Interferon is the therapeutic backbone of hepatitis C virus (HCV) treatment, as well as the major barrier to HCV treatment access, uptake, and completion. For many people, hepatitis C treatment does not work, and side effects can be debilitating. Fortunately, scientific advances and keen interest from the pharmaceutical industry have led to the development of dozens of new oral antiviral drugs for hepatitis C. Hopefully, it will soon be possible to replace interferon with a combination of HCV-specific oral drugs (commonly referred to as direct-acting antivirals, or DAAs) that will work for everyone.
Currently, two HCV treatment strategies are being evaluated: adding one or two DAAs to pegylated interferon and ribavirin (PEG-IFN/RBV), the current standard of care (SOC); and giving an all-oral DAA combination designed to inhibit different steps of the HCV life cycle (an approach that has been successful at controlling, but not curing, HIV infection). Adding a hepatitis C protease inhibitor to SOC has greatly improved response rates in phase II and phase III trials. Triple therapy (DAA plus SOC) may shorten treatment duration, depending on characteristics of the drug and the population it is used in. Drawbacks to triple therapy include more side effects, increased cost of treatment, and complex treatment algorithms that require frequent monitoring, and consideration of host, virus, and drug specific characteristics.
The current SOC works by bolstering the immune response so that it can kill infected cells (immunologic effect), and protecting healthy cells by preventing HCV replication (antiviral effect). Oral antiviral agents can suppress HCV, but no one knows whether combination therapy with DAAs will render immune-based therapies such as peginterferon unnecessary; the answer will come from trials of interferon-free regimens. Results from the first of these trials are expected in 2012. Although DAAs will change the HCV treatment paradigm, their effectiveness may be significantly limited by the emergence or development of drug resistance. In fact, HCV genetic mutations (polymorphisms) that render the virus resistant to one or more DAA classes have already been detected in people who have never used DAAs, and these mutations have also emerged during clinical trials -- even when a DAA was used with peginterferon and ribavirin.
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