Over 260,000 male veterans accessing VA healthcare between 2000 and 2014 had a laboratory confirmed diagnosis of hepatitis C virus (HCV) infection. Chronic HCV infection (HCV+) is the leading cause of liver disease progression to cirrhosis, liver transplant and liver cancer. HCV+ males have much higher rates of liver disease progression than HCV+ females. One factor that may contribute to this difference is large and gender- defining biological differences in the levels of circulating sex hormones like testosterone. However, the role normal variability in these major sex hormones plays in risk of liver disease progression among HCV+ individuals of the same gender is not known. The long-term effects of medications that substantially alter sex hormone levels like testosterone therapy on risk of disease progression in HCV+ males are also unknown. We previously recruited baseline cohort of 1072 male veterans with chronic HCV infection seen for routine care at single VA. All completed a lifetime risk factor survey and had a blood sample taken to obtain DNA and to store for biomarker testing in approved future research studies. We propose to measure circulating levels of major sex hormones at baseline using stored blood samples for this cohort of 1,072 HCV+ male veterans. We will also perform DNA tests to assess specific variations in several genes related to sex hormone function. We will prospectively follow all cohort members for liver disease progression with outcomes determined using electronic medical record review and VA database searches and expert physician consensus review. We will examine the association between baseline levels of sex hormones after accounting for sex hormone gene variants on risk of liver disease progression including to cirrhosis and liver cancer in our baseline HCV+ male cohort from 1-9 years later. We propose to measure use of commonly prescribed medications that alter levels of androgen sex hormones like testosterone in the >267,000 males with laboratory confirmed HCV and seen at the VA between 2000 and 2014. We will extract extensive information about each individual at baseline to account for their likelihood to ever receive these medications and calculate medication propensity scores. We will account for these propensity scores in our assessment of the association between use of these hormone altering medications and risk of HCV-related liver disease progression from 1-18 years later. In addition to uncovering new potential therapeutic targets for HCV-related liver disease progression, this study has rapid and important potential impact on clinical practice in terms of better criteria to risk stratify veterans and help prioritize them for early access to costly new anti-HCV medications and may alter practice for prescribing sex hormone altering medications in aging HCV-infected males.

Public Health Relevance

Chronic infection with the hepatitis C virus (HCV) is the leading cause of cirrhosis, liver transplant, and liver cancer in the U.S. Veterans using the VA are particularly negatively impacted given HCV infection rates three times higher than that the overall U.S. population. One factor which greatly increases risk of liver disease progression is male gender. It is thought that large gender-defining differences in levels of sex hormones may help explain this. Yet, the role sex hormones play in the risk of liver disease progression among HCV+ veterans of the same sex is not known. There are several medications that alter levels of sex hormones used in aging males like testosterone therapy. However, their impact on liver disease progression in HCV+ males is not known. We propose to evaluate the association between sex hormones and hormone altering medications by performing two studies, one using stored research samples and the other using VA healthcare databases. .

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Epidemiology (EPID)
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Michael E Debakey VA Medical Center
United States
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