Impact of HCV Therapy on CNS Outcomes

HCV 治疗对 CNS 结果的影响

• 批准号: 9283537
• 负责人: AJAY R BHARTI
• 金额: $ 69.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9283537
• 关键词: Address; Adult; Alcohol or Other Drugs use; Anti-Retroviral Agents; Antidepressive Agents; Antiviral Agents; Antiviral Therapy; Applications Grants; Astrocytes; Attention; Autopsy; Biological; Biological Markers; Blinded; Blood; Blood-Borne Pathogens; Brain; Brain Injuries; CD14 gene; CXCL10 gene; Central Nervous System Diseases; Cerebrospinal Fluid; Choline; Chronic Hepatitis C; Clinical; Clinical Trials; Cognition; Data; Disease; Dose; Fatigue; Future; Goals; Guidelines; HIV; HIV-associated neurocognitive disorder; Hepatitis C; ISG15 gene; Image; Immune response; In Vitro; Individual; Infection; Inflammation; Inositol; Interferon Alfa-2a; Interferons; Interleukin-18; Intervention; Knowledge; Lead; Learning; Light; Liver; Liver diseases; Macrophage Activation; Measures; Memory; Microglia; Mono-S; Mood Disorders; Moods; N-acetylaspartate; Neopterin; Neuraxis; Neurocognitive; Neurocognitive Deficit; Neuronal Injury; Neurons; Oral; Outcome; Participant; Patient Self-Report; Patients; Performance; Pharmacology; Placebos; Population; Process; Randomized; Recovery; Regimen; Relapse; Research Personnel; Safety; Short-Term Memory; Statistical Models; Substance Use Disorder; Time; Viral; Viral Proteins; Virus Diseases; antiretroviral therapy; base; biomarker panel; brain tissue; central nervous system injury; chemokine; chronic liver disease; co-infection; cognitive ability; cytokine; daily functioning; drug distribution; executive function; follow-up; hepatitis C virus nucleocapsid protein; improved; indexing; injured; innovation; liver injury; macrophage; magnetic resonance spectroscopic imaging; neurofilament; neuroimaging; neurotoxic; neurotoxicity; placebo controlled study; prevent; processing speed; public health relevance; response; secondary analysis; success; tool; treatment response; viral RNA; virology; white matter

 DESCRIPTION (provided by applicant): Chronic HCV infection frequently causes neurocognitive (NC) and mood disorders but whether these disorders are caused by HCV or by the concomitant substance use and liver disease is unclear. Response to treatment has been obscured by the neurotoxicity of interferon-based HCV therapies. Newer direct acting antivirals (DAAs) are not neurotoxic and are expected to treat HCV-induced brain injury. However, clinical trials have yet to be performed to determine their central nervous system (CNS) benefits. This presents a critical barrier to progress in the field that the proposed clinical trial will directly address. The overall objective of the proposed partially blinded placebo-controlled trial will be t determine the impact of curing HCV with an oral DAA fixed-dose combination regimen, sofosbuvir and ledipasvir, on CNS outcomes in mono- or HIV co-infected substance users. The specific aims will be to: AIM 1: To determine whether curing HCV, as indexed by 12-week sustained virologic response, results in improvement in NC performance, neuroimaging, and measures of daily functioning; AIM 2: To determine the viral, host, and pharmacologic correlates of neurocognitive and neuroimaging outcomes; and AIM 3: To explore how HIV alters the relationships observed in Aims 1 and 2. The proposed, innovative clinical trial will improve scientific knowledge by determining the biological and imaging correlates of the CNS and systemic effects of DAAs as well as the distribution of these drugs into the CNS. Our findings will also inform clinical guidelines and practice about the safety and benefits of treating HCV in substance using populations. In people who have HIV-associated NC disorder and HCV infection, treatment with DAAs may prove to be a critical adjunct to antiretroviral for improving cognition and returning patients to more functional lives.

 描述（由申请人提供）：慢性丙型肝炎病毒感染经常引起神经认知（NC）和情绪障碍，但这些障碍是由丙型肝炎病毒引起还是由伴随的物质使用和肝病引起，目前尚不清楚干扰素的神经毒性对治疗的反应。新型直接作用抗病毒药物 (DAA) 不具有神经毒性，有望治疗 HCV 引起的脑损伤，但尚未进行临床试验以确定其中枢神经系统。这对拟议的临床试验将直接带来的领域的进展构成了关键障碍。 拟定的部分盲法安慰剂对照试验的总体目标是确定口服 DAA 固定剂量组合方案索磷布韦和雷迪帕韦治疗 HCV 对单一或 HIV 合并感染物质使用者的中枢神经系统结果的影响。 .具体目标是： 目标 1：确定治愈 HCV（以 12 周持续病毒学应答为指标）是否会导致 NC 表现、神经影像学和日常功能测量的改善； 目标 2：确定神经认知和神经影像结果的病毒、宿主和药理学相关性； 目标 3：探索 HIV 如何改变目标 1 和 2 中观察到的关系。 拟议的创新试验将通过确定中枢神经系统的生物学和成像相关性以及 DAA 的全身效应以及这些药物在中枢神经系统中的分布来提高科学知识，我们的研究结果还将为有关安全性和益处的临床指南和实践提供信息。在患有 HIV 相关 NC 疾病和 HCV 感染的人群中，DAA 治疗可能被证明是抗逆转录病毒治疗的重要辅助手段，可改善认知功能并使患者恢复正常生活。