The Effectiveness and Safety of Bulevirtide Monotherapy are Similar in Chronic Hepatitis Delta Patients with and Without Cirrhosis: Results from The Prospective Multicenter D-Shield Study

Background: Bulevirtide (BLV) has been approved in Italy in May 2023 for patients with chronic hepatitis Delta (CHD), but no studies have addressed their responses to treatment and the differences in responses among patients with and without cirrhosis yet.
Methods: CHD patients starting BLV 2 mg/day as monotherapy were included in a multicenter prospective real-life Italian study (D-SHIELD). Patients’ features and treatment responses were assessed at baseline and trimonthly afterwards. The primary endpoint was the achievement of a virological response (VR) (>2 LogIU/mL HDV-RNA decline vs. baseline or HDV RNA undetectable) in patients with and without cirrhosis. Secondary endpoints included biochemical and combined responses (BR and CR), incidence of virological breakthroughs (VBK), and safety.
Results: 486 patients from 46 centers were enrolled, 354 (73%) with cirrhosis, 130 without cirrhosis. Patients were treated with BLV monotherapy up to 72 weeks.At baseline, patients without cirrhosis were younger (56 vs. 50, p<0.001), were less commonly treated with NA for CHB (91% vs. 98%, p<0.001), had lower LSM values (8.0 vs. 15.8 kPa, p<0.001), and had higher HDV RNA levels (5.5 vs. 5.2 Log U/L p=0.03). During BLV monotherapy, median HDV RNA and ALT levels declined to a simile extent in patients with cirrhosis and patients with chronic hepatitis from baseline (median 74 vs. 75 U/L and 5.2 vs. 5.5 LogU/L) until week 72 (31 vs. 33 U/L and 2.9 vs. 3.4 LogU/L) (p=ns at all time points). No significant differences were observed in VR, BR and CR rates at all time points in patients with and without cirrhosis, with 70% vs. 63% patients achieving a VR (p=0.24), 74% vs 71% achieving a BR (p=0.36), and 60% vs. 47% achieving a CR (p=0.12). Only HDV RNA undetectability rates at week 72 differed (32% vs. 13% p=0.01, p=ns for other time-points). 3% (10/78) of patients with VR at week 24 experienced a VBK at week 48, all with cirrhosis; 15% (17/111) of those with a VR at week 48 experienced a VBK at week 72, 65% with cirrhosis (p=0.08). No significant differences were observed in the incidence of adverse events among patients with and without cirrhosis, (15% vs. 15%, p=1.00), with mild and transient pruritus and injection site reaction being the most common. Patients with cirrhosis showed higher baseline and on-therapy bile acids levels (p<0.001 at all time-points).
Conclusions: The effectiveness and safety profile of BLV monotherapy did not differ in patients with or without compensated cirrhosis in this large prospective multicenter Italian study.