title: Treatment Selection Choices Should Not Be Based on Benefits or Costs Alone: A Head-to-Head Randomized Controlled Trial of Antiviral Drugs for Hepatitis C.
abstract: BACKGROUND
  Clinicians often face dilemmas with decisions related to formulary choices when two similar drugs are simultaneously available in the market. We studied the comparative safety, effectiveness, and treatment costs of the two first generation direct-acting antiviral agents (DAA), boceprevir and telaprevir as uncertainty existed regarding the drug of choice between these two seemingly equally Hepatitis-C treatment options.
  
  
  METHODS
  We randomly assigned 50 patients in an open-label, pragmatic randomized controlled trial (RCT) at a VA Medical Center to either boceprevir or telaprevir in combination with peginterferon and ribavirin, stratified by the presence of cirrhosis and prior treatment experience. Tolerability was assessed at each visit and reasons for discontinuation of treatment and severity of adverse events due to PI treatment were adjudicated using a blinded adjudication committee. The primary outcome was difference in tolerability between boceprevir vs. telaprevir. Secondary outcomes included viral response rates and cost-per cure achieved.
  
  
  RESULTS
  Higher rates of treatment discontinuations and/or severe DAA associated adverse events were seen in 10/25 (40%) patients randomized to telaprevir compared to 2/25 (8%) patients randomized to boceprevir (RR: 5; 95% CI: 1.2, 20; p<0.01). Cure rates did not appear to be significantly different between groups (telaprevir vs. boceprevir: RR 1.23; 95% CI: 0.76, 1.99; p = 0.39). On an intention-to-treat basis, total cost per cure was $44,329 for boceprevir vs. $57,115 for telaprevir. The significant side effect profile of telaprevir combined with the availability of highly efficacious second generation DAAs led to the early discontinuation of the trial.
  
  
  CONCLUSIONS
  Telaprevir is associated with a significantly higher rate of severe adverse events leading to treatment discontinuations, hospitalizations or severe anemia and a substantially higher cost per SVR when compared to boceprevir. Real-time, point of care, pragmatic randomized controlled trials are necessary for guidance beyond just acquisition costs and to make evidence-based formulary selections when multiple effective treatments are available. (Clinicaltrials.gov registration: NCT02113631).
authors.affiliation: Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America.|University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.|Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Perica
authors.initials: P
authors.lastname: Davitkov
authors.affiliation: Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America.|University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.|Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Apoorva Krishna
authors.initials: AK
authors.lastname: Chandar
authors.affiliation: Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America.|Geriatric Research Education and Clinical Center (GRECC), Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Hirsch
authors.affiliation: Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Anita
authors.initials: A
authors.lastname: Compan
authors.affiliation: Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America.|University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.|Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Marina G
authors.initials: MG
authors.lastname: Silveira
authors.affiliation: Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America.|University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.|Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Anthony
authors.affiliation: Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Smith
authors.affiliation: Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Clare
authors.initials: C
authors.lastname: Gideon
authors.affiliation: Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America.|University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.|Case Western Reserve University, Cleveland, Ohio, United States of America.|Geriatric Research Education and Clinical Center (GRECC), Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bonomo
authors.affiliation: Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America.|University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.|Case Western Reserve University, Cleveland, Ohio, United States of America.|Geriatric Research Education and Clinical Center (GRECC), Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Yngve
authors.initials: Y
authors.lastname: Falck-Ytter
mesh_terms: D000740:Anemia / Q000209:etiology / Q000473:pathology; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003362:Cost-Benefit Analysis; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D005260:Female; D006526:Hepatitis C / Q000188:drug therapy* / Q000191:economics*; D006760:Hospitalization; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D019964:Mood Disorders / Q000209:etiology; D009842:Oligopeptides / Q000009:adverse effects / Q000627:therapeutic use; D011392:Proline / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D012254:Ribavirin; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline