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

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，使那些能够耐受并遵守该方案的个体的存活率越来越接近未感染者。然而，尽管取得了巨大的成功，cART并没有消除艾滋病毒相关的神经认知障碍（HAND）。由于HAND即使在接受cART的患者中也是进行性的，因此已经表明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CNS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，至少部分导致认知障碍的持续和进展。增加这种情况的是HIV感染个体的存活率增加，这意味着HIV感染人群正在变老，并且cART-老化的相互作用在CNS损伤方面可能是协同的。确定与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影响的老年人中，并研究具有最小CNS毒性的ART最佳组合。这项研究的发现还将为开发具有更好的中枢神经系统特征的新药提供动力。因此，本提案的主要目的是确定慢性暴露于cART是否会改变大脑结构和功能，以及这在年轻与老年HIV感染者中是否存在差异。主要假设是长期暴露于cART将影响神经功能，如通过静息脑血流量减少（通过动脉自旋标记测量）评估的，并改变白色物质完整性，如通过扩散张量成像指标评估的[各向异性分数（FA）降低和平均扩散率（MD）增加]。与年轻的HIV感染受试者相比，这些对大脑结构和功能的影响在老年受试者中更为明显，因为预计cART对细胞能量稳态的影响在老年受试者中比年轻受试者更大。我们选择这些神经影像学生物标志物的变化作为CNS损伤的主要结局，因为它们的敏感性，尽管认知能力的测量将被用作次要结局。为了研究cART-老化的相互作用，并估计HIV感染对稳定cART受试者和病毒复制控制良好的受试者的贡献，我们建议建立一个由开始cART的年轻（40例受试者<50岁）和老年（40例受试者<50岁）ART初治受试者组成的队列。这些受试者将与HIV对照组年龄匹配。将招募另外30名HIV感染的长期非进展者，以测量在不存在cART的情况下残留HIV复制对大脑的影响。预计需要24-30个月的时间招募受试者，然后对受试者进行两年的随访。先前的神经影像学研究表明两年内可观察到变化，因此cART神经毒性应在两年随访内可测量。

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.