All-Oral 12-Week Treatment With Daclatasvir Plus Sofosbuvir in Patients With Hepatitis C Virus Genotype 3 Infection: ALLY-3 Phase III Study

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Abstract

Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all-oral regimens requiring 24-week treatment and the addition of ribavirin (RBV). This phase III study (ALLY-3; http://ClinicalTrials.gov: NCT02032901) evaluated the 12-week regimen of daclatasvir (DCV; pangenotypic nonstructural protein [NS]5A inhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment naïve (n = 101) or treatment experienced (n = 51) and received DCV 60 mg plus SOF 400 mg once-daily for 12 weeks. Coprimary endpoints were the proportions of treatment-naïve and treatment-experienced patients achieving a sustained virological response (SVR) at post-treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment-naïve and treatment-experienced patients, respectively; no virological breakthrough was observed, and ≥99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF-containing regimen and 2 of 2 who previously failed treatment with an alisporivir-containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV-RNA levels, and interleukin-28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on-treatment, which was unrelated to study medications. The few treatment-emergent grade 3/4 laboratory abnormalities that were observed were transient. Conclusion: A 12-week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3–infected patients with cirrhosis is underway. (H epatology 2015;61:1127–1135)

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Most cited references 14

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Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options.

Ira M Jacobson, Stuart Gordon, Kris V Kowdley … (2013)

Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment with peginterferon is not an option, or who have not had a response to prior interferon treatment, currently have no approved treatment options. In phase 2 trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection. We conducted two randomized, phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection. In one trial, patients for whom treatment with peginterferon was not an option received oral sofosbuvir and ribavirin (207 patients) or matching placebo (71) for 12 weeks. In a second trial, patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks (103 patients) or 16 weeks (98). The primary end point was a sustained virologic response at 12 weeks after therapy. Among patients for whom treatment with peginterferon was not an option, the rate of a sustained virologic response was 78% (95% confidence interval [CI], 72 to 83) with sofosbuvir and ribavirin, as compared with 0% with placebo (P<0.001). Among previously treated patients, the rate of response was 50% with 12 weeks of treatment, as compared with 73% with 16 weeks of treatment (difference, -23 percentage points; 95% CI, -35 to -11; P<0.001). In both studies, response rates were lower among patients with genotype 3 infection than among those with genotype 2 infection and, among patients with genotype 3 infection, lower among those with cirrhosis than among those without cirrhosis. The most common adverse events were headache, fatigue, nausea, and insomnia; the overall rate of discontinuation of sofosbuvir was low (1 to 2%). In patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon and ribavirin was not an option, 12 or 16 weeks of treatment with sofosbuvir and ribavirin was effective. Efficacy was increased among patients with HCV genotype 2 infection and those without cirrhosis. In previously treated patients with genotype 3 infection, 16 weeks of therapy was significantly more effective than 12 weeks. (Funded by Gilead Sciences; POSITRON and FUSION ClinicalTrials.gov numbers, NCT01542788 and NCT01604850, respectively.).

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Sofosbuvir and ribavirin in HCV genotypes 2 and 3.

Stefan Zeuzem, Geoffrey M Dusheiko, Riina Salupere … (2014)

In clinical trials, treatment with a combination of the nucleotide polymerase inhibitor sofosbuvir and the antiviral drug ribavirin was associated with high response rates among patients with hepatitis C virus (HCV) genotype 2 infection, with lower response rates among patients with HCV genotype 3 infection. We conducted a study involving patients with HCV genotype 2 or 3 infection, some of whom had undergone previous treatment with an interferon-based regimen. We randomly assigned 91 patients with HCV genotype 2 infection and 328 with HCV genotype 3 infection, in a 4:1 ratio, to receive sofosbuvir-ribavirin or placebo for 12 weeks. On the basis of emerging data from phase 3 trials indicating that patients with HCV genotype 3 infection had higher response rates when they were treated for 16 weeks, as compared with 12 weeks, the study was unblinded, treatment for all patients with genotype 3 infection was extended to 24 weeks, the placebo group was terminated, and the goals of the study were redefined to be descriptive and not include hypothesis testing. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. Of the 419 patients who were enrolled and treated, 21% had cirrhosis and 58% had received previous interferon-based treatment. The criterion for a sustained virologic response was met in 68 of 73 patients (93%; 95% confidence interval [CI], 85 to 98) with HCV genotype 2 infection who were treated for 12 weeks and in 213 of 250 patients (85%; 95% CI, 80 to 89) with HCV genotype 3 infection who were treated for 24 weeks. Among patients with HCV genotype 3 infection, response rates were 91% and 68% among those without and those with cirrhosis, respectively. The most common adverse events were headache, fatigue, and pruritus. Therapy with sofosbuvir-ribavirin for 12 weeks in patients with HCV genotype 2 infection and for 24 weeks in patients with HCV genotype 3 infection resulted in high rates of sustained virologic response. (Funded by Gilead Sciences; VALENCE ClinicalTrials.gov number, NCT01682720.).

