Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial.
BACKGROUND
Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV.


METHODS
In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 μg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770.


RESULTS
48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups.


CONCLUSIONS
Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection.


BACKGROUND
Bristol-Myers Squibb.
Hôpital Cochin, Paris, France. stanislas.pol@cch.aphp.fr
Stanislas
S
Pol
Reem H
RH
Ghalib
Vinod K
VK
Rustgi
Claudia
C
Martorell
Greg T
GT
Everson
Harvey A
HA
Tatum
Christophe
C
Hézode
Joseph K
JK
Lim
Jean-Pierre
JP
Bronowicki
Gary A
GA
Abrams
Norbert
N
Bräu
David W
DW
Morris
Paul J
PJ
Thuluvath
Robert W
RW
Reindollar
Philip D
PD
Yin
Ulysses
U
Diva
Robert
R
Hindes
Fiona
F
McPhee
Dennis
D
Hernandez
Megan
M
Wind-Rotolo
Eric A
EA
Hughes
Steven
S
Schnittman
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage*; D002219:Carbamates; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005602:France; D005838:Genotype; D016174:Hepacivirus / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D016898:Interferon-alpha / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011759:Pyrrolidines; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins / Q000008:administration & dosage; D012254:Ribavirin / Q000008:administration & dosage; D016896:Treatment Outcome; D014481:United States; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load
D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D016898:Interferon-alpha; D010919:Placebos; D011759:Pyrrolidines; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D014633:Valine; C549273:daclatasvir; C100416:peginterferon alfa-2a