Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C

依折麦布作为慢性丙型肝炎安全有效的治疗方法

• 批准号: 10158395
• 负责人: Steven J Scaglione
• 金额: --
• 依托单位: EDWARD HINES JR VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158395
• 关键词: Accounting; Address; Affect; Age; Alcohol consumption; Antiviral Agents; Antiviral Therapy; Cell Culture Techniques; Cells; Cholesterol; Chronic; Chronic Hepatitis C; Clinical; Conduct Clinical Trials; Country; Data; Databases; Drug Combinations; Drug Synergism; Drug Targeting; Drug usage; Ensure; FDA approved; Fatty Liver; Fibrosis; General Population; Goals; HCV Cirrhosis; Health system; Healthcare Systems; Hepatitis C; Hepatitis C Prevalence; Hepatitis C Therapy; Hepatitis C Viremia; Hepatitis C virus; Hepatocyte; Hepatocyte transplantation; Human; In Vitro; Infection; Inflammation; Insulin Resistance; Interferons; Kinetics; Knowledge; Laboratories; Lead; Lipids; Liver; Logistic Regressions; Malignant neoplasm of liver; Mathematics; Mediating; Modeling; Mus; Outcome; Patients; Pharmaceutical Preparations; Phase; Placebos; Play; Population; Primary carcinoma of the liver cells; RNA Viruses; Race; Regimen; Research Personnel; Ribavirin; Risk; Role; SCID Mice; Serum; Testing; Therapeutic; Time; Treatment Cost; Treatment Protocols; United States; Veterans; Viral; Viral Load result; Work; animal data; base; clinical care; comorbidity; cost; drug efficacy; efficacious treatment; efficacy testing; experimental study; ezetimibe; hepatoma cell; high risk; hypercholesterolemia; improved; in vivo; inhibitor/antagonist; kinetic model; mathematical model; military veteran; prevent; prophylactic; receptor; response; sex; study population; therapy duration; treatment duration; treatment response; uptake; viral resistance

The rationale for this application is to take action to improve/expand HCV treatment options, an issue that effects ~10% of veterans. While chronic HCV infection can lead to liver steatosis, insulin resistance, chronic inflammation, and fibrosis, and hepatocellular carcinoma, the astronomical cost of the new HCV antivirals represents a significant burden on the VA healthcare system and the risk of viral escape has not been determined in less than ideal compliance populations. To address the need for more affordable HCV antivirals with high barriers to viral resistance and/or strategies to shorten the current treatment duration, our goal is to develop affordable therapeutic regimens to prevent HCV entry/spread and test the efficacy of those inhibitors for treating HCV infection. Viral entry into cells is often an effective antiviral drug target. In addition, blocking viral cell-to-cell spread has been suggested to enhance antiviral drug efficacy, limit viral escape, and enhance drug synergy. Relevant to Aim 1 of this proposal, studies in chronically HCV infected chimeric mice with humanized livers have shown that an entry/spread inhibitor alone can reduce and even clear HCV infection when administered as monotherapy. Relevant to Aim 2 of this proposal, we and others have shown that HCV entry inhibitors act synergistically with HCV direct acting antivirals (DAA) resulting in more rapid viral clearance, allowing for shorter treatment while also reducing viral escape Importantly, we recently discovered that the Niemann-Pick C1 Like-1 (NPC1L1) cellular cholesterol uptake receptor is required for HCV entry into hepatocytes and that ezetimibe, an FDA-approved drug that inhibits NPC1L1-mediated cholesterol uptake potently blocks HCV entry in human hepatoma cells and human hepatocytes transplanted into uPA-SCID mice.. Further, retrospective analysis of the National VA database using multivariable logistic regression models to control for age, sex, race, alcohol use, drug use, and other co-morbidities, we found HCV prevalence to be lower (p <.001) and IFN/RBV treatment response to be better (i.e. larger viral log reduction) in patients taking ezetimibe. Hence, the specific objective of this application is to assess the efficacy of EZE for the treatment of chronic HCV. Based on preliminary in vitro, in vivo, clinical retrospective data and HCV/DAA modeling, we hypothesize that when administered as monotherapy EZE will reduce HCV viremia perhaps allowing for viral clearance and that when included in combination treatment regimens that EZE will augment 2nd phase HCV decline resulting in faster viral clearance (i.e. shorter/cheaper DAA therapy). To test these hypotheses, we have assembled an interdisciplinary team of basic researchers, mathematical modelers, and clinicians to execute the following aims: (1) Assess the efficacy of EZE monotherapy in chronically HCV infected and predict time to cure; (2) Assess the efficacy of EZE as an adjunct therapy in chronically HCV infected patients undergoing currently approved HCV DAA treatment. Importantly, veterans are not only the ideal study population, but also would derive immediate benefit if the proposed study confirms that EZE improves HCV outcomes and/or can shorten DAA treatment. Additionally, this study would provide proof-of-concept regarding the importance of blocking viral cell-to-cell spread as part of an optimal antiviral strategy advancing knowledge about drug synergy and increasing the barrier to viral escape, a critical concern for all emerging RNA viruses the might affect our troops. Finally, our mathematical modeling focus ensures that the data generated will provide inherently useful HCV DAA kinetic information to help determine if modeling can be individualized in real time to inform about duration of therapy required to cure infection.

