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

• 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
• 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

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）：引入高度活跃的抗逆转录病毒疗法（HAART）用于HIV/AIDS的生存率提高了。但是，抑郁症的患病率没有显着改变。抑郁症与临床结局不佳有关。假设中枢神经系统（CNS）中较高浓度的抗HIV药物是有益神经系统反应的主要调节剂。关于医学相关抑郁症的几项研究表明，炎症细胞因子是抑郁症的挑衅者。 最近描述的抗逆转录病毒疗法（ART）评分中枢神经系统渗透效果（CPE）得分的概念允许在中枢神经系统中改善抗逆转录病毒（ARV）药物浓度的估计，同时消除了对每位患者获得CSF药物浓度的挑战。 利用中枢神经系统HIV抗逆转录病毒疗法研究（宪章）同类研究的数据，我们建议研究是否更好的ART CPE是否减少了抑郁症，从而导致更好的HIV临床结果。我们将评估CPE对ARV药物依从性的影响。 我们假设更好的CPE将与情绪和依从性改善有关。我们还建议评估中枢神经系统的炎症和营养环境的变化以及ART CPE产生的外周血。我们将评估ART方案的CPE与抑郁症的CSF/血液促炎细胞因子介质之间的关联，而与病毒负荷抑制无关。我们假设增加的CPE将降低CSF和血细胞因子（肿瘤坏死因子-Alpha，interleukins-1、6和12，以及单核细胞化学诱导蛋白1），从而改善抑郁症。我们还试图阐明抑郁症与CSF病毒学衰竭之间的关联。 这项研究将提高我们对HIV的神经病的理解以及ARV治疗相对于其CPE的神经行为影响。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。 对与ART CPE相关的CSF/血液促炎细胞因子的变化的洞察力可能有助于开发艾滋病毒治疗，这些治疗具有改善情绪的额外作用。