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) log10 copies/mL and reductions in HBsAg levels by 0.08 (IQR 0.02-0.12) log10 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.