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

抗病毒药物中枢神经系统渗透对脑脊液/血液细胞因子和艾滋病毒抑郁的影响

基本信息

批准号：
8541046
负责人：
JUSTIN CHARLES. MCARTHUR
金额：
$ 7.78万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-06 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8541046
关键词：
AIDS/HIV problem Adherence Affect Animals Anti-Retroviral Agents Antiviral Agents Blood Cerebrospinal Fluid Clinical Clinical Research Cognition Cohort Studies Data Dementia Depressive disorder Development Disease Effectiveness Environment Failure Future HIV Highly Active Antiretroviral Therapy Human Impaired cognition Impairment Inflammation Inflammatory Interleukin-1 Interleukin-12 Interleukin-6 Mediating Mediator of activation protein Mental Depression Mental disorders Moods Neuraxis Neurocognitive Neurologic Neuropathogenesis Opportunistic Infections Outcome Patients Penetration Persons Pharmaceutical Preparations Plasma Play Prevalence Production Proteins RNA Regimen Reporting Research Risk Role Therapeutic Tumor Necrosis Factor-alpha Viral Viral Load result Viremia Virus antiretroviral therapy base central nervous system injury chemical property cytokine depression prevention improved inflammatory marker innovation insight monocyte mortality neurobehavioral peripheral blood response

项目摘要

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.

描述（由申请人提供）：针对 HIV/AIDS 引入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着变化。抑郁症与不良的临床结果相关。据推测，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。几项与医学相关的抑郁症研究表明，炎症细胞因子是抑郁症的诱发因素。最近描述的抗逆转录病毒治疗（ART）的中枢神经系统渗透有效性（CPE）评分概念可以改进对中枢神经系统中抗逆转录病毒（ARV）药物浓度的估计，同时消除了获得每个患者脑脊液药物浓度的挑战。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 更好的 CPE 是否可以减少抑郁症，从而带来更好的 HIV 临床结果。我们将评估 CPE 对 ARV 药物治疗依从性的影响。我们假设更好的 CPE 与改善情绪和依从性有关。我们还建议评估 ART 的 CPE 产生的 CNS 和外周血炎症和营养环境的变化。我们将评估 ART 方案的 CPE 与抑郁症的脑脊液/血液促炎细胞因子介质水平之间的关联，与病毒载量抑制无关。我们假设增加 CPE 会减少脑脊液和血液细胞因子（肿瘤坏死因子-α、白细胞介素-1、6 和 12 以及单核细胞化学吸引蛋白-1），从而改善抑郁症。我们还试图阐明抑郁症与脑脊液病毒学失败之间的关联。这项研究将提高我们对 HIV 神经发病机制以及 ARV 治疗对其 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 的 CPE 相关的脑脊液/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 治疗方法。