Differential cytokine pattern of HDV-specific cellular immune responses: Results from the hep-net/international HIDIT-1 study

Introduction: Delta hepatitis is the most severe form of chronic viral hepatitis with limited treatment options available. We recently reported data of a randomised study investigating pegylated-interferon-alpha-2a with or without adefovir vs. adefovir alone for the treatment of chronic delta hepatitis. Cellular immune responses in hepatitis D virus (HDV) infection are largely undefined and HDV-specific T cell responses during antiviral therapy of hepatitis D have not been studied at all.

Methods: PBMC of 17 patients treated in the HIDIT-1 trial were available for this analysis (5 IFN-responder, 7 IFN-nonresponder; 5 adefovir patients). Each individual was studied at 5 time-points (baseline, weeks 12, 24, 48 and FU-24). HDV-specific immune responses were studied using 51 overlapping 15mer peptides spanning the entire HDV genome. Peptides were synthesized from a genotype 1 consensus sequence and all patients were confirmed to be infected with HDV genotype 1. HBV-specific (recombinant HBsAg, HBcoreAg) and tetanus-specific responses were studied. Ag-specific cytokine responses were studied in the supernatant after 6 days by bead arrays for 10 type 1 and 2 cytokines.

Results: HDV-specific interferon gamma responses were detected in 12 patients (71%) without differences between the three groups. In contrast, HDV peptide-specific IP-10 secretion was detected significantly more often in IFN-responder patients than in nonresponder while the opposite pattern was observed for HDV-specific IL-10 responses. Amino acids 81–120 of the HD-antigen were recognized most often followed by the C-terminal part (aa 161–214). Delta-specific immune responses for all cytokines and peptide pools declined in frequency and strength during interferon treatment and increased again after therapy. The cytokine pattern differed between HDV- and HBV-specific responses with IP-10, IL-2 and IL-10 more often induced by HDV-peptides.

Conclusion: A differential cytokine pattern discriminates IFN-responder and nonresponder with declining responses during therapy. HBV- and HDV-specific cytokine secretion differs even within one individual showing the complexity of T cell responses in co-infected patients which needs to be considered in aiming to achieving immune control in delta hepatitis.