该申请的基本原理是采取行动改善/扩大HCV治疗选择，这是一个影响 10%的退伍军人。虽然慢性HCV感染可导致肝脏脂肪变性、胰岛素抵抗、慢性丙型肝炎和慢性乙型肝炎。 炎症、纤维化和肝细胞癌，新的HCV抗病毒药物的天文数字的成本 代表VA医疗保健系统的重大负担，病毒逃逸的风险尚未确定 在不太理想的人群中。为了满足对更负担得起的HCV抗病毒药物的需求， 病毒耐药性的障碍和/或缩短当前治疗持续时间的策略，我们的目标是开发 负担得起的治疗方案，以防止HCV进入/传播，并测试这些抑制剂的疗效， HCV感染。病毒进入细胞通常是有效的抗病毒药物靶点。此外，阻断病毒在细胞间的传播 已经提出扩散可以增强抗病毒药物功效、限制病毒逃逸和增强药物协同作用。 与该提案的目标1相关，在慢性HCV感染的人源化肝脏嵌合小鼠中进行的研究 显示当作为抗HCV药物给药时，单独的进入/扩散抑制剂可以减少甚至清除HCV感染。 单一疗法。与该提案的目标2相关，我们和其他人已经表明，HCV进入抑制剂作用于 与HCV直接作用抗病毒药物（DAA）协同作用，导致更快的病毒清除，从而缩短治疗时间 重要的是，我们最近发现，尼曼-皮克C1样-1 （NPC 1 L1）细胞胆固醇摄取受体是HCV进入肝细胞所必需的， FDA批准的抑制NPC 1 L1介导的胆固醇摄取的药物可有效阻断HCV进入人体 将肝癌细胞和人肝细胞移植到uPA-SCID小鼠中。此外，回顾性分析 使用多变量逻辑回归模型控制年龄、性别、种族、饮酒、 药物使用和其他合并症，我们发现HCV患病率较低（p <.001），IFN/RBV治疗 接受依折麦布治疗的患者的应答更好（即病毒对数减少更大）。 因此，本申请的具体目的是评估埃泽治疗慢性HCV的疗效。 基于初步的体外、体内、临床回顾性数据和HCV/DAA模型，我们假设， 当作为单一疗法施用时，埃泽将减少HCV病毒血症，可能允许病毒清除， 当包含在联合治疗方案中时，埃泽将增强第二阶段HCV下降， 更快的病毒清除（即更短/更便宜的DAA治疗）。为了验证这些假设，我们收集了一个 由基础研究人员、数学建模人员和临床医生组成的跨学科团队，以实现以下目标： (1)评估埃泽单药治疗慢性HCV感染的疗效，并预测治愈时间;（2）评估依泽治疗慢性HCV感染的疗效。 埃泽作为一种辅助疗法在接受目前批准的HCV治疗的慢性HCV感染患者中的疗效 DAA治疗。重要的是，退伍军人不仅是理想的研究人群， 如果拟议的研究证实埃泽可改善HCV结局和/或缩短DAA治疗，则可获益。 此外，这项研究将提供有关阻断病毒细胞间传播的重要性的概念验证。 作为最佳抗病毒策略的一部分进行传播，以推进有关药物协同作用的知识， 病毒逃逸的屏障，这是所有可能影响我们部队的新兴RNA病毒的关键问题。最后我们 数学建模的重点是确保产生的数据将提供固有的有用的HCV DAA动力学 帮助确定建模是否可以在真实的时间内个性化以告知治疗持续时间的信息 需要治愈感染。