Hepatitis B Virus e Antigen Loss during Adefovir Dipivoxil Therapy Is Associated with Enhanced Virus-Specific CD4 + T-Cell Reactivity

Abstract

ABSTRACT Weak T-cell reactivity to hepatitis B virus (HBV) is thought to be the dominant cause for chronic HBV infection. Treatment with adefovir dipivoxil (ADV) increases the rate of HBV e antigen (HBeAg) loss; however, the immune mechanisms associated with this treatment response are not understood. Serial analysis of HBV-specific CD4 + T-cell reactivity was performed during 48 weeks of therapy with ADV and correlated with treatment outcome for 19 HBeAg-positive patients receiving ADV ( n = 13) or the placebo ( n = 6). We tested T-cell reactivity to HBV at seven protocol time points by proliferation, cytokine production, and enzyme-linked immunospot assays. A panel of serum cytokines was quantitated by cytokine bead array. ADV-treated patients showed increased CD4 + T-cell responses to HBV and lower serum levels of cytokines compared to those of placebo-treated patients. Enhanced CD4 + T-cell reactivity to HBV, which peaked at treatment week 16, was confined to a subgroup of ADV-treated patients who achieved greater viral suppression (5.3 ± 0.3 log 10 copies/ml [mean ± standard error of the mean {SEM}] serum HBV DNA reduction from baseline) and HBeAg loss, but not to ADV-treated patients with moderate (3.4 ± 0.2 log 10 copies/ml [mean ± SEM]) viremia reduction who remained HBeAg positive or to patients receiving the placebo. In conclusion, T-cell reactivity to HBV increases in a proportion of ADV-treated patients and is associated with greater suppression of HBV replication and HBeAg loss.