Bulevirtide as the first specific agent against hepatitis D virus infections—mechanism and clinical effect

Abstract

Blocking the cell entry of pathogens is a suitable approach to prevent new infections. However, the therapeutic use of entry inhibitors in chronically infected patients has had limited success. For the treatment of chronic hepatitis D virus (HDV) infections, a promising agent based on this mode of action, Bulevirtide (BLV), was conditionally approved in July 2020. Previously, no drugs were available for HDV, and treatment relied on off-label use of interferon alpha/peginterferon alpha (IFNα/Peg-IFNα). In this review, we provide an overview of the basic mechanism of action of BLV and summarize the clinical data available to date. HDV infection manifests as a co-infection or superinfection of hepatitis B virus (HBV) infections and affects 4.5–15% of HBV patients worldwide. HDV utilizes the envelope proteins of HBV for dissemination. BLV acts by blocking the HBV/HDV receptor sodium taurocholate co-transporting polypeptide (NTCP), preventing HBV/HDV entry into hepatocytes. BLV lowers HDV serum RNA levels and normalizes alanine aminotransferase (ALT) levels in HBV/HDV-infected individuals. It has an excellent safety profile, even when administered at high doses (10 mg daily) for 48 weeks. In combination with Peg-IFNα, BLV shows synergistic effects on lowering serum HDV RNA, but also on hepatitis B surface antigen (HBsAg) levels. This resulted in a functional cure in a subset of patients when 2 mg BLV plus Peg-IFNα was administered. The mechanism of this likely immune-mediated elimination will be investigated in follow-up studies.