title: Balapiravir plus peginterferon alfa-2a (40KD)/ribavirin in a randomized trial of hepatitis C genotype 1 patients.
abstract: BACKGROUND
  Balapiravir (R1626, RG1626) is the prodrug of a nucleoside analogue inhibitor of the hepatitis C virus (HCV) RNA-dependent RNA polymerase (R1479, RG1479). This phase 2, double-blind international trial evaluated the optimal treatment regimen of balapiravir plus peginterferon alfa-2a (40KD)/ribavirin.
  
  
  METHODS
  Treatment-naive genotype 1 patients (N = 516) were randomized to one of seven treatment groups in which they received balapiravir 500, 1,000, or 1,500 mg twice daily, peginterferon alfa-2a (40KD) 180 or 90 µg/week and ribavirin 1,000/1,200 mg/day or peginterferon alfa-2a (40KD)/ribavirin. The planned treatment duration with balapiravir was reduced from 24 to 12 weeks due to safety concerns.
  
  
  RESULTS
  The percentage of patients with undetectable HCV RNA was consistently higher in all balapiravir groups from week 2 to 12. However, high rates of dose modifications and discontinuations of one/all study drugs compromised the efficacy assessment and resulted in similar sustained virological response rates in the balapiravir groups (range 32-50%) and the peginterferon alfa-2a (40KD)/ribavirin group (43%). Balapiravir was discontinued for safety reasons in 28-36% of patients (most often for lymphopenia) and the percentage of patients with serious adverse events (especially hematological, infection, ocular events) was dose related. Serious hematological adverse events (particularly neutropenia, lymphopenia) were more common in balapiravir recipients. Two deaths in the balapiravir/peginterferon alfa-2a/ribavirin combination groups were considered possibly related to study medication.
  
  
  CONCLUSIONS
  Further development of balapiravir for the treatment of chronic hepatitis C has been halted because of the unacceptable benefit to risk ratio revealed in this study (www.ClinicalTrials.gov NCT 00517439).
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainsville, USA. nelsodr@medicine.ufl.edu
authors.forename: David R
authors.initials: DR
authors.lastname: Nelson
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Pietro
authors.initials: P
authors.lastname: Andreone
authors.forename: Peter
authors.initials: P
authors.lastname: Ferenci
authors.forename: Robert
authors.initials: R
authors.lastname: Herring
authors.forename: Donald M
authors.initials: DM
authors.lastname: Jensen
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Pockros
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodríguez-Torres
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Rossaro
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Rustgi
authors.forename: Thomas
authors.initials: T
authors.lastname: Sepe
authors.forename: Mark
authors.initials: M
authors.lastname: Sulkowski
authors.forename: Isaac R
authors.initials: IR
authors.lastname: Thomason
authors.forename: Eric M
authors.initials: EM
authors.lastname: Yoshida
authors.forename: Anna
authors.initials: A
authors.lastname: Chan
authors.forename: George
authors.initials: G
authors.lastname: Hill
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D023381:Endpoint Determination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D007391:International Cooperation; D008297:Male; D008875:Middle Aged; D009705:Nucleosides / Q000009:adverse effects / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D016898:Interferon-alpha; D009705:Nucleosides; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a; C530825:balapiravir