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Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C.

Pierre-Yves Bochud, Tao Cai, Kathrin Overbeck … (2009)

While several risk factors for the histological progression of chronic hepatitis C have been identified, the contribution of HCV genotypes to liver fibrosis evolution remains controversial. The aim of this study was to assess independent predictors for fibrosis progression. We identified 1189 patients from the Swiss Hepatitis C Cohort database with at least one biopsy prior to antiviral treatment and assessable date of infection. Stage-constant fibrosis progression rate was assessed using the ratio of fibrosis Metavir score to duration of infection. Stage-specific fibrosis progression rates were obtained using a Markov model. Risk factors were assessed by univariate and multivariate regression models. Independent risk factors for accelerated stage-constant fibrosis progression (>0.083 fibrosis units/year) included male sex (OR=1.60, [95% CI 1.21-2.12], P F1: 0.126 (0.106-0.145) versus 0.091 (0.083-0.100), F1-->F2: 0.099 (0.080-0.117) versus 0.065 (0.058-0.073), F2-->F3: 0.077 (0.058-0.096) versus 0.068 (0.057-0.080) and F3-->F4: 0.171 (0.106-0.236) versus 0.112 (0.083-0.142, overall P<0.001). This study shows a significant association of genotype 3 with accelerated fibrosis using both stage-constant and stage-specific estimates of fibrosis progression rates. This observation may have important consequences for the management of patients infected with this genotype.

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Author and article information

Contributors

Eric A Hughes:

Comment :

on behalf of the ALLY-3 Study Team

Journal

Journal ID (nlm-ta): Hepatology

Journal ID (iso-abbrev): Hepatology

Journal ID (publisher-id): hep

Title: Hepatology (Baltimore, Md.)

Publisher: Blackwell Publishing Ltd (Oxford, UK )

ISSN (Print): 0270-9139

ISSN (Electronic): 1527-3350

Publication date (Print): April 2015

Publication date (Electronic): 10 March 2015

Volume: 61

Issue: 4

Pages: 1127-1135

Affiliations

[1 ]University of Florida Gainesville, FL

[2 ]Inova Fairfax Hospital Falls Church, VA

[3 ]Quest Clinical Research San Francisco, CA

[4 ]Texas Liver Institute, University of Texas Health Science Center San Antonio, TX

[5 ]Scripps Clinic La Jolla, CA

[6 ]Atlanta Gastroenterology Associates Atlanta, GA

[7 ]Kansas City Research Institute Kansas City, MO

[8 ]Gastro One Germantown, TN

[9 ]Asheville Gastroenterology Associates Asheville, NC

[10 ]Texas Clinical Research Institute Arlington, TX

[11 ]Midland Florida Clinical Research Center DeLand, FL

[12 ]Mercy Medical Center Baltimore, MD

[13 ]Fundación de Investigación de Diego Santurce, Puerto Rico

[14 ]University of Pittsburgh Pittsburgh, PA

[15 ]Hofstra North Shore–Long Island Jewish School of Medicine Manhasset, NY

[16 ]Medical Associates Research Group San Diego, CA

[17 ]Southwest CARE Center Santa Fe, NM

[18 ]Digestive Disease Associates Baltimore, MD

[19 ]Gastrointestinal Specialists of Georgia Marietta, GA

[20 ]Premier Medical Group of Hudson Valley Poughkeepsie, NY

[21 ]Digestive Disease Institute, Virginia Mason Medical Center Seattle, WA

[22 ]Bristol-Myers Squibb Research and Development Braine-l'Alleud, Belgium

[23 ]Bristol-Myers Squibb Research and Development Wallingford, CT

[24 ]Bristol-Myers Squibb Research and Development Princeton, NJ

[25 ]Swedish Medical Center Seattle, WA

Author notes

Address reprint requests to: David R. Nelson, M.D., University of Florida, 219 Grinter Hall, Gainesville, FL 32611. E-mail: nelsodr@ 123456ufl.edu ; fax: +1-352-294-5789.

