Weekly HBsAg Decline Dynamics During Combination Therapy with Interferon and Nucleos(t)ide Analogs: A Retrospective Real-World Study.

Functional cure, defined as sustained hepatitis B surface antigen (HBsAg) loss, remains a major goal in chronic hepatitis B (CHB) management. HBsAg kinetics during interferon (IFN)-based therapy are associated with treatment response and prognosis, but real-world data on weekly HBsAg dynamics remain limited. This retrospective real-world study enrolled 533 CHB patients treated with IFN monotherapy or IFN plus tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), or entecavir (ETV). Weekly HBsAg levels up to week 24 were analyzed using propensity score matching (PSM), subgroup analyses, and generalized estimating equations (GEEs). HBsAg kinetics showed marked heterogeneity, with some patients exhibiting transient early increases. Lower baseline HBsAg levels and rapid early decline were strongly associated with HBsAg loss. After PSM, IFN monotherapy and combination therapy showed comparable HBsAg decline trajectories. The three NA regimens demonstrated similar overall kinetics, although subgroup differences were observed by sex, immune activity, HBV DNA status, and prior treatment. TDF showed a faster decline in females, whereas ETV declined faster in males and immune-active patients. In conclusion, HBsAg kinetics during IFN-based therapy are highly heterogeneous and mainly influenced by baseline HBsAg levels, early on-treatment decline, and host factors. Weekly HBsAg monitoring may help predict treatment response and guide individualized CHB management.