Second wave direct acting antivirals such as sofosbuvir, simeprevir and daclatasvir can be combined with pegylated interferon alpha and ribavirin (PEG-IFN/RBV) as triple therapy in patients with hepatitis C virus (HCV) infection. In patients with HCV genotype 1 (HCV-1), a PEG-IFN/RBV-based regimen with sofosbuvir is highly effective but the presence of cirrhosis and the non-CC IFNL3 genotype have been associated with a poorer response. A PEG-IFN/RBV-based regimen with simeprevir or daclatasvir is based on response-guided therapy and its efficacy depends on predictors of response to IFN. HCV-1 subtype is also a major predictor of response. In HCV-1a infected patients, the K80Q mutation in NS3 or the presence of NS5A variants at baseline are associated with poor response with simeprevir- or daclatasvir-containing regimens respectively. Thus, these regimens should be only used in HCV-1b patients with good predictors of response to IFN.