Efficacy and Safety of Danoprevir-Ritonavir plus Peginterferon Alfa-2a–Ribavirin in Hepatitis C Virus Genotype 1 Prior Null Responders

Abstract

f ; Genentech, South San Francisco, California, USA g Danoprevir (DNV) is a hepatitis C virus (HCV) protease inhibitor that achieves high sustained virologic response (SVR) rates in combination with peginterferon alfa-2a-ribavirin in treatment-naive HCV genotype 1 (G1)-infected patients. This study explored the efficacy and safety of ritonavir-boosted DNV (DNVr) plus peginterferon alfa-2a-ribavirin in G1-infected prior peginterferon-ribavirin null responders. Null responders (<2-log 10 reduction in HCV RNA level at week 12) were given an open-label combination of 100 mg of ritonavir and 100 mg of DNV (100/100 mg DNVr) every 12 h (q12h) plus peginterferon alfa-2a-ribavirin for 12 weeks. All patients achieving an early virologic response (EVR; >2-log 10 decrease in HCV RNA by week 12) continued treatment with peginterferon alfa-2a-ribavirin; those without an EVR discontinued all study drugs. Twenty-four prior null responders were enrolled; 16 patients (67%) were infected with HCV G1b, and 8 (33%) were infected with G1a. Ninety-six percent of patients had an IL28B non-CC genotype. A sustained virologic response at 24 weeks posttreatment (SVR24) was achieved in 67% of patients, with a higher rate in G1b-infected (88%) than G1a-infected (25%) patients. Resistance-related breakthrough occurred in 4/8 G1a and 1/16 G1b patients through the DNV resistance-associated variant (RAV) NS3 R155K. NS3 R155K was also detected in 2/2 G1a patients who relapsed. Treatment was well tolerated. Two patients withdrew prematurely from study medications due to adverse events. Two serious adverse events were reported; both occurred after completion of DNVr therapy and were considered unrelated to treatment. No grade 3 or 4 alanine aminotransferase (ALT) elevations were observed. DNVr plus peginterferon alfa-2a-ribavirin demonstrated high SVR24 rates in HCV G1b-infected prior null responders and was well tolerated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01185860.)

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

“…This observation is in line with prior studies in which MCB was well tolerated as a component of triple or quadruple therapy regimens including peginterferon alfa/ribavirin and/or danoprevir/r [ 18 , 22 , 23 ]. Consistent with the more favorable tolerability profile of danoprevir/r compared with first-generation protease inhibitors [ 35 ], serious adverse events and withdrawals due to adverse events were more common in the present studies than reported for MCB in combination with danoprevir/r and peginterferon alfa/ribavirin [ 18 ].…”

New Hepatitis C Therapies: The Toolbox, Strategies, and Challenges

“…In null responders receiving the same combination for 12 weeks, 25% (2 of 8) of those with subtype 1a and 88% (14 of 16) of those with subtype 1b HCV infections achieved SVR. 55 With vaniprevir (a drug that will be commercialized only in Japan) the rates of SVR in treatment-experienced patients without cirrhosis, infected with HCV genotype 1, were 67% (26 of 39) and 78% (91 of 117) with 300 or 600 mg twice daily, respectively, vs 19% (8 of 42) in the control group. 56 Among patients with cirrhosis, rates of SVR were 53% (8 of 15) and 68% (28 of 41), respectively, vs 14% in the control group (2 of 14).…”

<p>Danoprevir for the Treatment of Hepatitis C Virus Infection: Design, Development, and Place in Therapy</p>

“… 33 Among these studies, the approved danoprevir-based regimen (danoprevir 100 mg twice daily (BID) plus ritonavir 100 mg twice daily; peginterferon alpha-2a 180 μg once weekly; and ribavirin 1000 mg/day for bodyweight <75 kg, 1200 mg/day for ≥75 kg, twice daily for 12 weeks) in treatment-naïve non-cirrhotic patients was evaluated by the MANASA study, 26 the MAKALU study, 29 the DAUPHINE study, 28 and a phase 1 study (NCT01185860). 33 …”