Interchanging of Direct Acting Antiviral Agents in the Treatment of Hepatitis C Infection: Are All Protease Inhibitors Created Equal?

Abstract

Purpose: The standard of care (SOC) therapy for patients with chronic Hepatitis C has changed due to the emergence of direct acting antiviral agents (DAA). These novel serine NS3/4A protease inhibitors are now used in combination with pegylated interferon and ribavirin in the treatment of genotype 1 chronic hepatitis C infection in adult patients with liver diseases (including cirrhosis) who are treatment naïve or who have failed previous treatment. Although pegylated interferon and ribavirin remain core components of therapy, these DAAs have led to a substantial improvement in SVR rates and the option of abbreviated therapy in many patients. However, the efficacy of these medications has not been established for patients who have failed previous treatment regimens that contained HCV protease inhibitors. We report the case of a 48-year-old male with stage 2 fibrosis, Hep C genotype 1b infection who had previously completed a 60 week course of pegylated interferon and ribavirin therapy and proved to be a partial responder with HCV RNA detectable at week 24. The patient subsequently had a course of consensus interferon and ribavirin therapy for an additional 26 weeks that proved to be a null responder. In our clinical setting, the patient was started on triple therapy comprising of pegylated interferon, ribavirin and boceprevir. Unfortunately, the patient met treatment futility rule at week 12 with a HCV RNA PCR assay of 190 IU which was confirmed on repeat testing. The patient's treatment strategy was reinstituted with the substitution of boceprevir for telaprevir, in addition to pegylated interferon and ribavirin. The patient obtained a rapid virological response (RVR) with undetectable HCV RNA by PCR at week 4 of treatment. The patient has currently received 10 weeks of treatment on this new regimen. This is potentially the first case reported of induction of virologic response with one protease inhibitor in a patient who failed treatment with another one. The emergence of antiviral resistance Hep C variants (conferred by substitutions of the NS3 amino acid sequence) was observed in phase 2 and 3 clinical trials of both protease inhibitors and was associated clinically with virological failure and relapse. A cohort of these substitutions was found common to both protease inhibitors, suggesting that some degree of cross resistance may exist. This has led to weak evidence not recommending the initiation of one protease inhibitors in the face of failure of treatment on another. Further studies are needed to assess this and the potential for substitutions of HCV protease inhibitors in patients with an inadequate viral response.