Bulevirtide in the Treatment of Hepatitis Delta: Drug Discovery, Clinical Development and Place in Therapy

Abstract

It has been ten years since the identification of NTCP as the cell surface receptor for HBV and HDV entry into hepatocytes. The search for molecules interfering with the binding of NTCP and HBV/HDV led to design bulevirtide (BLV). This large polypeptide mimics a region of the pre-S1 HBsAg and blocks viral entry by inhibitory competition. BLV was initially tested in cell cultures, animal models and more recently in Phase I–III human trials (called ‘MYRS’). As monotherapy or in combination with peginterferon, BLV is well tolerated and exhibits potent antiviral activity. Plasma viremia significantly declines and/or becomes undetectable in more than 75% of patients treated for >24 weeks. However, serum HBsAg concentrations remain unchanged. No selection of BLV resistance in HBV/HDV has been reported in vivo to date. BLV is administered subcutaneously once daily at doses between 2 and 10 mg. BLV received conditional approval in Europe in 2020 to treat chronic hepatitis delta. The advent of peginterferon lambda or new specific anti-HDV antivirals (lonafarnib, etc.) will open the door for combination therapies with BLV. Since there is no stable reservoir for HDV-RNA within infected hepatocytes, viral clearance might be achieved using antivirals for a minimum timeframe. This is what happens in hepatitis C combining several antivirals, curing nearly all patients treated for 3 months. Clearance of HDV-RNA genomes may occur despite HBV persistence as cccDNA or chromosome integrated HBV-DNA within hepatocytes. This is supported by cases of HDV elimination using BLV despite persistence of serum HBsAg. Another path for HDV cure will derive from achieving HBsAg clearance, the goal of new promising anti-HBV gene therapies (bepirovirsen, etc.). In summary, the advent of BLV has triggered a renovated interest for antiviral therapy in hepatitis delta. We envision combination therapies that will lead to HDV cure in the near future.

Prevalence and determinants of hepatitis delta virus infection among HIV/hepatitis B‐coinfected adults in care in the United States

“…Benefits to earlier HDV screening and detection include earlier initiation of HDV therapy and closer monitoring for liver‐related complications, which may improve clinical outcomes. With the advent of novel HDV therapies on the horizon, our findings emphasize the importance of HDV serological screening and reflex RNA testing among PWH with HBV coinfection, especially those with a history of IDU 26–28 …”

“…With the advent of novel HDV therapies on the horizon, our findings emphasize the importance of HDV serological screening and reflex RNA testing among PWH with HBV coinfection, especially those with a history of IDU. [26][27][28] Our study has several potential limitations. First, selection bias is possible since only patients who had an available serum/plasma sample on or after their initial HBV test were included.…”

“…Despite the adverse clinical impact of HDV infection in the setting of HIV/HBV coinfection, there is a paucity of data on the prevalence and determinants of HDV among PWH with HBV coinfection in the US. If the prevalence of HDV infection is high among people with HIV/HBV coinfection, or certain subgroups, routine testing for HDV infection would be further supported to identify chronically HDV‐infected persons and prompt early initiation of HDV therapy, especially considering novel HDV therapies on the horizon 26–28 . Moreover, knowledge of the factors associated with HDV infection could identify subgroups of PWH with HBV coinfection who might be at increased risk of developing HDV infection and warrant close monitoring for liver complications.…”

Viral hepatitis in persons living with HIV in the post-COVID era

“…As hepatitis delta is the most aggressive of all chronic viral hepatitis, most PLWH with hepatitis delta progress to liver cirrhosis and may develop liver cancer 61,62 . No effective antiviral therapy had been developed until recently to treat hepatitis delta, but the advent of a subcutaneous entry inhibitor, bulevirtide, has opened a new era for hepatitis delta 83 (Table 2).…”

Prospects for Controlling Hepatitis B Globally

“…It blocks the NTCP receptor at the hepatocyte surface, causing inhibitory competition with the physiologic substrate, the bile acids. In several clinical trials, bulevirtide has demonstrated excellent tolerability and minimal side effects [ 24 ]. Serum HBV-DNA goes down in most treated patients; however, no effect is seen on serum HBsAg concentrations.…”