Impact of early viral kinetics on T-cell reactivity during antiviral therapy in chronic hepatitis B

Abstract

Background: The patterns of hepatitis B viral dynamics during different antiviral therapies and the associated changes in HBV-specific T-cell reactivity are not well defined.

Methods: We investigated the impact of early viral load decline on virus-specific T-cell reactivity in 30 hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B randomized to monotherapy with adefovir dipivoxil (ADV) or in combination with emtricitabine (ADV/FTC). Viral kinetics were analysed by mathematical modelling. T-cell reactivity to HBV core and/or surface antigens and natural killer T cell frequency were tested longitudinally, baseline to week 48, using EliSPOT assays and/or flow cytometry.

Results: Mathematical modelling of early HBV kinetics identified two subsets of patients: 11 fast responders (undetectable viraemia by week 12; eight on ADV/FTC three on ADV) and 19 slow responders who remained viremic (six on ADV/FTC 13 on ADV). The rate of infected hepatocyte loss was higher in fast than in slow responders (P = 0.0007), and correlated inversely with pre-treatment levels of intrahepatic covalently closed circular HBV DNA. The frequency of HBV core-specific CD4+ T-cells increased significantly only in fast responders, peaking between week 16 and 24, while the HBV surface-specific CD4+ T-cells increased in both subsets. These changes in CD4+ T-cell reactivity were transient however, and no increase in HBV-specific CD8+ T-cells was observed. By week 48, HBeAg seroconversion occurred only in 3/30 (10%) patients.

Conclusions: Early viraemia clearance facilitates recovery of virus-specific CD4+ T-cell reactivity, but appears insufficient to establish clinically relevant antiviral immunity.