title: Mechanisms of Hyperbilirubinemia During Peginterferon Lambda-1a Therapy for Chronic Hepatitis C Infection: A Retrospective Investigation.
abstract: The phase 2b EMERGE study compared the efficacy/safety of peginterferon lambda-1a (Lambda) and peginterferon alfa-2a (Alfa), both with ribavirin (RBV), for treatment of chronic hepatitis C virus (HCV) infection. A key safety finding was a higher frequency of hyperbilirubinemia with Lambda/RBV versus Alfa/RBV. To characterize mechanisms of hyperbilirubinemia associated with Lambda/RBV, we conducted a retrospective analysis of safety data from the HCV genotype 1 and genotype 4 cohort of the EMERGE study. Subjects were randomized to once-weekly Lambda (120/180/240 μg) or Alfa (180 μg), with daily RBV, for 48 weeks. Early-onset Lambda/RBV-related hyperbilirubinemia events (6-12 weeks) resulted mostly from RBV-induced hemolysis evidenced by sustained reticulocytosis and a predominantly unconjugated pattern of hyperbilirubinemia. The higher hyperbilirubinemia frequency with Lambda/RBV versus Alfa/RBV was attributed to bone marrow suppression known to occur with Alfa but not Lambda. Late-onset (>12 weeks) Lambda/RBV-related hyperbilirubinemia events occurred most frequently with higher Lambda doses and were associated with increased levels of hepatic transaminase and direct bilirubin fractions compared with early events. This dual pattern of hyperbilirubinemia observed while on Lambda/RBV treatment is thought to be caused by exaggerated RBV-induced hemolysis in early-onset events compared with possible direct Lambda-induced hepatocellular toxicity in late-onset events.
authors.affiliation: 1 Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Zwirtes
authors.affiliation: 2 Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey.
authors.forename: Premkumar
authors.initials: P
authors.lastname: Narasimhan
authors.affiliation: 2 Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Wind-Rotolo
authors.affiliation: 1 Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut.
authors.forename: Dong
authors.initials: D
authors.lastname: Xu
authors.affiliation: 2 Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Hruska
authors.affiliation: 2 Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey.
authors.forename: Narendra
authors.initials: N
authors.lastname: Kishnani
authors.affiliation: 2 Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Colston
authors.affiliation: 1 Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut.
authors.forename: Subasree
authors.initials: S
authors.lastname: Srinivasan
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced* / Q000378:metabolism*; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use; D007378:Interleukins / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012189:Retrospective Studies; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007378:Interleukins; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; C000600496:peginterferon lambda-1a; D000095022:Interferon Lambda; C100416:peginterferon alfa-2a
keywords: anemia; hepatitis C; hyperbilirubinemia; interferon lambda-1a; ribavirin