Gastroenterology

Gastroenterology

Volume 149, Issue 3, September 2015, Pages 649-659
Gastroenterology

Original Research
Full Report: Clinical—Liver
Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease

https://doi.org/10.1053/j.gastro.2015.05.010Get rights and content
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open access

Background & Aims

There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease.

Methods

In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12).

Results

We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%–89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%–98% of patients without cirrhosis or with compensated cirrhosis, by 85%−88% of patients with moderate hepatic impairment, by 60%–75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation.

Conclusion

The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.

Keywords

Hepatitis C Virus Infection
Decompensated Cirrhosis
Liver Transplantation
Fibrosing Cholestatic Hepatitis

Abbreviations used in this paper

CPT
Child–Pugh–Turcotte
FCH
fibrosing cholestatic hepatitis
HCV
hepatitis C virus
MELD
model for end-stage liver disease
RAV
resistance-associated variant
SVR12
sustained virologic response at 12 weeks after the end of treatment

Cited by (0)

Conflicts of interest These authors disclose the following: Michael Charlton has received research support and grants from Gilead; Gregory Everson has received research support and grants from AbbVie, BMS, Eisai, Gilead, Janssen, Merck, and Roche/Genentech, and has served on advisory boards for AbbVie, BMS, Gilead, Janssen, and Merck; Princy Kumar has served as a consultant for Janssen and ViiV Healthcare, and is a stock shareholder of GSK, Gilead, J&J, Merck, and Pfizer; Charles Landis has received research support and grants from AbbVie, BMS, and Gilead; Robert Brown Jr has received research support and grants from Gilead, and has served as a consultant for Gilead; Norah Terrault has received research support and grants from Gilead; Jacqueline O'Leary has served as a consultant for AbbVie, Janssen, and Gilead, and was on the speakers bureau for AbbVie and Gilead; Hugo Vargas has received research support and grants from AbbVie, BMS, Eisai, Gilead, and Merck; Alexander Kuo has received research support and grants from Gilead, and has served as a consultant for AbbVie; Eugene Schiff has received research support and grants from Abbot, BMS, Beckman Coulter, Conatus, Discovery Life Sciences, Gilead, MedMira, Merck, Orasure Technologies, Roche Molecular, Janssen, and Siemens, has received personal fees from Acorda, Arrowhead, BMS, Gilead, Merck, Janssen, Pfizer, and Salix, and has received nonfinancial support from Merck and Salix; Mark Sulkowski has received research support and grants from AbbVie, BMS, Gilead, Janssen, and Merck, has served as a consultant for AbbVie, BMS, Gilead, Janssen, and Merck, has served on an advisory board for Gilead, and has been involved with the National Institutes of Health; Richard Gilroy has received research support and grants from Gilead, and has received personal fees from AbbVie, Gilead, NPS, and Salix; Kymberly Watt has served as a sponsor for Gilead; Kimberly Brown has received research support and grants from AbbVie, BMS, Centers for Disease Control Foundation, Gilead, Hyperion, Janssen, and Vertex, has served as a consultant for AbbVie, BMS, Gilead, Janssen, and Merck, has served on the speakers bureau for AbbVie, CLDF, Gilead, HCV Viewpoints, and Simply Speaking, has served on advisory boards for AJT Images, AST Past, CLDF, and CLD Journal, and was involved with Medscape; Paul Kwo has received research support and grants from AbbVie, BMS, Conatus, Gilead, Janssen, Merck, Roche, and Vertex, has served as a consultant for Gilead, has served on advisory boards for AbbVie, BMS, Gilead, Janssen, Merck, Novartis, and Vertex, and was on the speakers’ bureau for Merck and Vertex; Surakit Pungpapong has received research support and grants from BMS and Gilead; Andrew Muir has received research support and grants from Gilead, and has served on advisory boards for Gilead; Robert Fontana has received research support and grants from BMS, Gilead, Janssen, and Vertex; K. Rajender Reddy has received research support and grants from AbbVie, BMS, Genentech-Roche, Gilead, Janssen, Merck, and Vertex, has served as a consultant for AbbVie, BMS, Genentech-Roche, Gilead, Idenix, Janssen, Merck, and Vertex, has served on advisory boards for CLDF and Novartis, and has received payment for the development of educational presentations from ViralEd; Nezam Afdhal has received research support and grants from AbbVie, BMS, and Gilead, has served on advisory boards for Gilead, has served as a consultant for Gilead, and has received personal fees from AbbVie, Achillion, BMS, Merck, Janssen, and SprinBank; and Jill Denning, Sarah Arterburn, Theo Brandt-Sarif, Phillip Pang, and John McHutchison are employees of Gilead. The remaining authors disclose no conflicts.

Funding Supported by Gilead Sciences. Gilead Sciences collected the data, monitored the study conduct, and performed the statistical analyses.

§

Authors share co-senior authorship.