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      Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY‐3+)

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          Abstract

          Patients with hepatitis C virus (HCV) genotype 3 infection, especially those with advanced liver disease, are a challenging population in urgent need of optimally effective therapies. The combination of daclatasvir (DCV; pangenotypic nonstructural protein 5A inhibitor) and sofosbuvir (SOF; nucleotide nonstructural protein 5B inhibitor) for 12 weeks previously showed high efficacy (96%) in noncirrhotic genotype 3 infection. The phase III ALLY‐3+ study (N = 50) evaluated DCV‐SOF with ribavirin (RBV) in treatment‐naïve (n = 13) or treatment‐experienced (n = 37) genotype 3‐infected patients with advanced fibrosis (n = 14) or compensated cirrhosis (n = 36). Patients were randomized 1:1 to receive open‐label DCV‐SOF (60 + 400 mg daily) with weight‐based RBV for 12 or 16 weeks. The primary endpoint was sustained virological response at post‐treatment week 12 (SVR12). SVR12 (intention‐to‐treat) was 90% overall (45 of 50): 88% (21 of 24) in the 12‐week (91% observed) and 92% (24 of 26) in the 16‐week group. All patients with advanced fibrosis achieved SVR12. SVR12 in patients with cirrhosis was 86% overall (31 of 36): 83% (15 of 18) in the 12‐week (88% observed) and 89% (16 of 18) in the 16‐week group; for treatment‐experienced patients with cirrhosis, these values were 87% (26 of 30), 88% (14 of 16; 93% observed), and 86% (12 of 14), respectively. One patient (12‐week group) did not enter post‐treatment follow‐up (death unrelated to treatment). There were 4 relapses (2 per group) and no virological breakthroughs. The most common adverse events (AEs) were insomnia, fatigue, and headache. There were no discontinuations for AEs and no treatment‐related serious AEs. Conclusion: The all‐oral regimen of DCV‐SOF‐RBV was well tolerated and resulted in high and similar SVR12 after 12 or 16 weeks of treatment among genotype 3‐infected patients with advanced liver disease, irrespective of past HCV treatment experience. (H epatology 2016;63:1430‐1441)

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          EASL Recommendations on Treatment of Hepatitis C 2015.

          (2015)
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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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                Author and article information

                Journal
                Journal ID (nlm-ta): Hepatology
                Journal ID (iso-abbrev): Hepatology
                Journal ID (doi): 10.1002/(ISSN)1527-3350
                Journal ID (publisher-id): HEP
                Title: Hepatology (Baltimore, Md.)
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0270-9139
                ISSN (Electronic): 1527-3350
                Publication date (Electronic): 04 March 2016
                Publication date (Print): May 2016
                Volume: 63
                Issue: 5 ( doiID: 10.1002/hep.v63.5 )
                Pages: 1430-1441
                Affiliations
                [ 1 ] Clinique Universitaire d'Hepato‐Gastroentérologie, Pôle DigiduneCHU de Grenoble and Unité INSERM/Université Grenoble Alpes U823, IAPC Institut Albert Bonniot GrenobleFrance
                [ 2 ]Austin Hospital HeidelbergAustralia
                [ 3 ] INSERM U954, CHU de NancyUniversité de Lorraine NancyFrance
                [ 4 ] St. Vincent's Hospital and Kirby InstituteUNSW Australia SydneyAustralia
                [ 5 ]CHU Henri Mondor CréteilFrance
                [ 6 ]Monash Medical Centre ClaytonAustralia
                [ 7 ]Hôpital Cochin ParisFrance
                [ 8 ]Gallipoli Medical Research Foundation GreenslopesAustralia
                [ 9 ]South Australia Health AdelaideAustralia
                [ 10 ]Bristol‐Myers Squibb Research & Development Wallingford CT
                [ 11 ]Bristol‐Myers Squibb Research & Development Princeton NJ
                [ 12 ]St Vincent's Hospital and the University of Melbourne MelbourneAustralia
                Author notes
                [*] [* ]ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:

                Alexander J. Thompson, M.D., Ph.D.

                St Vincent's Hospital and the University of Melbourne

                SVHM Level 4 Daly Wing

                35 Victoria Pde

                P.O. Box 2900

                Fitzroy, Victoria 3065, Australia

                E‐mail: alexander.thompson@ 123456svhm.org.au

                Article
                Publisher ID: HEP28473
                DOI: 10.1002/hep.28473
                PMC ID: 5069621
                PubMed ID: 26822022
                SO-VID: e58c15ef-c53c-46fd-8630-12e10fdfc0e2
                Copyright © © 2016 The Authors. HEPATOLOGY published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.
                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 : 22 December 2015
                Date revision received : 20 January 2016
                Date accepted : 24 January 2016
                Page count
                Pages: 12
                Funding
                Funded by: Bristol‐Myers Squibb
                Categories
                Subject: Rapid Communication
                Subject: Rapid Communication
                Custom metadata
                source-schema-version-number 2.0
                component-id hep28473
                cover-date May 2016
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.5 mode:remove_FC converted:19.10.2016

                ScienceOpen disciplines: Gastroenterology & Hepatology
                Data availability:
                ScienceOpen disciplines: Gastroenterology & Hepatology

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