title: Hepatitis C virus-specific immune responses and quasi-species variability at baseline are associated with nonresponse to antiviral therapy during advanced hepatitis C.
abstract: Pretreatment hepatitis C virus (HCV)-specific lymphoproliferative (LP) responses, neutralizing antibody (NA) responses, intrahepatic cytotoxic T lymphocyte (CTL) responses, and HCV quasi-species (QS) diversity and complexity were examined in patients with advanced hepatic fibrosis (Ishak fibrosis score of > or = 3) and prior nonresponse to interferon (IFN)- alpha therapy who were enrolled in the initial phase of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial. Positive baseline HCV E1- and/or E2-specific NA responses (P = .01) and higher baseline HCV QS diversity (P = .01) were more commonly found in patients who did not become sustained virologic responders (SVRs) at week 72 (W72) than they were in those who did. No patients with positive results for both the LP and NA assays achieved a sustained virologic response. Multiple logistic regression analysis revealed that, when the presence of cirrhosis, prior ribavirin therapy, genotype 1 infection, log serum HCV RNA level, and receipt of >80% of the prescribed medication were controlled for, a sustained virologic response (W72) was negatively correlated with positive baseline LP assay results (P = .02) and with 1 or more positive assays (LP, NA, or CTL) (P = .02). No differences were noted in baseline intrahepatic CTL activity between SVRs and non-SVRs. Thus, in patients with advanced hepatic fibrosis due to HCV infection, pretreatment HCV-specific immune responses and increased QS variability appear to hinder viral clearance by pegylated IFN- alpha 2a and ribavirin combination therapy.
authors.affiliation: Department of Laboratory Medicine and Pediatrics, University of Washington, Seattle, USA. chihiro@u.washington.edu
authors.forename: Chihiro
authors.initials: C
authors.lastname: Morishima
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Polyak
authors.forename: Ranjit
authors.initials: R
authors.lastname: Ray
authors.forename: Michael C
authors.initials: MC
authors.lastname: Doherty
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Di Bisceglie
authors.forename: Peter F
authors.initials: PF
authors.lastname: Malet
authors.forename: Herbert L
authors.initials: HL
authors.lastname: Bonkovsky
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Sullivan
authors.forename: David R
authors.initials: DR
authors.lastname: Gretch
authors.forename: Alan L
authors.initials: AL
authors.lastname: Rothman
authors.forename: Margaret James
authors.initials: MJ
authors.lastname: Koziel
authors.forename: Karen L
authors.initials: KL
authors.lastname: Lindsay
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000097:blood; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D014644:Genetic Variation; D016174:Hepacivirus / Q000145:classification / Q000235:genetics* / Q000276:immunology; D006526:Hepatitis C / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000473:pathology; D008875:Middle Aged; D009500:Neutralization Tests; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a