Response-guided bulevirtide ± pegylated interferon alfa-2a: Long-term outcomes observed in the nationwide Austrian hepatitis D cohort study

Background & Aims Chronic hepatitis D (CHD) often progresses to advanced chronic liver disease (ACLD). Bulevirtide (BLV) is approved for CHD, yet treatment duration, management of suboptimal response, and the potential for finite treatment remain unclear. Methods Patients receiving BLV at ten Austrian centers were included. Virological, biochemical, and combined response (VR/BR/CR) were assessed every six months (M6-M24). Pegylated interferon alfa-2a (PEG-IFN) was offered to suboptimal responders. Results Sixty-one patients (median age: 45 years, 60.7% male, ACLD: 68.9%) receiving BLV for a median of 29.0 months were included. VR (M6: 36.4%, M12: 64.2%, M24: 61.9%), BR (M6: 56.4%, M12: 69.8%, M24: 66.7%), and CR (M6: 25.5%, M12: 47.2%, M24: 42.9%) were maintained through two years. Liver stiffness and systemic inflammation (i.e., CRP and PCT) decreased under BLV treatment (all p<0.01). Nineteen patients (31.1%) received add-on PEG-IFN to BLV monotherapy after a median of 10.5 months, inducing a further HDV-RNA decline by 1.65 (IQR 0.81-2.11) log 10 copies/mL and reductions in HBsAg levels by 0.08 (IQR 0.02-0.12) log 10 IU/L after 24 weeks of combined therapy (both p<0.01). Overall, 32.8% (20/61 patients) achieved HDV-RNA target not detected (TND). Ten (7 BLV mono, 3 BLV+PEG-IFN) stopped treatment after 23.0 (IQR 12.0-29.0) months. Seven patients maintained HDV-RNA TND through the last follow-up (median 36.0 months), whereas three patients relapsed but achieved TND again following BLV re-treatment. Conclusions High response rates to bulevirtide were observed in this nationwide cohort. In suboptimal bulevirtide responders, PEG-IFN add-on was associated with a significant and partly sustained decline in HDV-RNA and HBsAg, indicating a relevant contribution to long-term viral infection control. Sustained negative HDV-RNA may help identify candidates for finite BLV treatment. Impact and implications Chronic hepatitis D is a severe form of viral hepatitis with rapid progression to cirrhosis and hepatocellular carcinoma, highlighting the need for effective treatments. In this real-world cohort of 61 Austrian patients, bulevirtide significantly reduced HDV-RNA, ALT, and liver stiffness (p<0.001). Add-on pegylated interferon 2a-alfa resulted in a further decline of HDV-RNA and HBsAg by 24 weeks of combined treatment (p<0.01) in 19 patients with suboptimal response to bulevirtide treatment, and long-term HDV-RNA TND allowed elective treatment discontinuation in ten patients under close surveillance.