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.

PUBLIC HEALTH RELEVANCE: 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 truly game-changers, with greater than 90% cure rates for hepatitis C with 3 month all-oral regimens, and a favorable side effect profile. Evidence that all patients need or benefit from this therapy, however, does not exist. To understand the benefits of combination HCV therapy, we will conduct a prospective study of all patients considered for therapy at our medical center over the next three years (approximately 500). We will know how much liver disease patients have at the beginning of the study, and will re-evaluate this two years later. We will also evaluate genetic factors in poor outcomes from liver disease, including being very sick with cirrhosis and developing liver cancer (HCC).