Immune drivers of HBsAg loss in HBeAg-negative CHB patients after stopping nucleotide analog and administration of Peg-IFN

Abstract

Background: The stoppage of nucleoside analog (NA) can lead to immune flare and loss of HBsAg in a proportion of HBeAg-negative chronic hepatitis B (CHB) patients. HBsAg loss could be improved by instituting Peg-Interferon therapy in those who show an immune flare after the stoppage of NA. We investigated the immune drivers of HBsAg loss in NA-treated HBeAg-negative CHB patients after stopping NAs and administration of Peg-IFN-α2b therapy. Methods: Fifty-five NA-treated eAg-ve, HBV DNA not detected CHB patients were subjected to stopping NA therapy. Twenty-two (40%) patients relapsed (REL-CHBV) within 6 months (HBV DNA ≥ 2000 IU/mL, ALT ≥ 2XULN) and were started on Peg-IFN-α2b (1.5 mcg/kg) for 48 weeks (PEG-CHBV). Cytokine levels, immune responses, and T-cell functionality were assessed. Results: Only 22 (40%) of 55 patients clinically relapsed, of which 6 (27%) cleared HBsAg. None of the 33 (60%) nonrelapsers cleared HBsAg. REL-CHBV patients had significantly increased IL-6 (p = 0.035), IFN-γ (p = 0.049), Th1/17 (p = 0.005), CD4 effector memory (EM) (p = 0.01), Tfh1/17 (p = 0.005), and mature B cells (p = 0.04) compared with CHBV. Six months after Peg-IFN therapy, immune resetting with a significant increase in CXCL10 (p = 0.042), CD8 (p = 0.01), CD19 (p = 0.001), and mature B cells (p = 0.001) was observed. HBV-specific T-cell functionality showed increased Tfh-secreting IFN-γ (p = 0.001), IL-21 (p = 0.001), and TNF-α (p = 0.005) in relapsers and IFN-γ-secreting CD4 T cell (p = 0.03) in PEG-CHBV. Conclusions: Stopping NA therapy induces flare in about 40% of HBeAg-negative patients. Peg-IFN therapy given to such patients causes immune restoration with HBsAg loss in one fourth of them.