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

Published:October 23, 2021DOI:https://doi.org/10.1016/j.jhep.2021.10.012

      Summary

      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 No HDV-specific interferon-γ-producing T cells were detected, neither after HDV reactivation (after BLV withdrawn in Patient 1) nor during 3 years of BLV treatment.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.

      Keywords

      Linked Article

      • Mathematical modeling suggests that entry-inhibitor bulevirtide may interfere with hepatitis D virus clearance from circulation
        Journal of HepatologyVol. 76Issue 5
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          Loglio and colleagues,1 published a unique case study on hepatitis D virus (HDV) RNA kinetics under entry-inhibitor bulevirtide (BLV) monotherapy in 3 patients. Historically, mathematical modeling of viral hepatitis kinetics predicts a monophasic viral decline under antiviral treatment that blocks virus infection. Modeling suggests that the monophasic decline is driven by the rate of loss/death of virus productive-infected cells (parameter δ, Fig. 1A). Indeed, assuming that BLV’s only mode of action (MOA) is blocking HDV entry/infection (assuming η∼100%, Fig. 1A),2 the model (Fig. 1A) fits well with the measured HDV data in patients 2 and 3 (Fig. S1) but not in patient 1, in whom a transient viral increase was seen during the first 4 weeks of treatment, consisting of a 0.4 log increase from pretreatment HDV-RNA level at week 2, followed by a monophasic HDV decline thereon (Fig. 1B).
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