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: 8676942
• 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/8676942
• 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）：拟议的 K-23 拨款重新提交将为初级首席研究员的职业发展提供支持，该首席研究员的目标是成为人类免疫缺陷病毒 (HIV) 临床研究的领导者，重点关注中枢神经系统 (CNS) HIV 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 HIV 相关神经认知障碍 (HAND) 的患病率正在增加 HAND 的存在是工作残疾的一个危险因素。拟议的研究计划涉及艾滋病毒中枢神经系统（CNS）研究的三个最重要领域：某些抗逆转录病毒药物对 HAND 认知改善有不同影响的可能性，特定脑脊液（CSF）的作用。 ） 生物标志物作为 HAND 活性的指标，以及单核细胞和淋巴细胞激活在 HIV 神经发病机制中的不完全确定的作用。拟议的研究与 NIMH 任务相关，其中包括开发新的治疗方法来减轻 HIV 的中枢神经系统并发症。齐多夫定是一种抗逆转录病毒药物，目前在美国是通用药物，是最有效的药物之一。抗逆转录病毒药物可以穿透中枢神经系统，并且是历史上研究最充分的治疗艾滋病毒相关痴呆的抗逆转录病毒药物。研究者的主要假设是在抗逆转录病毒药物中添加齐多夫定。患有 HAND 的受试者将在 48 周内获得更大的神经认知改善和生物标志物，这将在一项小型临床研究中进行测试，如果研究表明，受试者将接受标准的抗逆转录病毒治疗方案以及齐多夫定或安慰剂。为了改善随机服用齐多夫定的受试者的神经认知和/或生物标志物，该团队将对患有 HAND 的个体进行更大规模的齐多夫定添加研究。该提案的次要目标是。假设生物标志物是 HAND 的反映，细胞因子和外周免疫激活独立地促成 HAND，并且可能是未来疗法修改的目标。研究小组旨在根据已建立的大型数据库来估计正常的 CSF 生物标志物值。他们已经表明，某些生物标志物与手部疾病的严重程度相关，并在治疗过程中得到改善。作为 HAND 的相关项。研究小组在之前的工作中还证明，CSF IFN-α 水平与 HAND 受试者的神经心理学评分呈负相关。他们还表明，在 HIV 脑炎小鼠模型中，IFN-α 阻断治疗与工作获益相关。拟议的临床研究将使研究小组能够在这些发现的基础上进一步发现，尽管接受了有效的抗逆转录病毒治疗，但仍有残余神经认知障碍的个体仍具有较高的残余脑脊液。 IFN-α 水平。这将构成研究小组为 HAND 患者开发的 IFN-α 修饰疗法的临床研究的基础。另一个次要目标是检查外周单核细胞和淋巴细胞激活在 HAND 中的作用。外周淋巴细胞的激活有助于艾滋病的整体发病机制。然而，目前的证据表明外周单核细胞的激活是艾滋病病毒在大脑中建立的最初步骤之一。然而，目前尚不清楚外周单核细胞的激活是否可以通过某些抗逆转录病毒药物进行更有效的调节。如果拟议的研究表明，齐多夫定（已在单核细胞中表现出抗逆转录病毒活性），则本研究将检查是否具有较少的外周单核细胞激活。严重程度与外周免疫激活有关，某些抗逆转录病毒药物的有益作用可能与免疫激活的改变有关，这将导致未来直接针对免疫激活的疗法的研究改善 HAND 或作为中断大脑中 HIV 储存库建立的一种手段，这是根除 HIV 的障碍之一。该提案的主要研究人员组建了一个由来自 HIV 临床研究、神经科学、这些导师都为多学科研究计划带来了重要优势，并同意定期与首席研究员会面，以便为研究和职业发展提供指导。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。除了他的医学学位之外，他拥有健康科学研究硕士学位。他在美国最大的艾滋病毒护理中心之一工作。作为研究计划的一部分，他还将接受神经艾滋病毒/艾滋病研究、临床试验的正式课程。 、神经心理学、生物统计学和负责任的研究行为。他将定期参加国际艾滋病毒研究会议，并在会上展示他的研究成果。总体而言，该职业发展项目将使首席研究员能够实现成为一名知名研究者和领导者的目标。从事艾滋病毒中枢神经系统研究。