The research program funded by R01 013806 is focused on liver fibrosis progression in HIV/HCV coinfected persons. Liver disease is one of the leading causes of death in HIV infected persons, and its public health importance is expected to increase. As treatments for both HIV and HCV improve, the important clinical questions now are treatment-related. Does antiretroviral therapy (ART) affect progression of liver disease and therefore need to be given to HIV/HCV coinfected persons even at high CD4+ lymphocyte counts? Is suppression of HCV replication by treatment sufficient to stop fibrosis progression? Does the chronic immune activation caused by HIV contribute to IFN resistance and can ART diminish that effect? In the next funding cycle, we plan to answer these and other questions related to the "treated" history of HIV/HCV coinfected persons by a series of integrated clinical and laboratory studies that build on the models of natural history and pathogenesis that we and others have developed over the past decade.
The specific aims are as follows:
Aim 1 is to test the hypothesis that effective antiretroviral therapy reduces progression of liver fibrosis in HIV/HCV coinfected persons.
Aim 2 is to test the hypothesis that suppression of HCV replication by treatment reduces liver fibrosis progression in HIV/HCV coinfected persons.
Aim 3 is to test the hypothesis that interferon alfa (IFN) sensitivity is improved by antiretroviral therapy.
The aims of prior funding cycles have been accomplished and reported among 25 peer reviewed articles supported by R01 013806. The current aims are revised to answer significant scientific questions during the next period using innovative research tools. There is a high likelihood that these studies will inform U.S. Public Health Service guidelines on when to start antiretroviral therapy and provide a scientific basis for existing guidelines governing treatment of HCV infection in persons with HIV.

Public Health Relevance

The proposed research is designed to guide significant clinical decisions, such as when to start antiretroviral therapy in the 25% of HIV infected persons who have chronic hepatitis C and whether treatment for HCV infection can be justified to prevent progression of liver disease. The studies might also explain why treatments for chronic hepatitis C are not as effective in persons dually infected with HIV.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Method to Extend Research in Time (MERIT) Award (R37)
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AIDS Clinical Studies and Epidemiology Study Section (ACE)
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Khalsa, Jagjitsingh H
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Bailey, Justin R; Wasilewski, Lisa N; Snider, Anna E et al. (2015) Naturally selected hepatitis C virus polymorphisms confer broad neutralizing antibody resistance. J Clin Invest 125:437-47
Konerman, Monica A; Mehta, Shruti H; Sutcliffe, Catherine G et al. (2014) Fibrosis progression in human immunodeficiency virus/hepatitis C virus coinfected adults: prospective analysis of 435 liver biopsy pairs. Hepatology 59:767-75
Balagopal, Ashwin; Kandathil, Abraham J; Higgins, Yvonne H et al. (2014) Antiretroviral therapy, interferon sensitivity, and virologic setpoint in human immunodeficiency virus/hepatitis C virus coinfected patients. Hepatology 60:477-86
Cox, Andrea L; Thomas, David L (2013) Hepatitis C virus vaccines among people who inject drugs. Clin Infect Dis 57 Suppl 2:S46-50
Walker Harris, V; Sutcliffe, C G; Araujo, A B et al. (2012) Hip bone geometry in HIV/HCV-co-infected men and healthy controls. Osteoporos Int 23:1779-87
Woreta, Tinsay A; Sutcliffe, Catherine G; Mehta, Shruti H et al. (2011) Incidence and risk factors for steatosis progression in adults coinfected with HIV and hepatitis C virus. Gastroenterology 140:809-17
Vachon, Marie-Louise C; Factor, Stephanie H; Branch, Andrea D et al. (2011) Insulin resistance predicts re-treatment failure in an efficacy study of peginterferon-*-2a and ribavirin in HIV/HCV co-infected patients. J Hepatol 54:41-7
Mehta, Shruti H; Buckle, Geoffrey C (2011) Assessment of liver disease (noninvasive methods). Curr Opin HIV AIDS 6:465-71
El-Maouche, Diala; Mehta, Shruti H; Sutcliffe, Catherine et al. (2011) Controlled HIV viral replication, not liver disease severity associated with low bone mineral density in HIV/HCV co-infection. J Hepatol 55:770-6
Brown, Todd T; Mehta, Shruti H; Sutcliffe, Catherine et al. (2010) Hepatic steatosis associated with increased central body fat by dual-energy X-ray absorptiometry and uncontrolled HIV in HIV/hepatitis C co-infected persons. AIDS 24:811-7