Potential conflict of interest: Dr. Nelson received grants from Bristol-Myers Squibb, Gilead, and Merck. Dr. Lawitz consults, advises, is on the speakers' bureau for, and received grants from AbbVie, Gilead, Janssen, Merck, and Vertex. He consults, advises, and received grants from Achillion, Bristol-Myers Squibb, Idenix, Novartis, Santaris, and Theravance. He consults and advises BioCryst, Biotica, and Regulus. He is on the speakers' bureau for Kadmon. He received grants from Boehringer Ingelheim, GlaxoSmithKline, Presidio, and Roche. Dr. Pockros consults, advises, is on the speakers' bureau for, and received grants from Bristol-Myers Squibb, Gilead, and Janssen. Dr. Gitlin is on the speakers' bureau for and received grants from Bristol-Myers Squibb and Gilead. Dr. Freilich received grants from Bristol-Myers Squibb. Dr. Younes is on the speakers' bureau for and received grants from Vertex, Gilead, and AbbVie. He received grants from Bristol-Myers Squibb, Idenix, and Merck. Dr. Ghalib received grants from Gilead, AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Salix, Pharmasset, Boehringer Ingelheim, Anadys, Janssen, Evoke, Idenix, Takeda, Vertex, Virochem, Achillion, and Debio. Dr. Thuluvath is on the speakers' bureau and received grants from Gilead and AbbVie. He is on the speakers' bureau for Onyx. He received grants from Salix and Bristol-Myers Squibb. Dr. Bernstein consults, advises, is on the speakers' bureau for, and received grants from Gilead and AbbVie. He consults and received grants from Bristol-Myers Squibb. Dr. Hawkins consults, advises, is on the speakers' bureau for, and received grants from Gilead, AbbVie, and Janssen. He is on the speakers' bureau and received grants from ViiV. He received grants from Bristol-Myers Squibb. Dr. Ravendhran advises, is on the speakers' bureau for, and received grants from Gilead and AbbVie. He is on the speakers' bureau for Salix and Onyx. He received grants from Bristol-Myers Squibb and Merck. Dr. Sheikh advises, is on the speakers' bureau for, and received grants from Gilead. He advises and is on the speakers' bureau for AbbVie. He received grants from Bristol-Myers Squibb, Idenix, Merck, Achillion, Vertex, Genentech, and Hologic. Dr. Kowdley advises and received grants from AbbVie, Gilead, Merck, and Bristol-Myers Squibb. He advises Achillion and Trio Health. He received grants from Beckman, Boehringer Ingelheim, Ikaria, Intercept, Janssen, Mochida, Novartis, and Vertex. Dr. Hennicken is employed by Bristol-Myers Squibb. Dr. McPhee is employed by and owns stock in Bristol-Myers Squibb. Dr. Rana is employed by Bristol-Myers Squibb. Dr. Hughes is employed by Bristol-Myers Squibb.

This study was funded by Bristol-Myers Squibb.

Kris V. Kowdley is currently affiliated with Swedish Medical Center, Seattle, WA.

Article

DOI: 10.1002/hep.27726

PMC ID: 4409820

PubMed ID: 25614962

SO-VID: 8beef400-a047-4cee-86dc-2522dd192079

License:

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

History

Date received : 10 December 2014

Date accepted : 21 January 2015

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All-Oral 12-Week Treatment With Daclatasvir Plus Sofosbuvir in Patients With Hepatitis C Virus Genotype 3 Infection: ALLY-3 Phase III Study

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Most cited references 14

Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options.

Sofosbuvir and ribavirin in HCV genotypes 2 and 3.

Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C.

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