The entry inhibitor
bulevirtide (BLV) received conditional approval from the 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 patients with HDV-related
cirrhosis is presently unknown. Herein, 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 3 years on a compassionate use program. Patients were also monitored for HBcrAg and HBV
RNA levels, and HDV- and HBV-specific T-cell 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
alanine aminotransferase normalization coupled with low HDV
RNA and
HBsAg levels. In the 2 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/laboratory 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, HBV core-related
antigen 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interferon-γ-producing T cells were detected, neither after HDV reactivation (after BLV withdrawn in Patient 1) nor during 3 years of BLV treatment.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 3 years leads to excellent virological and clinical responses in patients with HDV-related
cirrhosis who had
contraindications to
interferon-based
therapies.