究将使该团队能够在这些发现的基础上再接再厉。该团队假设，尽管进行了有效的抗逆转录病毒治疗，但仍有神经认知障碍的个体将有更高的残留脑脊液干扰素-α水平。这将为研究小组为手部患者开发的干扰素-α修饰疗法的临床研究奠定基础。另一个次要目标是研究外周血单核细胞和手部淋巴细胞活化的作用。很明显，外周淋巴细胞的激活在整个艾滋病的发病机制中起着重要作用。然而，目前尚不清楚淋巴细胞激活是否独立地对HAND起作用。目前的证据表明，外周血单核细胞激活是在大脑中建立艾滋病毒储存库的最初步骤之一。然而，目前尚不清楚某些抗逆转录病毒药物是否更能改变外周血单核细胞的激活。这项研究将检验随机服用齐多夫定的受试者是否外周血单核细胞活化较少。齐多夫定在单核细胞中显示出抗逆转录病毒活性。如果拟议的研究表明手的严重程度与外周免疫激活有关，并且某些抗逆转录病毒药物的有益效果可能与免疫激活的改变有关，这将导致未来研究直接针对免疫激活的治疗方法，以改善手的症状或作为一种手段来干扰艾滋病毒在大脑中的建立，这是根除艾滋病毒的障碍之一。这项提案的首席研究员已经组建了一个多样化的指导团队，其中包括来自艾滋病毒临床研究、神经科学和艾滋病毒基础研究的专家。这些导师每个人都为多学科研究计划带来了重要优势，并同意定期与首席调查员会面，以便在研究和职业发展方面提供指导。首席研究员在艾滋病毒临床护理和研究方面拥有丰富的经验。除了医学学位，他还拥有健康科学研究硕士学位。他的总部设在美国最大的艾滋病毒护理中心之一。作为研究提案的一部分，他还将接受神经艾滋病毒/艾滋病研究、临床试验、神经心理学、生物统计学和负责任的研究指导方面的正式课程。他将定期参加国际艾滋病毒研究会议，在会上介绍他的研究成果。总体而言，这一职业发展项目将使首席调查员能够追求成为艾滋病毒中枢神经系统研究的既定调查员和领导者的目标。