Pilot Study of Treatment Augmentation on CNS Immunoactivation in Treated HIV-1 In

描述（由申请方提供）：该初步研究调查了在接受治疗的HIV-1感染情况下持续低水平中枢神经系统免疫激活的原因。解释在病毒抑制性抗逆转录病毒治疗的背景下持续免疫激活的主要假设是，HIV-1复制在脑内继续，其水平太低而无法在脑脊液（CSF）中检测到，但足以刺激局部免疫激活。我们建议使用HIV整合酶的强效抑制剂雷特格韦（raltegravir）加强治疗，以测试是否额外抑制低级CNS病毒复制会降低CNS免疫活化水平。将采用与持续性全身免疫激活相关的一组平行假设，以了解全身和CNS免疫激活之间的相互作用，因为成功治疗患者的持续性CNS免疫激活可能是全身免疫激活“溢出”到CNS的结果，而不是由局部CNS HIV-1复制驱动。因此，主要的方法是利用雷特格韦的特性（效力，独特的作用部位，以及受试者人群中缺乏既往暴露）作为“实验性”探针，以评估HIV-1发病机制中的一个基本问题：HIV-1持续复制是否低于标准检测水平驱动免疫激活。这将是一项非盲、开放标签、对照研究，评估与持续非强化治疗相比，雷特格韦强化治疗3个月后CSF细胞因子水平和T细胞活化的变化。24例接受抗逆转录病毒联合治疗并记录血浆病毒抑制至少1年的HIV感染受试者将在确认合格性后随机分配至这两个治疗组之一。受试者将在开始400 mg雷特格韦每日两次治疗（或无治疗）前返回进行基线评估，并将在第4周、第8周和第3个月再次进行观察。这项初步研究首先测试了强化治疗是否会影响CNS免疫活化，其次，提供了设计一项更明确的研究所需的信息，该研究可以将这种情况下对CNS的治疗效果与对全身免疫活化的治疗效果分开。该研究旨在阐明治疗患者中HIV-1相关神经认知障碍的潜在机制。即使在目前的抗逆转录病毒治疗时代，神经认知障碍也困扰着至少20%的HIV-1感染者。中枢神经系统内免疫系统的激活是HIV-1感染中神经损伤的关键介质。由于患者在治疗中存活多年，在明显成功的全身治疗的情况下持续存在的低水平CNS免疫活化可能导致脑损伤，损害神经认知功能。这项初步研究调查了在治疗HIV-1感染的情况下持续低水平CNS免疫激活的原因。我们的目标是阐明HIV-1相关神经认知障碍的潜在机制，并最终优化预防和治疗这种疾病的疗法。

DESCRIPTION (provided by applicant): This pilot study investigates the causes of ongoing low-level central nervous system immune activation in the setting of treated HIV-1 infection. A leading hypothesis explaining persistent immunoactivation in the setting of virally-suppressive antiretroviral therapy is that HIV-1 replication continues within the brain at a level too low for detection in cerebrospinal fluid (CSF), yet sufficient to stimulate local immunoactivation. We propose to use augmented treatment with the potent inhibitor of the HIV integrase enzyme, raltegravir, to test whether additional suppression of low-grade CNS viral replication will reduce levels of CNS immunoactivation. A parallel set of hypotheses related to persistent systemic immune activation will be pursued to understand the interactions between systemic and CNS immunoactivation, since it is possible that persistent CNS immunoactivation in successfully treated patients is a consequence of 'overflow' of systemic immunoactivation into the CNS rather than driven by local CNS HIV-1 replication. Thus, the main approach is to exploit the properties of raltegravir (potency, unique site of action, and lack of previous exposure in the subject population) as an 'experimental' probe to assess a fundamental issue in HIV-1 pathogenesis: whether continued HIV-1 replication below the level of standard detection drives immunoactivation. This will be an unblinded, open-label, controlled study assessing changes in CSF cytokine levels and T cell activation after 3 months of augmented therapy with raltegravir compared to continued, non-augmented therapy. Twenty-four HIV-infected subjects on combination antiretroviral therapy with documented plasma viral suppression for at least one year will be randomized after confirmation of eligibility to one of these two arms. Subjects will return for a baseline evaluation before beginning treatment with 400 mg raltegravir twice daily (or no therapy) and will be seen at 4 weeks, at 8 weeks, and again at three months. This pilot study first tests whether augmented therapy impacts CNS immunoactivation and, second, provides information needed to design a more definitive study that can segregate treatment effects on CNS from those on systemic immunoactivation in this setting. The study aims to elucidate mechanisms underlying HIV-1 related neurocognitive impairment in treated patients. Even in the current era of antiretroviral therapy, neurocognitive impairment afflicts at least 20% of individuals infected with HIV-1. Activation of the immune system within the central nervous system is a critical mediator of neurological injury in HIV-1 infection. As patients survive for years on treatment, low-level CNS immunoactivation that persists in the setting of apparently successful systemic therapy likely leads to brain injury that compromises neurocognitive function. This pilot study investigates the causes of ongoing low- level CNS immune activation in the setting of treated HIV-1 infection. We aim to elucidate mechanisms underlying HIV-1 related neurocognitive impairment and ultimately optimize therapy for the prevention and treatment of this disorder.