Efficacy of Sofosbuvir Plus Ribavirin With or Without Peginterferon-Alfa in Patients With Hepatitis C Virus Genotype 3 Infection and Treatment-Experienced Patients With Cirrhosis and Hepatitis C Virus Genotype 2 Infection

doi:10.1053/j.gastro.2015.07.043

Gastroenterology

Volume 149, Issue 6, November 2015, Pages 1462-1470

https://doi.org/10.1053/j.gastro.2015.07.043 Get rights and content

Background & Aims

We conducted an open-label, randomized, phase 3 trial to determine the efficacy and safety of sofosbuvir and ribavirin, with and without peginterferon-alfa, in treatment-experienced patients with cirrhosis and hepatitis C virus (HCV) genotype 2 infection and treatment-naïve or treatment-experienced patients with HCV genotype 3 infection.

Methods

The study was conducted at 80 sites in Europe, North America, Australia, and New Zealand Patients were randomly assigned (1:1:1) to groups given sofosbuvir and ribavirin for 16 weeks (n = 196); sofosbuvir and ribavirin for 24 weeks (n = 199); or sofosbuvir, peginterferon-alfa, and ribavirin for 12 weeks (n = 197). The primary end point was the percentage of patients with HCV RNA <15 IU/mL 12 weeks after stopping therapy (sustained virologic response [SVR12]). From October 2013 until April 2014, we enrolled and treated 592 patients—48 with genotype 2 HCV and compensated cirrhosis who had not achieved SVR with previous treatments and 544 with genotype 3 HCV (279 treatment-naïve and 265 previously treated). Overall, 219 patients (37%) had compensated cirrhosis. The last post-treatment week 12 patient visit was in January 2015.

Results

Rates of SVR12 among patients with genotype 2 HCV were 87% and 100%, for those receiving 16 and 24 weeks of sofosbuvir and ribavirin, respectively, and 94% for those receiving sofosbuvir, peginterferon, and ribavirin for 12 weeks. Rates of SVR12 among patients with genotype 3 HCV were 71% and 84% in those receiving 16 and 24 weeks of sofosbuvir and ribavirin, respectively, and 93% in those receiving sofosbuvir, peginterferon, and ribavirin. On-treatment virologic failure occurred in 3 patients with HCV genotype 3a receiving sofosbuvir and ribavirin for 24 weeks. The most common adverse events were fatigue, headache, insomnia, and nausea. Overall, 1% of patients discontinued treatment due to adverse events.

Conclusions

Among patients with genotype 3 HCV infection, including a large proportion of treatment-experienced patients with cirrhosis, the combination of sofosbuvir, peginterferon, and ribavirin for 12 weeks produces high rates of SVR. Treatment-experienced patients with cirrhosis and genotype 2 HCV infection had high rates of SVR in all groups. EudraCT ID 2013-002641-11.

Section snippets

Study Design and Patients

We conducted this randomized, phase 3, open-label trial at 80 sites in the United Kingdom, Australia, the United States, Canada, and New Zealand. Patients were enrolled between October 18, 2013 and April 1, 2014; the last post-treatment week-12 visit was on January 7, 2015. Eligible patients were at least 18 years old and were chronically infected with HCV, with plasma HCV RNA ≥10⁴ IU/mL. There were no upper limits on age or body mass index. Patients were required to have a platelet count of

Baseline Characteristics

We screened 776 patients, of which 601 were randomized, and 592 received at least one dose of study treatment (Supplementary Material). The baseline demographic and disease characteristics of the patients in the 3 treatment groups are shown in Table 1. A majority of patients were white (84%) and 67% were male. Forty-eight (8%) patients had genotype 2 HCV and 544 (92%) had genotype 3 HCV (of the 522 patients with genotype 3 HCV who could be subtyped, 512 [98%] had genotype 3a HCV). Overall, 37%

Discussion

The results of this phase 3 trial have shown that patients with genotype 3 HCV achieve superior rates of SVR12 with 12 weeks of sofosbuvir plus peginterferon and ribavirin than they do with 16 or 24 weeks of sofosbuvir and ribavirin. Numerically superior SVR 12 rates were observed across all major subgroups of genotype 3 patients who received triple therapy as compared with those receiving IFN-free treatment. Additionally, genotype 2 treatment-experienced HCV-infected patients with cirrhosis

Acknowledgments

The authors thank the patients and their families as well as the study-site personnel. Jennifer King of August Editorial and David McNeel of Gilead Sciences helped draft the manuscript. Funding for this study was provided by Gilead Sciences, Inc. The authors thank Xiaoru Wu of Gilead Sciences for her work on the statistical analysis of the study. The STOP-HCV consortium is funded by a grant from the Medical Research Council, UK.

Author contributions: Graham R. Foster, Diana M. Brainard, G. Mani

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: Conflicts of interest The authors disclose the following: Graham R. Foster: Grants Consulting and Speaker/Advisory Board: AbbVie, Alcura, Bristol-Myers Squibb, Gilead, Janssen, GlaxoSmithKline, Merck, Roche, Springbank, Idenix, Tekmira, Novartis. Stephen Pianko: Advisory board: Roche, Novartis, Gilead, Roche, Novartis; Consulting: Gilead; Speaker: Janssen. Ashley Brown: grants: Gilead; Advisory Board: Gilead; Speaker: Gilead. Daniel Forton: grants: Gilead; Speaker/Advisory Board: Gilead, AbbVie, Bristol-Myers Squibb, Merck and Roche. Ronald G. Nahass: Grants: Gilead; Advisory Board: Gilead; Speaker: Gilead. Jacob George: Advisory Boards: Gilead, Merck, Abbvie, Roche, Janssen, Bristol-Myers Squibb. Eleanor Barnes: no relevant conflicts of interest; Curtis Cooper: Consultant/Advisory Board member: Merck, Roche, Gilead, BMS, Abbvie. Kosh Agarwal: Grants: Bristol-Myers Squibb, Gilead; Consultancy/ Speaker: Achillon, AbbVie, Astellas, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, Novartis. All remaining authors are current employees of Gilead Sciences.

: Funding The sponsor, Gilead Sciences, designed and undertook the study, and collected and analyzed the data in collaboration with external investigators. The sponsor and Graham R. Foster interpreted data. Writing assistance, paid for by Gilead Sciences, was provided by Jennifer King of August Editorial, and David McNeel, an employee of Gilead Sciences.

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Original ResearchFull Report: Clinical—LiverEfficacy of Sofosbuvir Plus Ribavirin With or Without Peginterferon-Alfa in Patients With Hepatitis C Virus Genotype 3 Infection and Treatment-Experienced Patients With Cirrhosis and Hepatitis C Virus Genotype 2 Infection

Background & Aims

Methods

Results

Conclusions

Section snippets

Study Design and Patients

Baseline Characteristics

Discussion

Acknowledgments

Global distribution and prevalence of hepatitis C virus genotypes

Hepatology

HCV genotype 3 is associated with an increased risk of cirrhosis and hepatocellular cancer in a national sample of US Veterans with HCV

Hepatology

Is genotype 3 of the hepatitis C virus the new villain?

Hepatology

Sofosbuvir for previously untreated chronic hepatitis C infection

N Engl J Med

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

N Engl J Med

Original Research
Full Report: Clinical—Liver
Efficacy of Sofosbuvir Plus Ribavirin With or Without Peginterferon-Alfa in Patients With Hepatitis C Virus Genotype 3 Infection and Treatment-Experienced Patients With Cirrhosis and Hepatitis C Virus Genotype 2 Infection