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

## TL;DR

Adding a PD-1 inhibitor to Peg-IFNα therapy improves HBsAg clearance in chronic hepatitis B patients who did not respond to interferon alone.

## Contribution

The study introduces a new treatment strategy combining PD-1 inhibitors with Peg-IFNα for interferon-refractory chronic hepatitis B patients.

## Key findings

- 30.3% of patients in the PD-1 inhibitor plus Peg-IFNα group achieved HBsAg clearance compared to 9.7% in the Peg-IFNα-only group.
- Patients who cleared HBsAg showed a transient ALT increase at week 12 and higher OAS1 concentrations.
- Sintilimab caused more stomatitis and fever but no major additional toxicity compared to Peg-IFNα alone.

## Abstract

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.

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.

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 log10 IU/mL in the PD-1 inhibitor plus Peg-IFNα group compared with –0.067 log10 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).

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.