Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort

PLoS One. 2016 Mar 28;11(3):e0151703. doi: 10.1371/journal.pone.0151703. eCollection 2016.

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.

Trial registration: ClinicalTrials.gov NCT01344889.

Publication types

  • Clinical Trial
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anemia / chemically induced
  • Antiviral Agents / adverse effects
  • Antiviral Agents / therapeutic use
  • Asthenia / chemically induced
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Female
  • Hepacivirus / drug effects*
  • Hepacivirus / genetics
  • Hepacivirus / physiology
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / virology
  • Host-Pathogen Interactions / drug effects
  • Humans
  • Interferon-alpha / adverse effects
  • Interferon-alpha / therapeutic use*
  • Male
  • Middle Aged
  • Neutropenia / chemically induced
  • Outcome Assessment, Health Care / methods
  • Outcome Assessment, Health Care / statistics & numerical data
  • Polyethylene Glycols / adverse effects
  • Polyethylene Glycols / therapeutic use*
  • Proportional Hazards Models
  • RNA, Viral / blood
  • RNA, Viral / genetics
  • Recombinant Proteins / adverse effects
  • Recombinant Proteins / therapeutic use
  • Ribavirin / adverse effects
  • Ribavirin / therapeutic use*
  • Withholding Treatment

Substances

  • Antiviral Agents
  • Interferon-alpha
  • RNA, Viral
  • Recombinant Proteins
  • Polyethylene Glycols
  • Ribavirin
  • peginterferon alfa-2a

Associated data

  • ClinicalTrials.gov/NCT01344889

Grants and funding

This study was funded by F. Hoffmann-La Roche Ltd. F Hoffmann-La Roche provided support in the form of salaries for authors [GB], participated in the design and conduct of the study, in the analysis and interpretation of the data and in the preparation and review of the manuscript before submission. PROMETRIS GmbH is the clinical research organization contracted by F. Hoffmann-La Roche Ltd to provide data management and statistical services. PROMETRIS GmbH provided support in the form of salaries for authors [SA], participated in the design and conduct of the study, in the analysis and interpretation of the data, and in the preparation and review of the manuscript before submission. Third-party medical writing assistance, provided by Blair Jarvis MSc, ELS, of Health Interactions, but not editorial content development sufficient to meet International Committee of Medical Journal Editors (ICMJE) authorship criteria, was funded by F. Hoffmann-La Roche Ltd. The specific roles of these authors are articulated in the ‘author contributions’ section.