January 23, 2014

Gastroenterology
Volume 146, Issue 2 , Pages 420-429, February 2014

Parts of this study were presented at The Liver Meeting: The 63rd Annual Meeting of the AASLD, Boston, MA, November 9-13, 2012, Oral LB-3; and The International Liver Congress 2013: The 48th Annual Meeting of the European Association for the Study of the Liver, Amsterdam, The Netherlands, April 24–28, 2013.

Gregory T. Everson, Karen D. Sims, Maribel Rodriguez–TorresChristophe Hézode, Eric Lawitz, Marc Bourlière, Veronique Loustaud–RattiVinod Rustgi, Howard Schwartz,Harvey Tatum, Patrick Marcellin, Stanislas Pol, Paul J. Thuluvath, Timothy Eley, Xiaodong Wang, Shu–Pang Huang, Fiona McPhee, Megan Wind–Rotolo, Ellen Chung, Claudio Pasquinelli, Dennis M. Grasela, David F. Gardiner

Received 22 August 2013; accepted 26 October 2013. published online 01 November 2013.

Abstract

Background & Aims

The combination of peginterferon and ribavirin with telaprevir or boceprevir is the standard treatment of hepatitis C virus (HCV) genotype 1 infection. However, these drugs are not well tolerated because of their side effects and suboptimal virologic responses. In a phase 2a, open-label study, we examined the safety and efficacy of an interferon-free, ribavirin-free regimen of direct-acting antivirals, comprising daclatasvir (an NS5A replication complex inhibitor), asunaprevir (an NS3 protease inhibitor), and BMS-791325 (a non-nucleoside NS5B inhibitor), in patients with chronic HCV infection.

Methods

We analyzed data from 66 treatment-naive patients with HCV genotype 1 infection without cirrhosis who were assigned randomly to groups given daclatasvir (60 mg, once daily), asunaprevir (200 mg, twice daily), and BMS-791325 (75 or 150 mg, twice daily) for 12 or 24 weeks. The primary end point was an HCV-RNA level less than 25 IU/mL at 12 weeks after treatment (sustained virologic response at 12 weeks [SVR12]).

Results

In 64 patients, HCV-RNA levels were less than 25 IU/mL by week 4 of treatment (including 48 of 49 patients with HCV genotype 1a infection and 45 of 46 patients with the non-CC interleukin 28B genotype). Sixty-one patients (92%) achieved SVR12, based on a modified intention-to-treat analysis. Virologic responses were similar between 12 and 24 weeks of treatment. During the study, 2 patients experienced viral breakthrough and 1 patient relapsed. There were no grade 3–4 increases in levels of alanine or aspartate aminotransferases or bilirubin; there were no deaths or discontinuations resulting from serious adverse events or adverse events related to the treatment regimen. The most common adverse events were headache, asthenia, and gastrointestinal symptoms.

Conclusions

In a phase 2a study, the all-oral, interferon-free, and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 was well tolerated and achieved high rates of SVR12 in patients with HCV genotype 1 infection. Further studies of this regimen are warranted. ClinicalTrials.gov, number NCT01455090.

Keywords: Liver Disease, Therapy, DAA, Drug Combination

Abbreviations used in this paper: EC50, median effective concentration, GT, genotype, HCV, hepatitis C virus, IL, interleukin, SVR,sustained virologic response, SVR24, sustained virologic response at 12 weeks

Source