Hepatitis C Virus–Specific Immune Responses and Quasi‐Species Variability at Baseline Are Associated with Nonresponse to Antiviral Therapy during Advanced Hepatitis C
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 
3) and prior nonresponse to interferon (IFN)–α 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 (
) and higher baseline HCV QS diversity (
) 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 (
) and with 1 or more positive assays (LP, NA, or CTL) (
). 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‐α2a and ribavirin combination therapy.
Received 18 August 2005; accepted 1 November 2005; electronically published 22 February 2006.
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Presented in part: Annual Meeting of the American Association for the Study of Liver Diseases, Boston, Massachusetts, 28 October 2003 (abstract published in Hepatology 2003
[38]:A263). -
Potential conflicts of interest: Authors who have financial relationships with Roche Laboratories/Hoffmann–La Roche are as follows: A.M.D.B. is a consultant and speaker’s bureau member and receives research support; P.F.M. receives research support; H.L.B. is a consultant and speaker’s bureau member and receives research support; and K.L.L. is a consultant and receives research support. Authors who do not have financial relationships to disclose are C.M., R.R., S.J.P., D.G.S., M.C.D., D.R.G., A.L.R., and M.J.K.
Financial support: National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Allergy and Infectious Diseases (contract numbers N01 DK92318, DK92319, DK92321, DK92324, DK92325, DK92326, and DK92328); National Cancer Institute and the National Center for Minority Health and Health Disparities (supplemental funding); National Center for Research Resources, National Institutes of Health (General Clinical Research Center grants M01 RR00043, RR00633, and RR06192); Roche Laboratories.
This is publication number 11 from the Hepatitis C Antiviral Long‐Term Treatment against Cirrhosis Trial Group.
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Author affiliations and a partial list of study group members appear after the text.