title: Preliminary study of two antiviral agents for hepatitis C genotype 1.
abstract: BACKGROUND
  Patients with chronic hepatitis C virus (HCV) infection who have not had a response to therapy with peginterferon and ribavirin may benefit from the addition of multiple direct-acting antiviral agents to their treatment regimen.
  
  
  METHODS
  This open-label, phase 2a study included an exploratory cohort of 21 patients with chronic HCV genotype 1 infection who had not had a response to previous therapy (i.e., had not had ≥2 log(10) decline in HCV RNA after ≥12 weeks of treatment with peginterferon and ribavirin). We randomly assigned patients to receive the NS5A replication complex inhibitor daclatasvir (60 mg once daily) and the NS3 protease inhibitor asunaprevir (600 mg twice daily) alone (group A, 11 patients) or in combination with peginterferon alfa-2a and ribavirin (group B, 10 patients) for 24 weeks. The primary end point was the percentage of patients with a sustained virologic response 12 weeks after the end of the treatment period.
  
  
  RESULTS
  A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a sustained virologic response at 12 weeks after treatment and also at 24 weeks after treatment.. Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases; 1 patient had a viral response at the end of treatment but had a relapse after the treatment period. All 10 patients in group B had a sustained virologic response at 12 weeks after treatment, and 9 had a sustained virologic response at 24 weeks after treatment. Diarrhea was the most common adverse event in both groups. Six patients had transient elevations of alanine aminotransferase levels to more than 3 times the upper limit of the normal range.
  
  
  CONCLUSIONS
  This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents only. In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with peginterferon alfa-2a and ribavirin. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01012895.).
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, 3912 Taubman Center, SPC 5362, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. aslok@med.umich.edu
authors.forename: Anna S
authors.initials: AS
authors.lastname: Lok
authors.forename: David F
authors.initials: DF
authors.lastname: Gardiner
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.forename: Claudia
authors.initials: C
authors.lastname: Martorell
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Everson
authors.forename: Reem
authors.initials: R
authors.lastname: Ghalib
authors.forename: Robert
authors.initials: R
authors.lastname: Reindollar
authors.forename: Vinod
authors.initials: V
authors.lastname: Rustgi
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.forename: Megan
authors.initials: M
authors.lastname: Wind-Rotolo
authors.forename: Anna
authors.initials: A
authors.lastname: Persson
authors.forename: Kurt
authors.initials: K
authors.lastname: Zhu
authors.forename: Dessislava I
authors.initials: DI
authors.lastname: Dimitrova
authors.forename: Timothy
authors.initials: T
authors.lastname: Eley
authors.forename: Tong
authors.initials: T
authors.lastname: Guo
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Grasela
authors.forename: Claudio
authors.initials: C
authors.lastname: Pasquinelli
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002219:Carbamates; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use; D011759:Pyrrolidines; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012008:Recurrence; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D016898:Interferon-alpha; D011759:Pyrrolidines; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D014633:Valine; C549273:daclatasvir; C100416:peginterferon alfa-2a