Hepatitis C

Hepatitis C Virus (HCV) infection represents an important global healthcare burden, which is expected to increase over the coming years. HCV infection has reached pandemic proportions, affecting over 150 million people worldwide. According to the Centers for Disease Control (CDC), 3.9 million Americans have been exposed to HCV, resulting in 2.7 million cases of chronic infection and approximately 3 to 4 million new cases occurring each year worldwide. Often called the “silent epidemic”, HCV can be acquired through multiple routes and can remain in the host with minor or no symptoms for years before its harmful effects manifest. Ultimately, chronic HCV infection leads to serious liver disease in 70% of those infected and is responsible for 50–76% of all cases of liver cancer and two-thirds of all liver transplants in the United States.

At present, standard of care for HCV is based on 24 to 48 weeks of combination injected interferon (given once weekly) and oral ribavirin (given 2x daily). Fatigue, headache and fever are among the more common side effects and are often experienced during the entire course of treatment. Roughly half the patients who initiate therapy discontinue. Sustained virologic response or “SVR” measures success rates, and is defined as undetectable plasma viral load 24 weeks after completion of therapy. Ranges vary, but of the patients who do complete full courses, typically only half achieve this endpoint. Standard HCV regimens exist but are associated with significant toxicities, inconvenient dosing and suboptimal efficacy for many patients, highlighting the need for new therapies.

The 9.6 kb HCV genome is a positive single-stranded RNA that encodes an ~3,000 amino acid polyprotein. The latter is proteolytically processed by cellular and viral proteases into structural (components of the mature virus) and non-structural (NS) proteins (proteins that are involved in the replication of the virus). Research in HCV molecular virology has led to the development of NS3 protease and NS5B polymerase inhibitors. Although some of these agents have encouraging antiviral activity in vitro and in vivo , resistance to these classes of drugs often develops rapidly, precluding their use as monotherapies.

Effective pharmacologic control of HCV is expected to require a cocktail of multiple agents, each targeting an independent virus-specific function, as is the case for HIV and tuberculosis. The identification of new classes of drugs against novel HCV targets will be critical to the future successful treatment of HCV.