Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease.

Abstract

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.

• Authors: Michael Charlton, Gregory T Everson, Steven L Flamm, Princy Kumar, Charles Landis, Robert S Brown Jr, Michael W Fried, Norah A Terrault, Jacqueline G O'Leary, Hugo E Vargas, Alexander Kuo, Eugene Schiff, Mark S Sulkowski, Richard Gilroy, Kymberly D Watt, Kimberly Brown, Paul Kwo, Surakit Pungpapong, Kevin M Korenblat, Andrew J Muir, Lewis Teperman, Robert J Fontana, Jill Denning, Sarah Arterburn, Hadas Dvory-Sobol, Theo Brandt-Sarif, Phillip S Pang, John G McHutchison, K Rajender Reddy, Nezam Afdhal, SOLAR-1 Investigators
• Journal: Gastroenterology (Gastroenterology) Vol. 149 Issue 3 Pg. 649-59 (Sep 2015) ISSN: 1528-0012 [Electronic] United States
• PMID: 25985734 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antiviral Agents
• Benzimidazoles
• Drug Combinations
• Fluorenes
• ledipasvir, sofosbuvir drug combination
• Ribavirin
• Uridine Monophosphate
• Sofosbuvir

Topics

• Antiviral Agents (adverse effects, therapeutic use)
• Benzimidazoles (adverse effects, therapeutic use)
• Cholestasis, Intrahepatic (diagnosis, drug therapy, mortality, virology)
• Disease Progression
• Drug Combinations
• Drug Therapy, Combination
• Female
• Fluorenes (adverse effects, therapeutic use)
• Genotype
• Hepacivirus (drug effects, enzymology, genetics)
• Hepatitis C, Chronic (complications, diagnosis, drug therapy, mortality)
• Humans
• Liver Cirrhosis (diagnosis, drug therapy, mortality, virology)
• Liver Transplantation
• Male
• Middle Aged
• Ribavirin (adverse effects, therapeutic use)
• Sofosbuvir
• Time Factors
• Treatment Outcome
• United States
• Uridine Monophosphate (adverse effects, analogs & derivatives, therapeutic use)