CD4 T-cell Responses to HCV during and after Interferon-based Therapy for Chronic Hepatitis C

By Liz Highleyman

A majority of people initially infected with hepatitis C virus (HCV) are unable to control the virus, and go on to develop chronic infection. The rate of natural or spontaneous HCV clearance is even lower among HIV positive individuals.

Yet much remains to be learned about the factors associated with immune responses to HCV -- including the role of HCV-specific CD4 T-cells and regulatory T-cells -- both before and during antiviral therapy.

As reported in the September 2008 Journal of Hepatology, James Burton and colleagues assessed immune responses in chronic hepatitis C patients (HIV negative) treated with interferon-based therapy in the Virahep-C study.

Virahep-C, sponsored by the U.S. National Institutes of Health, looked at differences in hepatitis C treatment response, in particular the influence of race/ethnicity. Unlike most previous studies, it enrolled roughly equal numbers of African-American and Caucasian participants (about 200 each). People of African descent respond less well to interferon-based therapy, but the reasons are unclear.

Participants were treatment-naive and had HCV genotype 1. They were treated with 180 mcg/week pegylated interferon alpha-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted ribavirin, initially for 24 weeks. Those who did not achieve undetectable HCV RNA at this point stopped therapy, while early responders continued treatment for a total of 48 weeks.

To assess immune activity, interferon-gamma ELISPOT assays (n=58) and flow cytometric analysis of FoxP3-expressing T-regulatory cells (n=62) were performed at baseline, during, and after cessation of antiviral therapy.

Results

• Total HCV-specific interferon-gamma CD4 T-cell ELISPOT responses did not increase during interferon-based therapy.

• Rather, they decreased by week 8, and remained below baseline 24 weeks after cessation of therapy.

• There were no statistically significant differences with respect to HCV viral kinetics, race, and virological response.

• Viral relapse after treatment was associated with a 3-fold increase in HCV-specific T-cell responses.

• The frequency and phenotype of regulatory T-cells during therapy were not significantly different with respect to race, viral kinetics, or virological response.

"A contraction of HCV-specific CD4+ T-cell responses was found during treatment, with recovery of responses in patients experiencing virologic relapse after treatment," the study authors concluded.

"The levels of FoxP3-expressing regulatory T-cells did not vary by race and were not predictive of virologic outcome," they continued. "Work is ongoing to explore the contribution of mechanisms independent of CD4+ T-cells in therapy-induced viral clearance."

12/5/08

Reference
JR Burton, J Klarquist, K Im, and others. Prospective analysis of effector and regulatory CD4(+) T cells in chronic HCV patients undergoing combination antiviral therapy. Journal of Hepatology 49(3): 329-338. September 2008. (Abstract).