Gastroenterology

Gastroenterology

Volume 148, Issue 2, February 2015, Pages 355-366.e1
Gastroenterology

Original Research
Full Report: Clinical—Liver
Daclatasvir Plus Peginterferon and Ribavirin Is Noninferior to Peginterferon and Ribavirin Alone, and Reduces the Duration of Treatment for HCV Genotype 2 or 3 Infection

https://doi.org/10.1053/j.gastro.2014.10.007Get rights and content

Background & Aims

Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%–80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy.

Methods

Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24).

Results

Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above –20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those expected from peginterferon alfa and ribavirin therapy.

Conclusions

Twelve or 16 weeks of treatment with daclatasvir, in combination with peginterferon alfa-2a and ribavirin, is a well tolerated and effective therapy for patients with HCV genotype 2 or 3 infections. Daclatasvir-containing regimens could reduce the duration of therapy for these patients. Clinicaltrials.gov number: NCT01257204.

Section snippets

Study Design

The objective of this randomized, double-blind, 3-arm phase 2b study was to compare the antiviral activity and safety of 12 or 16 weeks of treatment with daclatasvir plus peg-alfa/RBV with 24 weeks of treatment with placebo plus peg-alfa-2a/RBV (Supplementary Figure 1) (study AI444-031; clinicaltrials.gov identifier NCT01257204). Patients on daclatasvir-containing regimens who achieved a protocol-defined response (PDR) (HCV-RNA level < lower limit of quantitation [LLOQ] at week 4 and < LLOQ

Patients

A total of 196 patients were screened; 152 were assigned randomly to treatment groups and 151 were treated (Figure 1). Forty-four patients were not randomized; the predominant reason was that these patients no longer met the study protocol entry criteria. One patient (in the daclatasvir 16-week group) was randomized but withdrew consent before initiating study treatment and was excluded from the modified intention-to-treat population for subsequent analyses. Study treatment was completed by 131

Discussion

Therapeutic regimens that include direct-acting antivirals can increase efficacy and reduce the required duration of therapy for patients with chronic HCV infection, providing advantages for both patients and health care providers. Results of this study confirm that the pan-genotypic in vitro activity of daclatasvir is reflected by clinical activity in patients infected with genotypes 2 and 3, consistent with previous data in patients infected with genotypes 1 and 4.12, 16, 17 Addition of

Acknowledgments

The authors thank the patients and their families, research staff at all participating sites, and Bristol-Myers Squibb Research and Development colleagues.

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    Conflicts of interest These authors disclose the following: Gregory Dore has been a clinical investigator, consultant, speaker, and/or has received travel sponsorship from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, Roche, and Vertex; Eric Lawitz has been a consultant, research grant recipient, and/or speaker for AbbVie, Achillion, BioCryst, Biotica, Boehringer Ingelheim, Bristol-Myers Squibb, Enanta, Gilead, GlaxoSmithKline, Idenix, Intercept, Janssen, Kadmon, Medtronic, Merck, Novartis, Presidio, Roche, Santaris, Theravance, and Vertex; Christophe Hézode has been a clinical investigator, speaker, and/or consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, and Roche; Stephen Shafran has been a clinical investigator, speaker, and/or consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, Pfizer, Roche, and Vertex; Alnoor Ramji has been a clinical investigator, consultant, speaker, and/or received research grants from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck, Roche, Vertex, Janssen, and Novartis; Harvey Tatum has been a clinical investigator and/or speaker for Gilead, Merck, AbbVie, Boehringer Ingelheim, and Genentech; Gloria Taliani has received personal fees from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck, and Roche; Albert Tran has been a clinical investigator for AbbVie, Bristol-Myers Squibb, Gilead, and Janssen; Maurizia Brunetto has received personal fees from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck, Novartis, and Roche; Simone Strasser has been a consultant, speaker, and has received travel support from Bristol-Myers Squibb; Nina Weis has been a clinical investigator, consultant, and/or speaker for Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck, and Roche; Samuel Lee has received research grants and personal fees from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, Roche, and Vertex; Dominique Larrey has been a consultant and/or clinical investigator for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, Roche, and Sanofi; Hugh Harley has been a consultant for Bristol-Myers Squibb; Jacob George has been a consultant and has received lecture fees from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, and Roche; Scott Fung has been a speaker/consultant for Gilead, Merck, Roche, and Vertex; Victor de Lédinghen has received personal fees from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Echosens, Gilead, Janssen, Merck, and Roche; Peggy Hagens, Fiona McPhee, Dennis Hernandez, David Cohen, Elizabeth Cooney, Stephanie Noviello, and Eric Hughes are employees of Bristol-Myers Squibb. The remaining authors disclose no conflicts.

    Funding This study was funded by Bristol-Myers Squibb; the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney (J.G.); and a National Health and Medical Research Council of Australia program grant (1053206) and project grant (1047417). Bristol-Myers Squibb also provided funding for the editorial assistance services of Richard Boehme, PhD, of Articulate Science, for the preparation of this manuscript.

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