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

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.

Conflict of interest statement

Competing Interests: HW: has served as a consultant/speaker for Abbott, AbbVie, Biolex, BMS, Boehringer Ingelheim, Gilead Sciences, ITS, J&J/Janssen-Cilag, Medgenics, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, ViiV; and has received research grants from Abbott, BMS, Gilead Sciences, Merck, Novartis, Roche, Roche Diagnostics, Siemens. XF: has received unrestricted grant support from Janssen and has served as an advisor for Janssen, Gilead and AbbVie. CH: has served as a consultant/speaker for Roche, Bristol-Myers Squibb, Merck, Janssen, AbbVie, and Gilead Sciences. SSL: Consulting for or research funding from: AbbVie, Achillion, Bristol Myers Squibb, Debiopharm, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Novartis, Roche, Vertex. Speakers Bureau: Bristol Myers Squibb, Gilead Sciences, Janssen, Merck, Roche, Vertex. AS: Employee of Roche Products Ltd. AV: Employee of Roche Products Ltd. SLP: Employee of Genentech Inc. IN: Employee of F. Hoffmann-La Roche Ltd. JAT: Employee of Genentech Inc. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Patient disposition in DYNAMO 1.

BOC, boceprevir; MCB, mericitabine; P/R, peginterferon alfa-2a + ribavirin.

Fig 2. Patient disposition in DYNAMO 2.

MCB, mericitabine; P/R, peginterferon alfa-2a + ribavirin; TVR, telaprevir.

Fig 3. Study designs of DYNAMO 1 (a) and DYNAMO 2 (b).

BOC, boceprevir 800 mg TID (at recommended intervals of 7–9 hours); MCB, mericitabine 1000 mg BID; P/R, peginterferon alfa-2a 180 μg once/week + ribavirin 1000 mg/day (

Fig 4. SVR12 rates by treatment arm in the overall populations and by HCV genotype and presence/absence of bridging fibrosis or cirrhosis in DYNAMO 1 (a) and DYNAMO 2 (b).

BOC, boceprevir; MCB, mericitabine; P/R, peginterferon alfa-2a + ribavirin; TVR, telaprevir.