1 Department of Virology, National Reference Center for Viral Hepatitis B, C and D, Université Paris-Est, Hôpital Henri Mondor, Créteil, France.
2 Research team "Viruses, Hepatology, Cancers", INSERM U955, Créteil, France.
The treatment of chronic hepatitis C virus (HCV) infection has considerably evolved with the development of safe and well-tolerated combinations of direct-acting antiviral (DAA) drugs yielding high rates of infection cure. However, some patients fail to achieve a sustained virological response while receiving the most recent DAA combinations. Several waves of treatment failures have occurred concomitantly to the use of different drug combinations. The outcome of their retreatment strongly depends on the DAA(s) received and the retreatment regimen(s) available. This article discusses virological failure rates with the successive waves of HCV combination regimens, the reasons for failure, the role of HCV resistance, and current retreatment options. The triple combination of sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks is the first-line retreatment strategy in patients previously exposed to DAAs. Difficult-to-retreat patients may benefit from the combination of sofosbuvir plus glecaprevir/pibrentasvir and/or the addition of ribavirin and/or longer retreatment duration.