Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders

Hepatology. 2012 Mar;55(3):742-8. doi: 10.1002/hep.24724. Epub 2012 Jan 30.

Abstract

Patients with chronic hepatitis C virus (HCV) infection and previous null response to pegylated interferon (Peg-IFN) and ribavirin (RBV) have limited therapeutic options. HCV genotype 1 is the most common worldwide and the most difficult to treat; genotype 1b is the most common subtype of genotype 1 outside North America. The enhanced antiviral activity achieved by combining two direct-acting antiviral (DAA) agents may improve clinical outcomes. This open-label, phase IIa study included 10 patients with chronic HCV genotype 1b infection and previous null response (<2 log(10) reduction in HCV RNA after 12 weeks) to Peg-IFN and RBV. Patients received dual DAA treatment for 24 weeks with the nonstructural protein 5A replication complex inhibitor, daclatasvir (60 mg once-daily), and the nonstructural protein 3 protease inhibitor, asunaprevir (initially 600 mg twice-daily, then subsequently reduced to 200 mg twice-daily). The primary efficacy endpoint was the proportion of patients with sustained virologic response (SVR) at 12 weeks post-treatment (SVR(12) ). Nine patients completed 24 weeks of treatment; 1 patient discontinued treatment after 2 weeks. In the 9 patients who completed the full course of treatment, HCV RNA was undetectable at week 8 and remained undetectable through the end of treatment; all 9 patients achieved SVR(12) and SVR(24) . HCV RNA also remained undetectable post-treatment in the patient who discontinued after 2 weeks. There was no viral breakthrough. Diarrhea and headache, generally mild, were the most common adverse events; transaminase elevations were reported in 3 patients, but did not result in discontinuation.

Conclusions: Dual therapy with daclatasvir and asunaprevir, without Peg-IFN and RBV, can achieve high SVR rates in difficult-to-treat patients with HCV genotype 1b infection and previous null response to Peg-IFN and RBV.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antiviral Agents / adverse effects
  • Antiviral Agents / therapeutic use*
  • Carbamates
  • Diarrhea / chemically induced
  • Diarrhea / epidemiology
  • Drug Therapy, Combination
  • Female
  • Genotype
  • Headache / chemically induced
  • Headache / epidemiology
  • Hepacivirus / genetics*
  • Hepatitis C / drug therapy*
  • Hepatitis C / ethnology
  • Humans
  • Imidazoles / adverse effects
  • Imidazoles / therapeutic use*
  • Incidence
  • Interferon-alpha / therapeutic use
  • Isoquinolines / adverse effects
  • Isoquinolines / therapeutic use
  • Japan
  • Male
  • Middle Aged
  • Polyethylene Glycols / therapeutic use
  • Protease Inhibitors / adverse effects
  • Protease Inhibitors / therapeutic use*
  • Pyrrolidines
  • Recombinant Proteins / therapeutic use
  • Ribavirin / therapeutic use
  • Sulfonamides / adverse effects
  • Sulfonamides / therapeutic use
  • Treatment Failure
  • Treatment Outcome
  • Valine / analogs & derivatives
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Antiviral Agents
  • Carbamates
  • Imidazoles
  • Interferon-alpha
  • Isoquinolines
  • Protease Inhibitors
  • Pyrrolidines
  • Recombinant Proteins
  • Sulfonamides
  • Viral Nonstructural Proteins
  • Polyethylene Glycols
  • Ribavirin
  • Valine
  • daclatasvir
  • peginterferon alfa-2a
  • asunaprevir