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

描述（由申请人提供）：本初步研究调查了HIV-1感染治疗后中枢神经系统持续低水平免疫激活的原因。一种解释病毒抑制性抗逆转录病毒治疗中持续免疫激活的主要假设是，HIV-1在大脑内的复制水平太低，无法在脑脊液（CSF）中检测到，但足以刺激局部免疫激活。我们建议使用强效HIV整合酶抑制剂雷替格拉韦（raltegravir）进行强化治疗，以测试额外抑制低级别中枢神经系统病毒复制是否会降低中枢神经系统免疫激活水平。为了理解系统性免疫激活和中枢神经系统免疫激活之间的相互作用，我们将寻求一组与持续系统性免疫激活相关的平行假设，因为在成功治疗的患者中，持续的中枢神经系统免疫激活可能是系统性免疫激活“溢出”到中枢神经系统的结果，而不是由局部中枢神经系统HIV-1复制驱动。因此，主要的方法是利用雷替重力韦的特性（效力，独特的作用部位，以及在受试者群体中缺乏先前的暴露）作为“实验性”探针来评估HIV-1发病机制中的一个基本问题：是否持续的HIV-1复制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，雷替格拉韦强化治疗3个月后脑脊液细胞因子水平和T细胞活化的变化。24名接受联合抗逆转录病毒治疗并记录血浆病毒抑制至少一年的hiv感染者将在确认符合资格后随机分配到这两个组中的一个。受试者将在开始使用每日两次的400mg雷替格拉韦治疗（或不治疗）之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增强治疗是否会影响中枢神经系统的免疫激活，其次，提供了设计一个更明确的研究所需的信息，可以在这种情况下将治疗对中枢神经系统的影响与对全身免疫激活的影响区分开来。该研究旨在阐明HIV-1治疗患者相关神经认知障碍的机制。即使在目前抗逆转录病毒治疗的时代，至少20%的HIV-1感染者仍存在神经认知障碍。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。当患者在治疗中存活多年时，在明显成功的全身治疗环境中持续存在的低水平中枢神经系统免疫激活可能导致损害神经认知功能的脑损伤。这项初步研究调查了在HIV-1感染治疗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机制，并最终优化预防和治疗这种疾病的治疗方法。

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.