Distinct plasma proteomic trajectories during PD-1 blockade and PEG-IFNα therapy are associated with HBsAg response in chronic hepatitis B

Background PD-1 blockade and pegylated interferon-α (PEG-IFNα) are promising immunomodulatory strategies for chronic hepatitis B (CHB), but their systemic immune effects and response-associated proteomic patterns remain poorly defined. Methods We performed longitudinal plasma proteomic profiling using the Olink Target 96 Inflammation panel in 25 nucleos(t)ide analogue-suppressed patients with CHB receiving PD-1 blockade (n=10) or PEG-IFNα (n=15). Plasma samples were collected at baseline, week 12, and week 24. Longitudinal protein changes were analyzed using linear mixed-effects models, and associations with week-24 HBsAg decline were evaluated using responder–non-responder comparisons and Spearman’s rank correlation. Responders were defined by an HBsAg decline of ≥1 log 10 IU/mL at week 24. Results Seventy-seven proteins passed quality-control criteria. PEG-IFNα induced substantially broader longitudinal proteomic remodeling than PD-1 blockade, with most changes occurring within the first 12 weeks. Treatment-by-time analyses identified distinct trajectories between therapies, including differential changes in IL-18R1, TNF, CX3CL1, CXCL9, and CXCL10. Response-associated analyses suggested treatment-specific patterns: IL-10 was the leading exploratory signal in the PD-1 cohort, whereas IL-12B, CDCP1, and FGF-21 were more prominent in the PEG-IFNα cohort. These response-related associations did not remain significant after false discovery rate correction and were therefore considered exploratory. Conclusions PD-1 blockade and PEG-IFNα induce distinct longitudinal circulating inflammatory proteomic programs in CHB. Favorable HBsAg decline was accompanied by treatment-specific rather than universal proteomic signatures, supporting the potential value of longitudinal proteomics for mechanistic and biomarker studies of HBV functional-cure strategies.