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Since the discovery of HCV in 1989, interferon α (IFNα)-based therapy has been the only treatment approach leading to HCV genotype-dependent sustained virological response (SVR) rates in a significant number of patients. However, the treatment uptake has been generally low due to numerous side effects and contraindications to IFNα-based regimens. Because of these limitations, the overall HCV-related health burden could only gradually be decreased, even though treatment efficacy was increased over recent years.1 ,2
The lack of cell culture systems to grow HCV had been a key limitation for the development of direct acting antivirals (DAAs). Nevertheless, in 1997, only a few years after the discovery of HCV, the first subgenomic HCV replicons were obtained allowing researchers to develop and assay DAAs with a robust methodology.3–5 In 2004, the safety and efficacy of the first DAA, the protease inhibitor BILN2061, were assessed in a proof-of-concept clinical trial.6 Now, a few years later, IFNα-containing or IFNα-free regimens based on DAAs showed the potential to cure HCV infection in very high percentages with overall good tolerability.7
DAAs targeting two major steps of the HCV life cycle have reached clinical development: (1) inhibitors of the NS3-4A protease, which block HCV polyprotein processing and (2) inhibitors of viral replication, including several drug families, such as nucleoside/nucleotide and non-nucleoside inhibitors of the RNA-dependent RNA polymerase (RdRp), and inhibitors of the NS5A viral protein which have a regulatory role in HCV replication.8–12
A perspective of the future treatment landscape for chronic HCV infection is depicted in figure 1. Peg-IFNα-containing regimens with second generation protease inhibitors like simeprevir and faldaprvir or the polymerase inhibitor sofosbuvir will become the first to be licensed for HCV type 1 infection. A significant number of different all oral IFNα-free regimens …
FvB and ZM have contributed equally to this work.
Contributors ZM, FvB, XF and TB have reviewed the literature, drafted and reviewed the manuscript. All authors have approved the final version to be published.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.