Monocyte-derived IL-1β predicts and promotes HBsAg decline in chronic hepatitis B patients under nucleoside analogue therapy.

BACKGROUND

Although nucleos(t)ide analogs (NAs) suppress HBV replication, functional cure-defined by hepatitis B surface antigen (HBsAg) loss-is rarely achieved in chronic hepatitis B (CHB). Immune correlates of HBsAg decline may inform new therapeutic strategies.

METHODS

We profiled peripheral blood mononuclear cells (PBMCs) from NA-treated CHB patients with declining versus sustained HBsAg levels by single-cell RNA sequencing (scRNA-seq), followed by validation in an independent multicenter cohort using transcriptomic and functional assays. In a retrospective cohort, we evaluated serum interleukin-1β (IL-1β) as a predictor of HBsAg decline during long-term follow-up.

RESULTS

scRNA-seq revealed that CD14+CD16- classical monocytes in the HBsAg-declining group expressed significantly higher levels of IL-1β, along with genes involved in antigen presentation and phagocytosis. In the validation cohort, IL-1β expression in circulating CD14+ classical monocytes was also significantly higher in the declining group. Ex vivo stimulation assays demonstrated that recombinant HBsAg induced IL-1β production in monocytes, with stronger responses in the declining group. Recombinant IL-1β suppressed HBsAg secretion from HBV-producing HepG2.2.15 cells in vitro in a dose-dependent manner. In a longitudinal cohort, elevated serum IL-1β predicted subsequent HBsAg decline with an AUROC of 0.71. Multivariate analysis confirmed IL-1β as an independent predictor.

CONCLUSIONS

Monocyte-derived IL-1β is linked to HBsAg decline during NA therapy and may serve as both a predictive biomarker and a potential therapeutic target to achieve functional cure.