Oral antiviral therapies for chronic hepatitis C infection

The treatment of hepatitis C virus (HCV) infection with pegylated interferon alpha and ribavirin leads to a sustained virologic response in around 50% of patients with HCV genotype 1, 65% with HCV genotype 4, 75% with HCV genotype 3 and around 80% with HCV genotype 2. A better understanding of the HCV lifecycle has resulted in the development of several potential direct-acting antiviral drugs (DAAs) targeting viral proteins [NS3/4A protease inhibitors, NS5B nucleos(t)idic and non-nucleos(t)idic polymerase inhibitors, NS5A replication complex inhibitors]. This review summarizes the main clinical data for the combinations of oral DAAs. DAAs, either in combination with pegylated interferon alpha or in interferon-free regimens, have demonstrated a high level of antiviral efficacy and a generally well-tolerated safety profile in treatment-naïve patients and in prior nonresponders to pegylated interferon alpha/ribavirin. Oral combination of new DAAs is likely to become the standard of care for chronic HCV in treatment-naïve or treatment-experienced patients. However, most studies so far have included small numbers of 'easy-to-treat' patients with short post-treatment periods for defining the sustained virologic response. Extension of the number of treated patients (including 'difficult-to-treat' patients, i.e. patients infected with genotype 3, who failed to respond to first-generation protease inhibitors or with cirrhosis as well as immunocompromised patients) and of the post-treatment follow up in a real-life setting could significantly worsen the rate of recovery. In these 'difficult-to-treat' patients, the rate of virologic cure with new DAAs could be lower than expected and consequently interferons may be still necessary in combination with the new drugs.