Insufficient immunity led to virologic breakthrough in NAs-treated chronic hepatitis B patients switching to Peg-IFN-ɑ.

BACKGROUND

Virologic breakthrough (VBT) may occur in chronic hepatitis B (CHB) patients after switching from nucleos(t)ide analogues (NAs) to pegylated interferon alpha (Peg-IFN-ɑ). This study aimed to characterize the clinical and immunological features of VBT.

METHODS

In NAs-treated patients switching to Peg-IFN-ɑ, innate and adaptive immune cell proportions were examined in peripheral blood and liver biopsy specimens. In vitro effect of IFN-ɑ on the expressions of toll-like receptors 2 (TLR2) and programmed cell death ligand 1 (PDL1) on monocytes, programmed cell death 1 (PD1) on CD8T cells was examined. Peripheral blood mononuclear cells (PBMCs) were treated with TLR2 agonist and/or PDL1 blockade to evaluate their effect on HBV replication.

RESULTS

33 of 166 patients switching to Peg-IFN-ɑ experienced VBT after NA cessation, with majority being hepatitis B e antigen (HBeAg) positive or having higher hepatitis B core-related antigen (HBcrAg) levels. Patients with VBT exhibited lower proportions of TLR2monocyte and increased PD1HBV-specific CD8T cell during the early phase of Peg-IFN-ɑ therapy after NA cessation in peripheral blood, as well as fewer TLR2CD68macrophages but more PDL1CD68macrophages and PD1CD8T cells in liver tissues. Simultaneous use of TLR2 agonist and PDL1 blockage ex vivo suppressed HBV replication by promoting cytokines production and CD8T cells cytotoxicity. Upon in vitro IFN-ɑ stimulation, PDL1monocytes and PD1CD8T cells were upregulated, whereas TLR2monocytes were not increased in PBMC isolated from HBeAg-positive patients, or those with high HBcrAg titers.

CONCLUSIONS

In NAs-treated patients, lower TLR2monocyte and increased PD1HBV-specific CD8T cell proportions potentially contribute to VBT after switching to Peg-IFN-ɑ therapy. This insufficient immunity may be associated with the HBeAg status and HBcrAg levels.