Bulevirtide-pegIFNα combo trumps monotherapy for chronic HDV

In a phase IIb open-label trial, combination therapy with bulevirtide and peginterferon alfa-2a (pegIFNα) yields a synergistic on-treatment effect, with more patients achieving undetectable HDV RNA levels compared to bulevirtide alone.

At 24 weeks after the end of treatment, HDV RNA levels were undetectable in 46 percent of patients with compensated chronic hepatitis D virus (HDV) infection who received bulevirtide 10 mg plus pegIFNα compared with 12 percent in those taking bulevirtide 10 mg alone (p<0.001), reported principal study author Dr Tarik Asselah from Hôpital Beaujon Assistance Publique-Hôpitaux de Paris in Clichy, France, at EASL 2024. The between-group difference was 34 percentage points. [N Engl J Med 2024;doi:10.1056/NEJMoa2314134]

Asselah stressed that patients included in the study had advanced liver disease. “One-third had compensated cirrhosis. They had inflammation with high alanine aminotransferase [levels], and the mean HDV RNA was around 5 log₁₀ IU/mL. Half of the cohort had prior interferon experience.

In patients who received the lower dose of bulevirtide (2 mg) and pegIFNα, 32 percent had undetectable HDV RNA levels at 24 weeks after treatment cessation, and so were 17 percent of those who received pegIFNα alone.

“The important question is – was the treatment durable?” Asselah asked. At 48 weeks after the end of treatment, HDV RNA levels remained undetectable in 46 percent of patients treated with bulevirtide 10 mg and pegIFNα, 26 percent of those treated with bulevirtide 2 mg and PegIFNα, 25 percent of those given pegIFNα only, and 12 percent of those who received bulevirtide 10 mg monotherapy.

The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia, most of which were grade 1 or 2.  

“These data support the potential of bulevirtide as a finite treatment option for chronic HDV,” said Asselah. “These long-term data are the highest post-treatment response rates ever reported for HDV.”

Study population

The trial included 175 patients with chronic HDV and an ALT level of more than one time but less than 10 times the upper limit of the normal range at screening. Across the four groups, the mean age was 40-41 years, and the majority were White men. Almost 34 percent had cirrhosis.

Patients were randomly assigned in a 1:2:2:2 ratio to receive PegIFNα 180 µg alone per week for 48 weeks, bulevirtide 2 mg or 10 mg plus PegIFNα for 48 weeks, followed by the same daily dose of bulevirtide for another 48 weeks, or bulevirtide 10 mg for 96 weeks.

HDV therapy in future

Until recently, off-label therapy with pegIFNα was the only treatment for chronic HDV. Bulevirtide 2 mg is approved in Europe for treating chronic HDV and compensated liver disease, but not in the US. Bulevirtide 10 mg remains investigational as of this writing and is not approved in any country.

More combination therapy approaches for HDV are likely in the future, commented Dr Norah Terrault from the Keck School of Medicine at the University of Southern California in Los Angeles, California, US, in an accompanying editorial. Still, the use of immunomodulatory drugs other than PegIFNα “would be desirable.” [N Engl J Med 2024;doi:10.1056/NEJMe2406180]

“The benefit of pegIFNα, when combined with bulevirtide, appears to be in achieving a higher response during treatment and less in reducing the incidence of virologic relapse among patients with a response,” she explained.

Side effects with pegIFNα are common and sometimes serious; these can include mood disturbances, cytopenia, and hepatitis flare, Terrault said. With bulevirtide monotherapy, there has been a high incidence of virologic relapse after treatment discontinuation, she added, suggesting that long-term treatment may be required. She said another drawback of the therapy is the need for subcutaneous injections daily.

“Ultimately, a treatment that has an acceptable safety profile and is easily administered is warranted in patients with HDV infection to achieve a cure,” Terrault emphasized.

The most effective strategy

HDV is considered the most aggressive form of viral hepatitis and can only infect individuals who are also infected by hepatitis B virus (HBV). Over time, HDV infection can lead to liver cancer or liver failure.

Currently, vaccination against HBV remains the most effective strategy to prevent HDV infection and its consequences. While treating HDV can be challenging, doctors hope better treatments are underway.