Anti-interferon-α neutralizing antibody induced telaprevir resistance under the interferon-α plus telaprevir treatment in vitro

Although the development of anti-interferon (IFN)-α neutralizing antibodies (NAbs) is likely to be a common clinical problem for patients with various diseases treated with IFN, anti-IFN-α NAb has been exceptionally considered to have no clinical significance in the treatment of chronic hepatitis C with pegylated IFN-α (Peg-IFN-α). However, we recently clarified that the presence of NAb was associated with a non-response to the Peg-IFN plus ribavirin (RBV) therapy. In this study, we used the HCV-replicon system with genotype 1b, and investigated the role of anti-IFN-α NAb in the response to telaprevir (TVR)-containing new antiviral therapy for hepatitis C virus (HCV). Anti-IFN-α NAb-positive sera specifically inhibited the anti-HCV effects of IFN-α, without any effect on the activity of IFN-β in vitro. The NAb-positive sera also inhibited the IFN-α-dependent induction of interferon-stimulated genes, MxA and OAS-1, in a dose-dependent manner. Although TVR monotherapy decreased the HCV-RNA in vitro, the HCV-RNA was increased again with the development of TVR-resistant mutations. When IFN-α was administrated with TVR, the replication of HCV was continuously suppressed for more than a month. However, in the presence of anti-IFN-α NAb-positive sera, even when IFN-α was combined with TVR, the levels of HCV-RNA exhibited a time-course similar to that with TVR monotherapy, and HCV with TVR-resistant mutations emerged. In conclusion, our findings suggest that the presence of IFN-α NAb decreases the antiviral effects of IFN-α and may be related to the development of TVR-resistant mutated viruses.