Impact of HCV Therapy on CNS Outcomes

 描述（由申请方提供）：慢性HCV感染经常导致神经认知（NC）和情绪障碍，但这些障碍是由HCV引起的还是由伴随药物使用和肝病引起的尚不清楚。对治疗的反应已经被基于干扰素的HCV疗法的神经毒性所掩盖。较新的直接作用抗病毒药物（DAA）没有神经毒性，有望治疗HCV引起的脑损伤。然而，临床试验尚未进行，以确定其中枢神经系统（CNS）的好处。这是该领域进展的关键障碍，拟议的临床试验将直接 地址.拟议的部分盲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（索非布韦和ledipasvir）治疗HCV对单一或HIV合并感染药物使用者CNS结局的影响。具体目标是： 目标1：以12周持续病毒学应答为指标，确定治愈HCV是否导致NC表现、神经影像学和日常功能指标的改善; 目的2：确定神经认知和神经影像学结果的病毒、宿主和药理学相关性; 目的3：探索艾滋病毒如何改变目的1和2中观察到的关系。 拟议的创新临床试验将通过确定DAA的CNS和全身效应的生物学和成像相关性以及这些药物在CNS中的分布来提高科学知识。我们的研究结果还将为临床指南和实践提供关于在物质使用人群中治疗HCV的安全性和益处的信息。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关键辅助手段，可改善认知并使患者恢复更正常的生活。

 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.