Combination Bulevirtide, Peginterferon Alfa-2a Therapy Bests Monotherapy for HDV

Fabien Zoulim, MD, PhD

Credit: Zhimeng Biopharma

New data from a phase 2b trial are highlighting greater rates of undetectable hepatitis D virus (HDV) RNA with a combination of bulevirtide and peginterferon alfa-2a therapy versus bulevirtide alone.¹

Findings were presented at the European Association for the Study of the Liver (EASL) Congress in Milan, Italy, and published in the New England Journal of Medicine and showed the greatest percentages of patients with an undetectable HDV RNA level at the end of treatment and 24 and 48 weeks after the end of treatment were observed with bulevirtide 10 mg daily for 96 weeks combined with weekly peginterferon alfa-2a therapy for the first 48 weeks.¹

The World Health Organization (WHO) does not have specific recommendations on hepatitis D prevention, although hepatitis B vaccination can prevent HDV infection. Treatment success rates with pegylated interferon alpha are generally low, highlighting a growing need for efforts to reduce the global burden of chronic hepatitis B and develop medicines that are safe and effective against hepatitis D.²

“Guidelines from the European Association for the Study of the Liver recommend that treatment with bulevirtide be considered in all patients with chronic hepatitis D and compensated liver disease and that peginterferon alfa-2a given alone or in combination with bulevirtide be considered in eligible patients,” Fabien Zoulim, MD, PhD, head of the hepatology department at the Hospices Civils de Lyon and head of the viral hepatitis research laboratory of INSERM Unit 1052, and colleagues wrote.¹ “However, whether bulevirtide combined with peginterferon alfa-2a would enhance viral suppression such that finite treatment could be possible has been unclear.”

To evaluate bulevirtide, with or without peginterferon alfa-2a, as a potential finite treatment regimen in patients with chronic hepatitis D, investigators conducted a multicenter, open-label, randomized, controlled, phase 2b trial. It enrolled patients 18 - 65 years of age who had chronic hepatitis D with positive HDV RNA detected by polymerase chain reaction as well as an alanine aminotransferase level > 1 time but < 10 times the upper limit of the normal (ULN) range at screening.¹

A total of 175 patients were randomly assigned in a 1:2:2:2 ratio to receive peginterferon alfa-2a alone (180 μg per week) for 48 weeks (n = 24); bulevirtide at a daily dose of 2 mg (n = 50) or 10 mg (n = 50) plus peginterferon alfa-2a (180 μg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks (n = 50), with randomization stratified according to the presence of liver cirrhosis.¹

The end of treatment was at week 48 in the peginterferon alfa-2a group and at week 96 in all groups that received bulevirtide. The study’s primary endpoint was an undetectable level of HDV RNA at 24 weeks after the end of treatment, and the primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group.¹

Among the total study population, the mean age was 41 years, 97% of patients had HDV genotype 1 infection, 79% had HBV genotype D infection, and 48% had a history of interferon therapy use. Investigators noted the demographic and baseline characteristics of the patients were generally balanced across the trial groups.¹

At the end of treatment, the HDV RNA level was undetectable in 44% of the patients in the 2-mg bulevirtide plus peginterferon alfa-2a group and in 70% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group. By comparison, the HDV RNA level was undetectable at the end of treatment in 21% of the patients in the peginterferon alfa-2a group and in 22% of those in the 10-mg bulevirtide monotherapy group.¹

At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group; 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group; 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group; and 12% of those in the 10-mg bulevirtide group. Investigators noted the percentage of patients with a primary endpoint response was significantly greater in the 10-mg bulevirtide plus peginterferon alfa-2a group than in the 10-mg bulevirtide monotherapy group (difference, 34 percentage points; 95% confidence interval [CI], 15 - 50; P <.001).¹

At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group; 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group; 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group; and 12% of those in the 10-mg bulevirtide group.¹

Safety results indicated a similar safety profile of bulevirtide in combination with peginterferon alfa-2a compared with the known safety profiles of each drug. Leukopenia, neutropenia, injection-site reaction, and anemia occurred more often with combined therapy than with either treatment alone, and the majority of adverse events were of grade 1 or 2 in severity.¹

Investigators noted several potential limitations to these findings, including the fact that the trial was not powered to compare the 2 doses of bulevirtide or the peginterferon alfa-2a monotherapy group; a lack of blinding to the treatment intervention due to ethical reasons; and limited generalizability due to the disproportionate amount of patients with HDV genotype 1 or HBV genotype A or D.¹

“In this phase 2b trial involving patients with chronic hepatitis D, combination therapy with 10 mg of bulevirtide daily for 96 weeks, plus peginterferon alfa-2a for the first 48 weeks, resulted in a significantly higher percentage of patients with an undetectable HDV RNA level at 24 weeks after the end of treatment than monotherapy with 10 mg of bulevirtide for 96 weeks,” investigators concluded.¹

References:

1. ^{Asselah TV, Chulanov P, Lampertico H, et al. Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D. N Engl J Med. doi:10.1056/NEJMoa2314134}
2. ^{World Health Organization. Hepatitis D. Newsroom. July 20, 2023. Accessed June 6, 2024. https://www.who.int/news-room/fact-sheets/detail/hepatitis-d}