title: Patient-reported outcomes with sofosbuvir and velpatasvir with or without ribavirin for hepatitis C virus-related decompensated cirrhosis: an exploratory analysis from the randomised, open-label ASTRAL-4 phase 3 trial.
abstract: Hepatitis C virus (HCV) treatment regimens with direct-acting antivirals have not been extensively studied in patients with decompensated cirrhosis. We assessed patient-reported outcomes (PROs) in patients with decompensated cirrhosis given a fixed-dose combination of sofosbuvir and velpatasvir with and without ribavirin.
  
  
  
  This study was an exploratory analysis of data collected in a randomised, open-label phase 3 trial (ASTRAL-4) in which patients with HCV-related decompensated cirrhosis were randomly assigned to an all-oral fixed-dose combination of sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks, sofosbuvir and velpatasvir plus oral ribavirin (weight-based 1000 mg or 1200 mg) for 12 weeks, or sofosbuvir and velpatasvir for 24 weeks. Eligible patients were aged 18 years or older with any HCV genotype and decompensated cirrhosis at screening. PROs were collected for the intention-to-treat population using four questionnaires, Short Form (36) Health Survey version 2 (SF-36v2), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), the Chronic Liver Disease Questionnaire-HCV Version (CLDQ-HCV), and the Work Productivity Activity Index:HCV (WPAI), which were given prospectively to patients before, during, and after treatment. The ASTRAL-4 study is registered with ClinicalTrials.gov, number NCT02201901.
  
  
  
  Patients were enrolled at 47 hepatology outpatient practices in the USA from Aug 19, 2014, to Dec 19, 2014. 267 patients with HCV-related decompensated cirrhosis were included. In patients given sofosbuvir and velpatasvir for 12 weeks (n=90), clinically significant improvements in PROs started 4 weeks after treatment initiation (+4·4 to +7·5 points on a 0-100 scale at treatment week 4). By the end of treatment, mean improvements in PROs of +5·3 to +16·0 points were noted in all PROs except for role emotional, mental component summary, and social wellbeing scores and work productivity metrics by WPAI:HCV. Similar end-of-treatment improvements (+3·8 to +17·0 points) were observed in patients given sofosbuvir and velpatasvir for 24 weeks (n=90). In patients given sofosbuvir and velpatasvir plus ribavirin (n=87), PRO scores decreased within 4 weeks of treatment (-3·6 to -6·9 points), although scores returned to the baseline levels by the end of treatment. After treatment cessation, significant improvements in all PROs were similar between the treatment groups (all p>0·01) and, by post-treatment week 24, improvements were between +4·9 and +21·2 points. In multivariate analysis, predictors of PRO impairment were treatment naivety, anxiety, use of anxiolytics, use of antidepressants, use of opioids, ribavirin use, the presence of ascites, encephalopathy, insomnia, and depression.
  
  
  
  A clinically significant early (within 4 weeks) and sustained improvement in PROs was observed in patients with HCV-related decompensated cirrhosis who were given sofosbuvir and velpatasvir without ribavirin. A similar regimen with ribavirin resulted in a temporary decrease in PROs, which completely resolved after 8 weeks of treatment. Accompanied by high efficacy, the favourable effect of treatment on PROs improves patients' experience in this difficult-to-treat population with HCV.
  
  
  
  Gilead Sciences.
authors.affiliation: Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA; Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA. Electronic address: zobair.younossi@inova.org.
authors.forename: Zobair M
authors.initials: ZM
authors.lastname: Younossi
authors.affiliation: Center for Outcomes Research in Liver Disease, Washington, DC, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Stepanova
authors.affiliation: Department of Gastroenterology, Intermountain Medical Center, Salt Lake City, UT, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Charlton
authors.affiliation: Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Curry
authors.affiliation: Liver Consultants of Texas, Baylor University Medical Center, Dallas, TX, USA.
authors.forename: Jacqueline G
authors.initials: JG
authors.lastname: O'Leary
authors.affiliation: Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Brown
authors.affiliation: Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Hunt
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002219:Carbamates / Q000008:administration & dosage* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D057194:Intention to Treat Analysis; D008103:Liver Cirrhosis / Q000821:virology*; D008297:Male; D008875:Middle Aged; D000071066:Patient Reported Outcome Measures; D011446:Prospective Studies; D012254:Ribavirin / Q000008:administration & dosage* / Q000627:therapeutic use; D000069474:Sofosbuvir / Q000008:administration & dosage* / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult; D001562:Benzimidazoles; D001578:Benzopyrans
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D006576:Heterocyclic Compounds, 4 or More Rings; D012254:Ribavirin; D000069474:Sofosbuvir; C000604171:velpatasvir; D001562:Benzimidazoles; D001578:Benzopyrans