Combination of Vaniprevir with Peginterferon and Ribavirin Significantly Increases the Rate of Sustained Viral Response in Treatment-Experienced Patients with Chronic HCV Genotype 1 Infection and Cirrhosis

Clinical Gastroenterology and Hepatology

Article in Press

Maribel Rodriguez-Torres, Albrecht Stoehr, Edward J. Gane, Lawrence Serfaty, Eric Lawitz, Amy Zhou, Michael Bourque, Sanhita Bhanja, Julie Strizki, Richard J.O. Barnard, Peggy M.T. Hwang, Mark J. DiNubile, Niloufar Mobashery,

Received 10 June 2013; received in revised form 20 September 2013; accepted 21 September 2013. published online 14 October 2013.
Accepted Manuscript

Abstract

Background

& Aims: The combination of vaniprevir (a NS3/4A protease inhibitor) with peginterferon and ribavirin was shown to significantly increase rates of sustained virologic response (SVR), compared with peginterferon and ribavirin alone, in treatment-experienced patients with chronic hepatitis C virus (HCV) genotype 1 infection without cirrhosis. We performed a blinded, randomized, controlled trial of the effects of vaniprevir with peginterferon and ribavirin in patients with cirrhosis who did not respond to prior therapy with peginterferon and ribavirin.

Methods

Treatment-experienced patients (88% white and 35% prior null responders) with HCV genotype 1 infection and compensated cirrhosis were randomly assigned to groups given vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 24 weeks (n=16), vaniprevir (600 mg twice daily) for 24 weeks with peginterferon and ribavirin for 48 weeks (n=14), vaniprevir (300 mg twice daily) with peginterferon and ribavirin for 48 weeks (n=15), vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 48 weeks (n=15), or placebo with peginterferon and ribavirin for 48 weeks (n=14, control). Cirrhosis was documented by liver biopsy (84%) or non-invasive methods (16%). Prior to randomization, participants were stratified based on their historical response to peginterferon and ribavirin.

Results

In the primary analysis, SVR rates among patients in the respective vaniprevir groups were 9/15 (60.0%), 9/13(69.2%), 8/15 (53.3%), and 10/13 (76.9%), compared with 2/14 (14.3%) in the control group (pairwise P values ≤0.016). Cirrhotic patients with null or partial responses to prior therapy achieved SVRs less often than patients with prior breakthrough or relapse, although 42.1% of prior null responders in the vaniprevir groups achieved SVRs. Patients in the vaniprevir groups more frequently experienced mild-moderate nausea, vomiting, and diarrhea than controls; 5% developed grade 2 anemia, compared with none in the control group (no patient developed grade 3 or 4 anemia). Among patients in the vaniprevir groups who experienced virologic failure, resistance-associated variants were predominantly detected at positions 155, 156, and 168 in the HCV protease gene.

Conclusions

In a controlled, Phase 2b trial, vaniprevir with peginterferon and ribavirin significantly increased rates of SVR among treatment-experienced patients with chronic HCV genotype 1 infection, compared to retreatment with peginterferon and ribavirin alone. Vaniprevir was generally well-tolerated for up to 48 weeks in patients with compensated cirrhosis.

ClinicalTrials.gov Identifier: NCT00704405

Keywords: clinical trial, fibrosis, DAA, direct-acting antiviral agent

Abbreviation: AE, adverse event, cEVR, complete early virologic response, CI, confidence interval, D/C, discontinuation, HCV, hepatitis C virus, ITT, intention to treat, IU/mL, international units per milliliter, LLD, lower limit of detection, LLQ, lower limit of quantification, mITT, modified intention to treat, P/R, peginterferon alfa/ribavirin, RVR, rapid virologic response, SVR, sustained virologic response, SVR₂₄, sustained virologic response at Week 24 of follow-up, TND, target not detected, TD(u), target detected but unquantifiable

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