A phase IIb trial has demonstrated that combining bulevirtide with pegylated interferon (peginterferon) alfa-2a may lead to higher rates of undetectable hepatitis D virus RNA compared with bulevirtide monotherapy in patients with chronic hepatitis D infections. 

In the multicenter, open-label, randomized, controlled trial, published in The New England Journal of Medicine, researchers assigned 174 patients to receive peginterferon alfa-2a alone for 48 weeks (n = 24), 2 mg of bulevirtide plus peginterferon alfa-2a (n = 50), 10 mg of bulevirtide plus peginterferon alfa-2a (n = 50), or 10 mg of bulevirtide alone (n = 50). The primary endpoint was undetectable hepatitis D virus RNA at 24 weeks after treatment completion.

The trial population consisted predominantly of patients with hepatitis D virus genotype 1 (97%) and hepatitis B virus genotypes A or D (95%). Most of the patients were male (72%) and White (86%), with a mean age of 41 years. Further, approximately one-third of the patients had cirrhosis.

The researchers found that 46% of the patients in the 10-mg bulevirtide plus peginterferon alfa-2a group achieved undetectable hepatitis D virus RNA 24 weeks following treatment cessation. This was significantly higher than the 12% response rate observed with 10 mg of bulevirtide monotherapy (P < .001).

Among the key findings were:

• At the end of treatment—96 weeks for the patients in the bulevirtide groups—70% of the patients in the 10 mg bulevirtide plus peginterferon alfa-2a group had undetectable hepatitis D virus RNA compared with 44% among the patients in the 2 mg combination group and 22% among those in the bulevirtide monotherapy group.
• The response was largely maintained 48 weeks posttreatment, with 46% of the patients in the 10 mg combination group maintaining undetectable hepatitis D virus RNA.
• Normalization of alanine aminotransferase levels at 24 weeks posttreatment was observed in 56% of the patients in the 10 mg combination group vs 30% among those in the bulevirtide monotherapy group.
• HBsAg loss, while rare, occurred in 4% of the patients in the 10 mg combination group at the end of the study period.

The researchers reported that the combination therapy was associated with a higher incidence of adverse events compared with monotherapy. Common adverse events included leukopenia (70% vs 18%), neutropenia (80% vs 14%), and thrombocytopenia (62% vs 18%) in the 10 mg combination group vs the monotherapy group, respectively. Most adverse events were grade 1 or 2 in severity. No serious adverse events related to bulevirtide were reported during the study period.

Posttreatment hepatic events, including elevations in alanine aminotransferase and aspartate aminotransferase, were observed in 10% to 28% of the patients across all of the study groups. These were generally asymptomatic and associated with hepatitis D virus RNA rebound.

The researchers underscored that the combination of 10 mg bulevirtide plus peginterferon alfa-2a for 96 weeks (with peginterferon alfa-2a given for the first 48 weeks) offered a potential finite treatment regimen for chronic hepatitis D infections—resulting in sustained undetectable hepatitis D virus RNA in a significant proportion of the patients. However, they noted limitations such as the lack of long-term follow-up beyond 48 weeks posttreatment and the predominance of specific hepatitis D virus and hepatitis B virus genotypes in the study population.

Disclosures are available in the original study.