Bulevirtide/Pegylated Interferon Combo Beats Monotherapy for Chronic Hepatitis D

Treatment with the investigational drug bulevirtide plus pegylated interferon alfa-2a (PegIFNα) resulted in more patients achieving undetectable levels of hepatitis D virus (HDV) RNA compared with bulevirtide alone, according to results of a phase IIb trial.

At 24 weeks after the end of treatment, HDV RNA levels were undetectable in 46% of patients who received 10 mg of bulevirtide plus PegIFNα versus 12% who received 10-mg bulevirtide alone (P<0.001), reported Tarik Asselah, MD, PhD, of Hôpital Beaujon Assistance Publique-Hôpitaux de Paris in Clichy, France, at the European Association for the Study of the Liver annual meeting in Milan.

The study was simultaneously published in the New England Journal of Medicine.

“I want to stress the fact that these were patients with advanced liver disease,” Asselah said. “One-third had compensated cirrhosis. They had inflammation with high ALT [alanine aminotransferase], and the mean HDV RNA was around 5 log₁₀ IU/mL. Half of the patients had prior interferon experience.”

In patients who received 2 mg of bulevirtide plus PegIFNα, 32% had undetectable HDV RNA levels at 24 weeks after treatment ended, as did 17% of those who received PegIFNα alone.

Until recently, off-label therapy with PegIFNα was the only treatment for chronic HDV, and was recommended by clinical practice guidelines as the standard of care in eligible patients, the researchers explained. In 2023, bulevirtide became the first drug approved in Europe for treating chronic HDV and compensated liver disease, but the FDA in 2022 rejected the sodium taurocholate cotransporting polypeptide (NTCP) entry inhibitor, citing manufacturing and delivery concerns.

“The important question is, was the treatment durable?” Asselah said. At 48 weeks after treatment ended, HDV RNA levels were undetectable in 46% of those in the 10-mg bulevirtide plus PegIFNα group, 26% of those who received 2-mg bulevirtide plus PegIFNα, 25% of those who received PegIFNα only, and 12% who received 10-mg bulevirtide monotherapy.

In an accompanying editorial, Norah Terrault, MD, MPH, of the Keck School of Medicine at the University of Southern California in Los Angeles, wrote that more combination therapy approaches are likely in the future, but the use of immunomodulatory drugs other than PegIFNα “would be desirable.”

“Indeed, peginterferon [PegIFNα] use in the United States is very uncommon, and the results of this trial are unlikely to change practice patterns,” she pointed out, though she noted that practice patterns may differ in other regions of the world where chronic HDV is more prevalent.

“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,” Terrault explained. Side effects of PegIFNα are common and sometimes serious, she added, and can include mood disturbances, cytopenias, and hepatitis flares.

Bulevirtide monotherapy has been associated with a high incidence of virologic relapse after treatment discontinuation, she wrote, suggesting that long-term treatment may be needed — “a prospect made less palatable by the requirement for daily subcutaneous injections.”

“Ultimately, therapy that has an acceptable safety profile and that is easily administered will be needed to ensure that HDV therapies can be broadly applied to achieve a cure for persons with HDV infection,” she concluded.

HDV infection cannot occur in the absence of hepatitis B virus (HBV). HDV-HBV co-infection is considered the most severe form of chronic viral hepatitis due to more rapid progression to hepatocellular carcinoma and liver-related death. HDV is estimated to affect nearly 5% of people with chronic HBV. Currently, vaccination against HBV is the only available method to prevent HDV infection.

Bulevirtide is an NTCP inhibitor. The NTCP receptor is the entry receptor for both HBV and HDV. A recent phase III trial showed that bulevirtide monotherapy resulted in a greater virologic response versus no treatment, although only 20% of patients in the 10-mg treatment group achieved undetectable HDV RNA levels.

In the current trial, 24 weeks after the end of treatment, ALT levels had normalized in 56% of patients in the 10-mg bulevirtide plus PegIFNα group, 42% of the 2-mg bulevirtide plus PegIFNα group, 30% in the 10-mg bulevirtide monotherapy group, and 25% in the PegIFNα monotherapy group.

Only a small percentage of patients in all groups had hepatitis B surface antigen (HBsAg) loss at 48 weeks after the end of treatment. Most of the patients who had undetectable HDV RNA levels during the follow-up period after treatment did not have HBsAg loss, which suggests that treatment of HDV can occur independently of functional clearance of HBV infection, Asselah and team noted.

This multicenter, open-label 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 normal range at screening. Patients with decompensated cirrhosis were excluded.

Across the four groups, mean age was 40-41, 66% to 76% were men, 83% to 88% were white, and 33% to 34% had cirrhosis.

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

The most frequent adverse events across treatment groups were cytopenias, though the majority were grade 1 or 2. Although there were serious adverse events during treatment in all four groups, those that were attributable to trial treatment were related to PegIFNα, according to the investigators.

However, four patients in the two bulevirtide treatment groups experienced grade 3 or higher adverse events, including injection site reaction and decreased neutrophil count in one patient in the 2-mg bulevirtide plus PegIFNα group, and increased liver enzymes in two patients in the 10-mg bulevirtide plus PegIFNα group. One fatal case of anaplastic astrocytoma occurred in the 2-mg bulevirtide plus PegIFNα group but was considered unrelated to treatment.

Bulevirtide was associated with dose-dependent elevations in bile acids, an expected effect, but did not lead to any symptoms such as pruritus.

Asselah and colleagues noted that the trial was not powered to formally compare the two doses of bulevirtide or PegIFNα monotherapy. Being an open-label trial for ethical reasons, treatment intervention was not blinded.

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