Interferon free therapy with direct acting antivirals for HCV

Abstract The current treatment for hepatitis C virus (HCV) genotype 1 chronic infection is the addition of direct-acting antivirals (DAA) with a protease inhibitor (telaprevir or boceprevir) to the pegylated interferon (PEG-IFN) plus ribavirin (RBV) regimen. Major progress has been made in the past few years: numerous ongoing trials with different compounds, increasing sustained virological response (SVR) rates with oral regimens and shortened treatment duration. Combinations of antivirals with additive potency that lack cross-resistance and with a good safety profile may provide new regimens in the future to make HCV the first chronic viral infection to be eradicated worldwide with a finite duration of combination DAA therapy without IFN. Hepatitis C virus (HCV) is a major cause of chronic liver disease, with an estimated 170 million people infected worldwide (1). Hepatitis C virus, identified in 1989, is an enveloped virus with a 9.6-kb singlestranded RNA genome (2), a member of the Flaviviridae family, genus Hepacivirus. The goal of treatment is to obtain a sustained virological response (SVR) defined as undetectable HCV RNA in serum after 24 weeks of post-treatment follow-up (3). Twelveweek post-treatment follow-up appears to be relevant at 24 weeks to define SVR (4). SVR results in the eradication of HCV infection and improvement of the histological outcome (5). In 2011, two direct acting antivirals (DAAs) were approved for HCV genotype 1 chronic infection, telaprevir and boceprevir and opened a new area for HCV therapy (6). These two NS3/4 protease inhibitors (PI) are given in combination with pegylated interferon (PEG-IFN) and ribavirin (RBV). Phase III clinical trials have shown that approximately 25-35% of G1 treatment-na€ ıve patients and 50-60% of G1 HCV patients who failed to respond to a first course of treatment with PEG-IFN and RBV do not achieve SVR and are not cured of HCV infection with this triple combination. Therefore, there is a need to develop new DAAs to improve SVR. Furthermore, IFN has several side effects. The aim of this review is to describe the mechanisms of action of DAAs and summarize the results obtained with DAA combinations without IFN. Viral cycle and targets for drug development The HCV life cycle begins with virion attachment to its specific receptor. The HCV RNA genome serves as a template for viral replication and as a viral messenger RNA for viral production. It is translated into a polyprotein that is cleaved by proteases. Then, viral assembly occurs. Potentially, each step of the viral cycle is a target for drug developmen