November 6, 2013

Gastroenterology

Article in Press

Gregory T. Everson,Karen D. Sims,Maribel Rodriguez-Torres,Christophe Hézode,Eric Lawitz,Marc Bourlière,Veronique Loustaud-Ratti, Vinod 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; received in revised form 21 October 2013; accepted 26 October 2013. published online 01 November 2013.
Accepted Manuscript

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, producing side effects and suboptimal virologic responses. In a phase 2a, open-label study, we examined 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 on 66 treatment-naive patients with HCV genotype 1 infection without cirrhosis who were randomly assigned 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 endpoint was HCV RNA <25 IU/mL at 12 weeks after treatment (SVR12).

Results

In 64 patients, levels of HCV RNA were <25 IU/mL by week 4 of treatment (including 48/49 patients with HCV genotype 1a infection and 45/46 patients with the non-CC IL28B 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 aminotransferase or bilirubin; there were no deaths or discontinuations due to 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- 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.

Keywords: liver disease, therapy, DAA, drug combination

Abbreviations: APRI, aminotransferase: platelet ratio, GT, genotype, HCV, hepatitis C virus, SVR, sustained virologic response

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