Interferon-free treatment regimens for hepatitis C: are we there yet?

See " Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection , " by Zuezem S, Asselah T, Angus P, et al, on page 2047. C ombination therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) was the standard of care for chronic hepatitis C (CHC) for over a decade. Sustained virologic response (SVR) rates vary from 40% to 45% among patients with genotype 1 to 75% to 80% in patients with genotype 2 or 3 infection. 1 However, PEG-IFN and RBV treatment are associated with many side effects. In registration trials that enrolled highly selected patients, 13%–15% of patients discontinued treatment early and 25%– 42% had dose reductions because of adverse events or laboratory abnormalities. 1–3 Because of the poor toler-ability, many patients with CHC have elected not to pursue treatment or were not offered treatment. IFN and RBV are also contraindicated in many conditions, such as autoimmune diseases and severe/uncontrolled psychiatric illnesses. 1 Therefore, there is an urgent need for more efficacious and better tolerated therapy for CHC. Advances in the understanding of the hepatitis C virus (HCV) life cycle have led to the development of many promising direct-acting antiviral agents (DAA) in the last decade (Figure 1). 4,5 Two DAAs—telaprevir and bocepre-vir—linear inhibitors of NS3/4A serine protease were approved for HCV treatment in the United States in May 2011. Although the approval of boceprevir and telaprevir represents a major breakthrough for the treatment of CHC with SVR rates of 67% and 73%, respectively, in treatment-naïve genotype 1 patients, both drugs require concomitant use of PEG-IFN and RBV to achieve SVR by preventing viral breakthroughs owing to drug resistance. 6,7 Furthermore, both drugs need to be administered every 8 hours and are associated with additional adverse events. With the development of DAAs directed at multiple targets in the HCV life cycle (Figure 1), the obvious question is, " Are we ready for IFN-free treatment regimens? " Clinical trials involving telaprevir and boceprevir as monotherapy showed a rapid decline in plasma HCV RNA levels within the first day followed by virologic breakthrough as early as day 3. 8,9 HCV circulates as quasispe-cies, a mixture of viruses with heterogeneous virus sequences. It has been estimated that preexisting drug resistance variants with 1, 2, 3, and even 4 mutations may be present in most HCV-infected patients, and account for the rapid development …