title: Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort.
abstract: BACKGROUND
  Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice.
  
  
  METHODS
  A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively.
  
  
  RESULTS
  SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5.
  
  
  CONCLUSIONS
  In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin.
authors.affiliation: Institute of Cellular and Molecular Sciences, Queen Mary University of London, London, United Kingdom.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Foster
authors.affiliation: Unità Operativa Epatologia ed Ecografia Interventistica Ospedale Gragnano, Naples, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Coppola
authors.affiliation: Hamad Medical Hospital, Doha, Qatar.
authors.forename: Moutaz
authors.initials: M
authors.lastname: Derbala
authors.affiliation: Medical University of Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Ferenci
authors.affiliation: Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Orlandini
authors.affiliation: University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: K Rajender
authors.initials: KR
authors.lastname: Reddy
authors.affiliation: Divisione di Medicina, Ospedale Elena D'Aosta, Naples, Italy.
authors.forename: Ludovico
authors.initials: L
authors.lastname: Tallarico
authors.affiliation: Liver Institute of Virginia, Bon Secours Health System, Newport News/Richmond, Virginia, United States of America.
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Shiffman
authors.affiliation: PROMETRIS GmbH, Mannheim, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Ahlers
authors.affiliation: F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Georgios
authors.initials: G
authors.lastname: Bakalos
authors.affiliation: University of California San Diego, San Diego, California, United States of America.
authors.forename: Tarek
authors.initials: T
authors.lastname: Hassanein
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use; D001247:Asthenia / Q000139:chemically induced; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D028761:Withholding Treatment
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a