Add-on PD-1 inhibitor with Peg-IFNα therapy favors functional cure of chronic hepatitis B patients

Abstract Background and Objectives The treatment options for hepatitis B surface antigen (HBsAg) clearance are limited for patients who have failed pegylated interferon-α (Peg-IFNα) therapy. Given preclinical evidence that PD-1 blockade boosts antiviral immunity, this study aims to evaluate the efficacy and safety of PD-1 inhibitors in chronic hepatitis B (CHB) patients who have failed interferon therapy. Methods This non-randomized controlled trial was conducted in CHB patients who failed to achieve HBsAg clearance after 48 weeks of Peg-IFNα therapy. Including two groups: (i) a PD-1 inhibitor plus Peg-IFNα group receiving sintilimab 1 mg/kg/12 weeks plus Peg-IFNα 180 μg/week ( n = 33) or (ii) a Peg-IFNα group continuing Peg-IFNα therapy ( n = 31). The primary endpoint was HBsAg clearance at week 24. Results The PD-1 inhibitor plus Peg-IFNα group included 33 patients and the Peg-IFNα group included 31 patients. At week 24, HBsAg clearance occurred in 30.3% of PD-1 inhibitor plus Peg-IFNα group versus 9.7% of Peg-IFNα group ( P = 0.047). Median HBsAg declined by –0.916 log 10 IU/mL in the PD-1 inhibitor plus Peg-IFNα group compared with –0.067 log 10 IU/mL in Peg-IFNα group ( P = 0.013). In the PD-1 inhibitor plus Peg-IFNα group, alanine transaminase (ALT) rose transiently at week 12 only among patients who ultimately cleared HBsAg. Sintilimab increased stomatitis (12.1%) and recurrent fever (36.4%), but the frequency of grade ≥ 3 adverse events did not differ from Peg-IFNα group. Enzyme-linked immunosorbent assay (ELISA) profiling showed progressive induction of ISG15 after sintilimab, and patients achieving HBsAg clearance displayed higher baseline and week-12 OAS1 concentrations than non-clearers (both P < 0.05). Conclusions Quarterly sintilimab add-on therapy triples the short-term HBsAg clearance rate in interferon-refractory CHB without major additional toxicity. A week-12 ALT surge and elevated OAS1 may serve as early biomarkers of response, but confirmation in larger randomized trials is needed.