Chronic Exposure to cART Predispose Older HIV Infected Individuals to CNS Injury?

长期接触 cART 会使老年 HIV 感染者容易遭受中枢神经系统损伤？

• 批准号: 8652502
• 负责人: GIOVANNI SCHIFITTO
• 金额: $ 64.18万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652502
• 关键词: Achievement; Affect; Age; Age-Years; Aging; Aging-Related Process; Anisotropy; Anti-Retroviral Agents; Basal Ganglia; Biological Markers; Blood - brain barrier anatomy; Brain; Brain Injuries; Cerebrovascular Circulation; Chronic; Cognitive; Control Groups; Diffusion Magnetic Resonance Imaging; Disease; Dose; Elderly; Energy Metabolism; Enrollment; Exposure to; Functional disorder; HIV; HIV Infections; Homeostasis; Image; Impaired cognition; Individual; Inflammatory; Inflammatory Response; Lead; Long-Term Effects; Magnetic Resonance Spectroscopy; Measurable; Measurement; Measures; Mental Health; Metric; Mitochondria; N-acetylaspartate; Natural History; Neuraxis; Neurocognitive; Neuronal Dysfunction; Neuronal Injury; Neurons; Neurophysiology - biologic function; Nucleosides; P-Glycoprotein; Performance; Pharmaceutical Preparations; Plasma; Population; Proteins; Regimen; Reporting; Research; Residual state; Rest; Reverse Transcriptase Inhibitors; Risk; Signal Transduction; Spin Labels; Structure; Survival Rate; Time; Toxic effect; Treatment Protocols; Vertebral column; Viral; Viral Proteins; age related; antiretroviral therapy; base; central nervous system injury; cohort; cytokine; efflux pump; follow-up; indexing; mitochondrial DNA mutation; nervous system disorder; neuroimaging; neurotoxic; neurotoxicity; primary outcome; public health relevance; secondary outcome; success; white matter

DESCRIPTION (provided by applicant): Combination antiretroviral therapy (cART) has changed the natural history of HIV infection, a remarkable achievement that allows those individuals that can tolerate and are compliant with the regimen a survival rate that is getting closer to those that are not infected. However, despite this great success, cART has not eliminated HIV-associated neurocognitive disorders (HAND). Because HAND is progressive even in those taking cART, it has been suggested that the residual viral replication may be sufficient to maintain an inflammatory response that leads to neuronal injury. Thus better CNS penetrating agents should be useful. However, several reports suggest that cART itself may be neurotoxic and at least in part responsible for the persistence and progression of cognitive impairment. Adding to this scenario is the increased survival of HIV infected individuals which it means that the HIV infected population is getting older and the interaction cART- aging may be synergistic in terms of CNS injury. Defining the potential central nervous system (CNS) toxicity associated with cART exposure and its interaction with aging, will create the bases for changing current practices such as adjusting cART doses, especially in the elderly who may be more vulnerable to cART effect and investigating the best combinations of ART with least CNS toxicity. Findings from this research would also provide impetus to develop new drugs with a better CNS profile. Therefore, the primary aim of this proposal is to determine whether chronic exposure to cART alters brain structure and function and whether this differs in young versus older HIV infected individuals. The primary hypothesis is that chronic exposure to cART will affect neural function, as assessed by decreased resting cerebral blood flow (measured by arterial spin labeling) and alter white matter integrity as assessed by diffusion tensor imaging metrics [decreased fractional anisotropy (FA) and increased mean diffusivity (MD)]. These effects on brain structure and function will be more pronounced in older as compared to younger HIV infected subjects because the impact of cART on cellular energy homeostasis is expected to be greater in older vs. younger subjects. We have chosen changes in these neuroimaging biomarkers as primary outcomes of CNS injury because of their sensitivity although measurements of cognitive performance will be used as secondary outcomes. To investigate the interaction cART-aging and to estimate the contribution of HIV infection in subjects on stable cART and well controlled viral replication, we propose to establish a cohort of younger (40 subjects <50 years of age) and older (40 subjects e 50 years of age) ART naive subjects starting cART. These subjects will be age-matched to HIV- controls. An additional 30 HIV infected long-term non progressors will be enrolled to measure the effect of residual HIV replication on the brain in the absence of cART. It is expected that it will take 24-30 months to enroll the subjects who will then be followed for two years. Previous neuroimaging studies suggest observable changes within two years thus cART neurotoxicity, should be measurable within the two-year follow-up.

描述（由申请人提供）：联合抗逆转录病毒疗法 (cART) 改变了 HIV 感染的自然史，这是一项了不起的成就，它使那些能够耐受并遵守该疗法的个体的生存率越来越接近那些不能耐受该疗法的个体已感染。然而，尽管取得了巨大成功，cART 并没有消除 HIV 相关的神经认知障碍 (HAND)。由于即使在接受 cART 的患者中，HAND 也会进行性进展，因此有人认为，残留的病毒复制可能足以维持导致神经元损伤的炎症反应。因此，更好的中枢神经系统渗透剂应该是有用的。然而，一些报告表明，cART 本身可能具有神经毒性，并且至少在一定程度上导致认知障碍的持续和进展。除此之外，HIV 感染者的存活率也有所增加，这意味着 HIV 感染者的年龄正在增长，并且 cART 衰老的相互作用可能在中枢神经系统损伤方面具有协同作用。定义与 cART 暴露相关的潜在中枢神经系统 (CNS) 毒性及其与衰老的相互作用，将为改变当前实践奠定基础，例如调整 cART 剂量，特别是在可能更容易受到 cART 效应的老年人中，并研究最佳方案具有最小中枢神经系统毒性的 ART 组合。这项研究的结果还将推动开发具有更好中枢神经系统特征的新药。因此，该提案的主要目的是确定长期暴露于 cART 是否会改变大脑结构和功能，以及年轻和老年 HIV 感染者的大脑结构和功能是否有所不同。主要假设是，长期暴露于 cART 会影响神经功能，通过静息脑血流量减少（通过动脉自旋标记测量）来评估，并改变白质完整性，通过扩散张量成像指标来评估[分数各向异性 (FA) 减少和增加平均扩散率（MD）]。与年轻的 HIV 感染者相比，这些对大脑结构和功能的影响在老年人中更为明显，因为与年轻的受试者相比，cART 对细胞能量稳态的影响预计更大。由于其敏感性，我们选择这些神经影像生物标志物的变化作为中枢神经系统损伤的主要结果，尽管认知表现的测量将用作次要结果。为了研究 cART 与衰老的相互作用，并估计受试者中 HIV 感染对稳定 cART 和良好控制的病毒复制的贡献，我们建议建立一个由年轻人（40 名 <50 岁受试者）和老年人（40 名受试者 = 50 岁）组成的队列。岁）未接受 ART 的受试者开始 cART。这些受试者的年龄将与艾滋病毒对照者相匹配。另外 30 名 HIV 感染的长期非进展者将被招募，以测量在没有 cART 的情况下残留的 HIV 复制对大脑的影响。预计将需要 24-30 个月的时间来招募受试者，然后进行为期两年的跟踪。先前的神经影像学研究表明，两年内可观察到变化，因此 cART 神经毒性应该在两年的随访内可测量。