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 10 Austrian centers were included. Virological, biochemical, and combined response (VR/BR/CR) were assessed every 6 months (M6-M24). Pegylated interferon alfa-2a (PegIFN) was offered to suboptimal responders.

RESULTS

Sixty-one patients (median age: 45 years, 60.7% men, ACLD: 68.9%) receiving BLV for a median of 29.0 months were included. VR (Month [M]6: 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 for 2 years. Liver stiffness and systemic inflammation (i.e. C-reactive protein [CRP] and procalcitonin [PCT]) decreased under BLV treatment (all p <0.01). Nineteen patients (31.1%) received add-on PegIFN 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 (seven BLV mono and three BLV + PegIFN) 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 retreatment.

CONCLUSIONS

High response rates to BLV were observed in this nationwide cohort. In suboptimal BLV responders, PegIFN 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 could help identify candidates for finite BLV treatment.

IMPACT AND IMPLICATIONS: CHD 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, BLV significantly reduced HDV-RNA, alanine aminotransferase, and liver stiffness (p <0.001). Add-on PegIFN 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 BLV treatment, and long-term HDV-RNA TND allowed elective treatment discontinuation in 10 patients under close surveillance.