Mericitabine and Either Boceprevir or Telaprevir in Combination with Peginterferon Alfa-2a plus Ribavirin for Patients with Chronic Hepatitis C Genotype 1 Infection and Prior Null Response: The Randomized DYNAMO 1 and DYNAMO 2 Studies.

Heiner Wedemeyer,Xavier Forns,Isabel Nájera,Christophe Hézode,Athina Voulgari,Sophie Le Pogam,James A Thommes,Astrid Scalori,Samuel S Lee,Chien-Wei Su

doi:10.1371/journal.pone.0145409

Abstract

Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-log10 reduction in HCV RNA by treatment week 12) to peginterferon/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60–70% in DYNAMO 1 and of 71–96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI.Trial Registration: ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390

Highlights

Chronic hepatitis C virus (HCV) infection is estimated to affect approximately 180 million people worldwide and is a leading cause of hepatocellular carcinoma, cirrhosis, and liver-related death [1, 2]
We studied the incremental benefits associated with adding mericitabine to protease inhibitor (PI) plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials
In addition to the requirement for prior null response, both studies recruited a high proportion of patients with bridging fibrosis or cirrhosis, and so included populations that have typically been regarded as difficult-to-treat with first-generation protease inhibitor-based combinations

Summary

Introduction

Chronic hepatitis C virus (HCV) infection is estimated to affect approximately 180 million people worldwide and is a leading cause of hepatocellular carcinoma, cirrhosis, and liver-related death [1, 2]. The first direct-acting antiviral agents (DAAs) approved for treatment of chronic HCV infection were the serine protease inhibitors boceprevir (BOC) and telaprevir (TVR), both of which are only effective against HCV genotype 1 and must be used in combination with peginterferon alfa/ribavirin [7, 8]. Compared with dual peginterferon alfa/ribavirin therapy, these protease inhibitor-based triple combinations increase SVR rates in treatment-naïve and previously treated patients and decrease the required duration of treatment for most previously untreated patients [9,10,11,12,13]. Compassionate use and expanded access studies in patients with more advanced liver disease have demonstrated the effectiveness of BOC- and TVR-based triple therapies, but have shown high rates of serious adverse events including anaemia, especially in patients with advanced cirrhosis [14,15,16]

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Results

Conclusion