Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C

这项申请的基本原理是采取行动改善/扩大丙型肝炎病毒治疗方案，这是一个影响 约10%的退伍军人。而慢性丙型肝炎病毒感染可导致肝脏脂肪变性、胰岛素抵抗、慢性 炎症、纤维化和肝细胞癌，新的丙型肝炎病毒抗病毒药物的天文数字 对退伍军人管理局的医疗系统造成了沉重的负担，病毒逃逸的风险尚未确定 在不太理想的合规人群中。为了满足对更实惠的抗丙型肝炎病毒药物的需求， 病毒耐药性的障碍和/或缩短目前治疗持续时间的策略，我们的目标是开发 预防丙型肝炎病毒进入/传播的负担得起的治疗方案并测试这些抑制剂的治疗效果 丙型肝炎病毒感染。病毒进入细胞通常是有效的抗病毒药物靶点。此外，阻止病毒在细胞间传播 已有研究表明，药物扩散可以提高抗病毒药物的疗效，限制病毒逃逸，增强药物的协同作用。 与该提案的目标1相关，对慢性丙型肝炎病毒感染的嵌合小鼠的人源化肝脏的研究 研究表明，单独使用进入/传播抑制剂可以减少甚至清除丙型肝炎病毒感染。 单一疗法。与本提案的目标2相关，我们和其他人已经证明了丙型肝炎病毒进入抑制物起作用。 与丙型肝炎病毒直接作用抗病毒药物(DAA)协同作用，导致更快的病毒清除，允许更短的时间 治疗的同时也减少病毒逃逸重要的是，我们最近发现Niemann-Pick C1Like-1 (NPC1L1)细胞胆固醇摄取受体是丙型肝炎病毒进入肝细胞所必需的，而ezetimibe，一种 FDA批准的抑制NPC1L1介导的胆固醇摄取的药物可有效阻止丙型肝炎病毒进入人体 将肝癌细胞和人肝细胞移植到uPA-SCID小鼠体内。此外，还回顾分析了 国家退伍军人数据库使用多变量Logistic回归模型控制年龄、性别、种族、饮酒、 药物使用和其他共病，我们发现丙型肝炎病毒感染率较低(P&lt；.001)，并接受干扰素/RBV治疗 在服用依折麦布的患者中，反应更好(即更大的病毒记录减少)。 因此，该应用的具体目标是评估EZE治疗慢性丙型肝炎的疗效。 基于初步的体外、体内、临床回顾数据和丙型肝炎病毒/DAA模型，我们假设 作为单一治疗药物，EZE可以减少丙型肝炎病毒血症，也许可以清除病毒。 当包括在联合治疗方案中时，EZE将增加第二阶段丙型肝炎病毒下降，导致 更快的病毒清除(即更短/更便宜的DAA疗法)。为了检验这些假设，我们组装了一个 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EZE单一疗法对慢性丙型肝炎病毒感染的疗效并预测治愈时间；(2)评估 EZE辅助治疗慢性丙型肝炎患者的疗效 DAA治疗。重要的是，退伍军人不仅是理想的学习人群，而且还会立即 如果拟议的研究证实EZE改善了丙型肝炎的转归和/或可以缩短DAA治疗，则将受益。 此外，这项研究将提供关于阻断病毒细胞间的重要性的概念验证。 传播作为最佳抗病毒策略的一部分，促进药物协同作用的知识，并增加 病毒逃逸的障碍，这是所有可能影响我们军队的新出现的RNA病毒的关键问题。最后，我们的 数学建模的重点是确保生成的数据将提供内在有用的丙型肝炎病毒DAA动力学 帮助确定是否可以实时个体化建模以告知治疗持续时间的信息 治愈感染所必需的。

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.