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. ? ? ?
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