Bulevirtide With Tenofovir Disoproxil Fumarate Shows Promise in Hepatitis B, Hepatitis D Coinfection

A combination of bulevirtide with tenofovir disoproxil fumarate (TDF) showed efficacy in treating patients coinfected with hepatitis B virus (HBV) and hepatitis D virus (HDV) in a recent phase 2 trial, published in The Lancet Infectious Diseases.

Investigators enrolled 120 patients with chronic HDV between February 2016 and December 2016, including 59 patients with cirrhosis. Patients were administered 2 mg, 5 mg, or 10 mg of bulevirtide in combination with TDF or TDF alone.

“Blocking HBV and hepatitis D virus entry with bulevirtide is a safe and promising strategy to treat patients with chronic hepatitis D virus infection, even when cirrhosis has already been diagnosed,” the study authors wrote.

HDV is dependent on HBV envelope proteins to complete its life cycle. Further, coinfection with HBV and HDV causes more rapid disease progression vs HBV infection alone. Coinfection can lead to cirrhosis within 5 to 10 years for 70% of patients and death within 10 years for 60% of patients.

Bulevirtide, a synthetic myristoylated peptide, is derived from the pre-S1 domain of the HBV large surface protein. The drug binds the sodium taurocholate contransporting polypeptide (NTCP) receptor, which is the entry pathway for the virus.

At week 24, 15 of 28 (54%) patients administered 2 mg bulevirtide achieved undetectable HDV RNA vs 16 of 32 (50%) patients administered 5 mg bulevirtide, 23 of 30 (77%) patients administered 10 mg bulevirtide, and 1 of 28 (4%) administered TDF alone. HDV RNA concentrations rebounded 24 weeks post treatment cessation among 91% of study participants.

A subgroup of 22 patients who underwent liver biopsy at baseline and completed treatment showed a decrease in hepatitis delta antigen-positive and HDV RNA-positive hepatocytes. Patients administered bulevirtide hadrapid showed improvements in alanine aminotransferase concentrations and liver stiffness.

Adverse events (AEs) included asymptomatic salt increases and increases in alanine and aspartate aminotransferases, with only 2 serious AEs that were attributed to bulevirtide. The study was limited by the duration of treatment being 24 weeks, which prevented long-term conclusions regarding safety, tolerability, or efficacy, according to the authors. Additionally, the results may not be generalizable to patients with different HDV genotypes or ethnicities.

Treatment with peginterferon alfa, which has been linked to AEs and high rates of relapse, is the only treatment currently recommended by the European Association for the Study of the Liver guideline for chronic HDV.

The researchers noted that although bulevirtide produced a significant reduction in HDV RNA over 24 weeks, the virus RNA concentrations rebounded following cessation of bulevirtide. As such, they recommend investigation of longer treatment durations and combination therapies.

“In summary, we show that blocking the HBV–hepatitis D virus receptor NTCP leads to a significant reduction of hepatitis D virus RNA concentrations in the serum and the liver of patients with chronic hepatitis D virus infection, indicating effectiveness at all three doses administered,” the study authors wrote. “Bulevirtide was safe and well tolerated, including in patients with cirrhosis.”

Reference

Wedemeyer, H. (n.d.). Safety and efficacy of bulevirtide in combination with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection (MYR202): a multicentre, randomised, parallel-group, open-label, phase 2 trial. The Lancet Infectious Diseases. Retrieved October 4, 2022, from https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00318-8/fulltext?dgcid=raven_jbs_aip_email#articleInformation