Hepatitis C (HCV), a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma, is the most common indication for liver transplantation in the United States. Although annual incidence of infection has declined since the 1980s, aging of the currently infected population is expected to result in an increase in HCV burden. HCV is prone to develop resistance to antiviral drugs, and despite considerable efforts to understand the virus for effective treatments, our knowledge remains incomplete. This paper reviews HCV resistance mechanisms, the traditional treatment with and the new standard of care for hepatitis C treatment. Although these new treatments remain PEG-IFN-α- and ribavirin-based, they add one of the newly FDA approved direct antiviral agents, telaprevir or boceprevir. This new “triple therapy” has resulted in greater viral cure rates, although treatment failure remains a possibility. The future may belong to nucleoside/nucleotide analogues, non-nucleoside RNA-dependent RNA polymerase inhibitors, or cyclophilin inhibitors, and the treatment of HCV may ultimately parallel that of HIV. However, research should focus not only on effective treatments, but also on the development of a HCV vaccine, as this may prove to be the most cost-effective method of eradicating this disease. 1. Introduction: Burden of Hepatitis C Hepatitis C (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma, as well as the most common indication for liver transplantation in the United States. The annual incidence of infection in the USA has declined from about 230,000 cases per year in the 1980s to an estimated 17,000 cases in 2007 [1, 2]. This decline has been largely attributed to changes in injection practices motivated by a concern for human immunodeficiency virus (HIV) risk . Approximately 3.2 million persons have chronic HCV infection in the United States; however, the reservoir of chronically infected persons is still estimated at approximately 2.35%, representing approximately 160 million worldwide infected individuals . Aging of the currently infected population is expected to result in an increase in the burden of hepatitis C in the next decade . During that period, the number of HCV-related cirrhosis cases is estimated to increase by 31% and that of hepatocellular carcinoma (HCC) cases is estimated to increase by approximately 50% . Estimates of hepatitis C prevalence range from <0.5% in very low endemic countries (e.g., northern European countries) to staggering rates of approximately 20% in
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