Twenty-four-week anti-PD-1 antibody regimen promoted HBsAg reduction and concurrently enhanced HBV-specific T cell responses in patients with chronic hepatitis B

Abstract

Background: PD-1 blockade has emerged as a promising approach for functional cure of chronic hepatitis B (CHB).

Objective: This study aimed to evaluate the safety profile of anti-PD-1 antibody (αPD-1), as well as its impact on hepatitis B surface antigen (HBsAg) and immune responses in a larger cohort of CHB patients.

Design: In this prospective, open-label study, virally suppressed patients with CHB on nucleos(t)ide analogue (NA) were assigned to receive either 24-week NA monotherapy (n=62) or αPD-1 (half-dose sintilimab) add-on therapy (n=59), with both groups subsequently receiving NA monotherapy for an additional 12-week observation period.

Results: 93.6% of adverse events (AEs) were grade 1 or 2. Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase were the most common AEs, and they represented the only severe AEs. αPD-1 add-on therapy induced greater HBsAg reductions (mean decline: -0.720 vs -0.034 log₁₀ IU/mL, p<0.001) and higher HBsAg loss rates (6.1% vs 0%, p=0.166) than NA monotherapy at week 24. Notably, significant HBsAg decline and seroclearance exclusively occurred in the initial 12 weeks of αPD-1 treatment. HBsAg levels did not rebound at 12 weeks after discontinuation of αPD-1 therapy. After αPD-1 therapy, the numbers of HBsAg-specific, HBpol-specific, HBx-specific and HBeAg/HBcAg-specific IFN-γ spots all increased (p<0.05), while frequencies of HBsAg-specific B cells remained stable. Furthermore, ALT elevation and enhanced HBsAg-specific T-cell responses following αPD-1 therapy correlated with HBsAg decline (p<0.05).

Conclusions: In virally suppressed CHB patients on NA therapy, 24-week half-dose sintilimab treatment demonstrated a favourable safety profile. This regimen can facilitate HBsAg reduction and even HBsAg loss, while concurrently enhancing HBV-specific T-cell responses. These findings support αPD-1 as a potential therapeutic alternative for CHB.

Trial registration number: NCT05769816.

Keywords: ANTIVIRAL THERAPY; CHRONIC HEPATITIS; HEPATITIS B; IMMUNE RESPONSE; IMMUNOTHERAPY.