Optimizing Hepatitis C Therapies and Predicting Liver Disease Outcomes

 描述（由申请人提供）： 从2014年年中到2015年年中，退伍军人事务部花费了超过12亿美元，用新的靶向抗病毒药物治疗了17万多名丙型肝炎病毒（HCV）感染患者中的2.8万人。这些联合治疗方案与之前的基于干扰素的治疗相比有了显著的改善，丙型肝炎的治愈率为90+%，全口服治疗方案通常持续3个月，副作用合理。在目前的HCV治疗指南中，VA承诺治疗所有希望接受治疗并适合使用这些药物治疗的HCV退伍军人。公平地说，这些药物的成本，约为40 - 90000美元每疗程的单一病人，是最大的新支出，VA药房和医疗服务将面临在未来3-5财政年度。由于药物费用和VA治疗能力有限，目前无法对所有患者进行治疗。我们也不知道哪些接受治疗的患者将获得最大的临床益处。丙肝肝硬化患者目前被给予最优先的治疗，但他们的肝病是否可以消退，他们的并发症的发生率是否可以通过治愈丙肝来降低还不清楚。很可能，肝硬化可能“为时已晚”，丙型肝炎治疗不会预防肝硬化并发症，如肝移植或肝细胞癌（HCC）的发展。事实上，没有肝硬化的中度肝病患者可能受益最大。一些患者也可能进展为肝硬化，尽管HCV治愈，并将受益于更密切的监测。这些微妙的问题需要前瞻性研究来回答，因为大型数据库无法对疾病进行如此精细的分类。目的1是建立一个前瞻性队列，包括大约500例已知肝病分期的患者，这些患者在未来两年内被考虑在San弗朗西斯科VA医学中心（SFVAMC）接受丙型肝炎治疗，并在入组后两年内通过肝脏成像（包括新的Fibroscan和MR电图方法）和血清纤维化检测重新评估肝病严重程度。目的2是分析最重要的基因及其多态性，除了临床变量，已链接到肝硬化的发展，肝硬化失代偿，并在这些患者的肝癌。我们目前还不能预测谁会患上丙型肝炎并发症，或者谁会从丙型肝炎治疗中获得可测量的临床益处，但是研究最近发现的遗传多态性的作用，并在治疗前后前瞻性地测量肝脏疾病，应该可以让我们解决这两个问题。

 DESCRIPTION (provided by applicant): From mid-2014 to mid-2015, the Department of Veterans Affairs spent over $1.2 billion to treat 28,000 of its more than 170,000 hepatitis C virus (HCV) infected patients with new targeted antiviral medications. These combination regimens are a dramatic improvement over prior interferon-based therapies, with 90+% cure rates for hepatitis C with all-oral regimens generally for 3 months, with a reasonable side effect profile. In its current HCV Treatment Guideline, the VA states its commitment to treat all Veterans with HCV who wish to be treated and are suitable for treatment with these medications. It is fair to say that the cost of these drugs, at approximately $40-90,000 per course of treatment for a single patient, is the largest new expenditure that VA Pharmacy and Medical Services will face over the next 3-5 fiscal years. Treatment of all patients is not currently feasible because of the cost of the medications and limited VA treating capacity. We also do not know which patients who are treated will derive the most clinical benefit. Patients with cirrhosis from HCV are currently given the highest priority fo treatment, but whether their liver disease can regress and their rates of complications can be lowered by cure of their hepatitis C is not known. Likely, cirrhosis may be "too late," and hepatitis C cure will not prevent complications of cirrhosis like the need for a liver transplant o the development of hepatocellular carcinoma (HCC). In fact, patients with moderate liver disease without cirrhosis may well derive the most benefit. Some patients may also progress to cirrhosis despite HCV cure, and would benefit from closer monitoring. Such subtle questions require prospective studies to answer, as large databases cannot classify disease so finely. Aim 1 is to establish a prospective cohort of approximately 500 patients with known stage of liver disease who are considered for hepatitis C therapy at the San Francisco VA Medical Center (SFVAMC) over the next two years, with reassessment of liver disease severity by liver imaging (including the novel methods of FIBROSCAN and MR electrography) and serum fibrosis testing at two years after enrollment. Aim 2 is to analyze the most important genes and their polymorphisms, in addition to clinical variables, that have been linked to cirrhosis development, cirrhosis decompensation, and HCC in these patients. We cannot currently predict who will develop complications from HCV, or who will derive measurable clinical benefits from hepatitis C cure, but studying the roles of recently identified genetic polymorphisms and prospectively measuring liver disease before and after therapy should allow us to address both questions.