Safety and effectiveness of up to 3 years' bulevirtide monotherapy in patients with HDV-related cirrhosis.

The entry-inhibitor Bulevirtide (BLV) received conditional approval by EMA in July 2020 for the treatment of adult patients with compensated chronic hepatitis Delta. However, the effectiveness and safety of BLV administered as monotherapy beyond 48 weeks in difficult to treat HDV cirrhotic patients is presently unknown. Here we describe the first patients with HDV-related compensated cirrhosis who were treated with BLV (10 mg/day as a starting dose) for up to three years as compassionate use. Patients were also monitored for HBcrAg and HBV-RNA levels and HDV and HBV specific T-cells markers. In the patient who stopped BLV at week 48 after achieving a virological and biochemical response, the initial virological and biochemical rebound was followed by ALT normalization coupled with low HDV-RNA and HBsAg levels. In the two patients treated continuously for 3 years, virological and biochemical responses were maintained throughout the treatment period even after dose reduction. In a patient with advanced compensated cirrhosis, liver function tests significantly improved, esophageal varices disappeared, and histological/lab features of autoimmune hepatitis resolved. Overall, no safety issues were recorded, as bile salt increase was asymptomatic. While serum HBV-RNA levels remained undetectable in all patients, HBcrAg levels showed a progressive, yet modest decline during long-term BLV-treatment. No HDV-specific Interferon-γ producing T-cells were detected, neither after HDV reactivation (after BLV withdrawn in Patient 1) nor during 3 years of BLV treatment. In conclusion, this report shows that continuous administration of BLV monotherapy for three years provides excellent virological and clinical response in HDV cirrhotic patients who had contraindications to IFN-based therapies. LAY SUMMARY: HDV-RNA levels became undetectable, and ALT normalized in all three patients treated with Bulevirtide (BLV). Virological and biochemical responses were maintained even after dose reduction.- Improvement of liver function tests, regression of esophageal varices and recovery of HDV-related autoimmune disease were documented in the male cirrhotic patient long-term treated with BLV.- An asymptomatic increase of bile acids was the only drug-related clinical adverse event.