title: Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: Division of Hepatology and Liver Transplantation, Intermountain Medical Center, Salt Lake City, Utah. Electronic address: michael.charlton@imail.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Charlton
authors.affiliation: Division of Gastroenterology and Hepatology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Everson
authors.affiliation: Division of Gastroenterology and Hepatology, Northwestern Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Flamm
authors.affiliation: Division of Infectious Diseases, Georgetown University, Washington, District of Columbia.
authors.forename: Princy
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Division of Gastroenterology and Hepatology, University of Washington/Harborview Medical Center, Seattle, Washington.
authors.forename: Charles
authors.initials: C
authors.lastname: Landis
authors.affiliation: Division of Digestive and Liver Diseases, Columbia University Medical Center/New York Presbyterian, New York, New York.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Brown
authors.affiliation: Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill/University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Fried
authors.affiliation: Division of Gastroenterology and Hepatology, University of California, San Francisco, California.
authors.forename: Norah A
authors.initials: NA
authors.lastname: Terrault
authors.affiliation: Division of Gastroenterology and Hepatology, Baylor University Medical Center, Dallas, Texas.
authors.forename: Jacqueline G
authors.initials: JG
authors.lastname: O'Leary
authors.affiliation: Division of Hepatology, Mayo Clinic Arizona, Phoenix, Arizona.
authors.forename: Hugo E
authors.initials: HE
authors.lastname: Vargas
authors.affiliation: Division of Gastroenterology and Hepatology, University of California, San Diego, California.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kuo
authors.affiliation: Division of Gastroenterology and Hepatology, University of Miami, Miami, Florida.
authors.forename: Eugene
authors.initials: E
authors.lastname: Schiff
authors.affiliation: Division of Infectious Diseases, Johns Hopkins University, Lutherville, Maryland.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sulkowski
authors.affiliation: Division of Gastroenterology and Hepatology, University of Kansas Medical Center Research Institute, Kansas City, Kansas.
authors.forename: Richard
authors.initials: R
authors.lastname: Gilroy
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Kymberly D
authors.initials: KD
authors.lastname: Watt
authors.affiliation: Division of Gastroenterology and Hepatology, Henry Ford Health System, Detroit, Michigan.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Brown
authors.affiliation: Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Paul
authors.initials: P
authors.lastname: Kwo
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Surakit
authors.initials: S
authors.lastname: Pungpapong
authors.affiliation: Division of Gastroenterology, Washington University, Saint Louis, Missouri.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Korenblat
authors.affiliation: Division of Gastroenterology and Hepatology, Duke University, Durham, North Carolina.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Muir
authors.affiliation: Division of Transplant Surgery, New York University School of Medicine, New York, New York.
authors.forename: Lewis
authors.initials: L
authors.lastname: Teperman
authors.affiliation: Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fontana
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Jill
authors.initials: J
authors.lastname: Denning
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Sarah
authors.initials: S
authors.lastname: Arterburn
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Hadas
authors.initials: H
authors.lastname: Dvory-Sobol
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Theo
authors.initials: T
authors.lastname: Brandt-Sarif
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Pang
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Division of Gastroenterology and Hepatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: K Rajender
authors.initials: KR
authors.lastname: Reddy
authors.affiliation: Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Electronic address: nafdhal@bidmc.harvard.edu.
authors.forename: Nezam
authors.initials: N
authors.lastname: Afdhal
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D002780:Cholestasis, Intrahepatic / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D018450:Disease Progression; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D005449:Fluorenes / Q000009:adverse effects / Q000627:therapeutic use*; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008103:Liver Cirrhosis / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D000069474:Sofosbuvir; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D014542:Uridine Monophosphate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D004338:Drug Combinations; D005449:Fluorenes; C000595958:ledipasvir, sofosbuvir drug combination; D012254:Ribavirin; D014542:Uridine Monophosphate; D000069474:Sofosbuvir
keywords: Decompensated Cirrhosis; Fibrosing Cholestatic Hepatitis; Hepatitis C Virus Infection; Liver Transplantation