Effect of Antiviral CNS Penetration on CSF/Blood Cytokines and Depression in HIV

描述（由申请人提供）：对艾滋病毒/艾滋病采用高效抗逆转录病毒疗法（HAART）提高了生存率。然而，抑郁症的患病率并没有显著变化。抑郁症与不良临床结局相关。假设中枢神经系统（CNS）中较高浓度的抗HIV药物是有益神经反应的主要调节剂。一些医学相关的抑郁症的研究表明，炎症细胞因子作为抑郁症的促发因子的作用。 最近描述的抗逆转录病毒治疗（ART）的CNS渗透有效性（CPE）评分的概念允许改善CNS中抗逆转录病毒（ARV）药物浓度的估计，同时消除了获得每个患者CSF药物浓度的挑战。 利用CNS HIV抗逆转录病毒治疗效果研究（CHARTER）队列研究的数据，我们建议调查ART的CPE是否更好地减少抑郁症，从而导致更好的HIV临床结局。我们将评估CPE对抗逆转录病毒药物依从性的影响。 我们假设，更好的CPE将与改善情绪和坚持。我们还建议，以评估由CPE的ART产生的CNS和外周血的炎症和营养环境的变化。我们将评估CPE的ART方案和CSF/血液促炎细胞因子介导的抑郁症的水平之间的关联，独立于病毒载量抑制。我们假设增加的CPE将减少CSF和血液细胞因子（肿瘤坏死因子-α，白细胞介素-1，6和12和单核细胞趋化蛋白-1），从而改善抑郁症。我们还试图阐明抑郁症和脑脊液病毒学失败之间的关联。 这项研究将提高我们对HIV的神经发病机制和ARV治疗对CPE的神经行为影响的理解。这将有助于改善艾滋病毒/艾滋病患者的治疗选择，从而改善临床结果。 深入了解与ART CPE相关的CSF/血液促炎细胞因子的变化可能有助于开发具有改善情绪的额外效果的HIV治疗。

DESCRIPTION (provided by applicant): The introduction of highly active antiretroviral therapy (HAART) for HIV/AIDS has improved survival. However, the prevalence of depression has not significantly changed. Depression is associated with poor clinical outcomes. A higher concentration of anti-HIV medication in the central nervous system (CNS) is hypothesized to be the primary modulator of beneficial neurological response. Several studies in medically related depressive disorders have suggested a role for inflammatory cytokines as provocateurs of depression. The recently described concept of CNS penetration effectiveness (CPE) scores of antiretroviral therapy (ART) allows improved estimation of concentration of antiretroviral (ARV) medication in the CNS whilst eliminating the challenge of obtaining CSF drug concentrations on each patient. Utilizing data from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort study, we propose to investigate if better CPE of ART reduces depression thereby resulting in better HIV clinical outcomes. We will assess the effect of CPE on adherence to ARV medication. We hypothesize that better CPE will be associated with improved mood and adherence. We also propose to evaluate changes in the inflammatory and trophic environment of the CNS and peripheral blood produced by the CPE of ART. We will assess the association between CPE of ART regimens and levels of CSF/blood pro-inflammatory cytokine mediators of depression, independent of viral load suppression. We hypothesize that increased CPE will decrease CSF and blood cytokines (Tumor Necrosis Factor-alpha, Interleukins-1, 6, and 12 and monocyte chemo attractant protein-1), thereby improving depression. We also seek to elucidate the association between depression and CSF virologic failure. This study will improve our understanding of the neuropathogenesis of HIV and the neurobehavioral effects of ARV treatment with respect to their CPE. This will help improve therapeutic choices for patients with HIV/AIDS and thereby improve clinical outcomes. An insight into changes in CSF/blood pro-inflammatory cytokines associated with the CPE of ART may be helpful in developing HIV treatments that have an additional effect of improving mood.