Sequential combination of anti-PD-1 antibody and PEG-IFNα in chronic hepatitis B patients: correlates of HBsAg loss with enhanced T-cell responses.

Pegylated interferon-α (PEG-IFNα) exhibits suboptimal efficacy in achieving a functional cure in patients with chronic hepatitis B (CHB), partially due to impaired hepatitis B virus (HBV)-specific T-cell function. We conducted a pilot study (ClinicalTrials.gov: NCT06457477) to explore the efficacy, safety, and immunological changes associated with a response-guided sequential strategy of anti-PD-1 antibody (αPD-1) and PEG-IFNα. Ten virologically suppressed CHB patients receiving nucleos(t)ide analogues (NAs), all of whom had previously received PEG-IFNα and had HBsAg levels ≤200 IU/mL at enrolment, were included. The patients continued background NA therapy and received αPD-1 (sintilimab) for up to 24 weeks; PEG-IFNα was added at week 12 if HBsAg decline was <1 log10 IU/mL. HBV-specific T-cell responses targeting surface, core, and polymerase peptide pools were quantified, and plasma inflammatory proteins were longitudinally assessed. Nine patients completed the study, and six achieved HBsAg loss: three during NAs plus αPD-1 treatment (Group A) and three after PEG-IFNα add-on (Group B). All six maintained HBsAg negativity 24 weeks after treatment discontinuation. Most adverse events were grade 1-2. Increases in HBV-specific IL-2 and IFN-γ responses were observed in several patients with HBsAg loss, whereas such responses remained limited in nonresponders (Group C). Among 12 prespecified cytokines, IL-10 showed an early longitudinal difference, with higher levels in Group A at week 3. Exploratory analyses showed that week-3 IL-10 was positively associated with early ALT elevation and subsequent HBsAg decline. These findings support further evaluation of response-guided sequential immunotherapy strategies in larger, controlled, and well-characterized cohorts.Trial registration: ClinicalTrials.gov identifier: NCT06457477..