The Trial
The investigators randomly assigned 174, largely male, patients ages 18-65 (mean, about 41) years to receive one of four treatments:
- Pegylated interferon alfa-2a alone at 180 μg per week) for 48 weeks (n = 24).
- Bulevirtide at a daily dose of 2 mg plus peginterferon alfa-2a at 180 μg per week for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks (n = 50).
- Bulevirtide at 10 mg plus peginterferon alfa-2a at 180 μg per week for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks (n = 50).
- Bulevirtide at a daily dose of 10 mg alone for 96 weeks (n = 50).
All were followed for 48 weeks after treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group.
At 24 weeks post-treatment, HDV RNA was undetectable in 17% of patients in the peginterferon alfa-2a group. In the other arms, HDV RNA was undetectable in 32% in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of the 10-mg bulevirtide group.
For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15-50; P < .001).
At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% in the peginterferon alfa-2a group, 26% in the 2-mg bulevirtide plus peginterferon alfa-2a group, 46% in the 10-mg bulevirtide plus peginterferon alfa-2a group, and 12% in the 10-mg bulevirtide group.
Also calling the findings promising, Anna Lok, MBBS, MD, AGAF, a gastroenterologist at the University of Michigan, Ann Arbor, said that, “Given that the European Medicines Agency’s approval is for bulevirtide alone at 2 mg, results of this study should prompt reassessment whether bulevirtide should be used in combination with pegylated interferon in patients with no contraindications, and if 10 mg is more appropriate than a 2-mg dose.”
Dr. Anna Lok
As to safety, the most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia, with the majority of adverse events being grade 1 or 2.
In comparison with other research, the current trial found that 70% in the 10-mg bulevirtide plus peginterferon alfa-2a group had an undetectable HDV RNA level at the end of treatment versus results of the Hep-Net International Delta Hepatitis Interventional Trial II (HIDIT-II), in which 33%-48% had undetectable levels after 96 weeks of peginterferon alfa-2a therapy, with or without tenofovir disoproxil. And in the phase 3 MYR301 trial, HDV RNA was undetectable in 20%-36% after 96 weeks of bulevirtide monotherapy.
The authors acknowledged that in addition to the lack of blinding, the trial was not designed to compare the two doses of bulevirtide and therefore lacked an adequate sample size to allow for formal comparisons. And although it included a peginterferon alfa-2a monotherapy group, it was not sufficiently powered to allow for comparison. They are currently considering plans for further studies in this area.
This study was funded by Gilead Sciences. Dr. Asselah disclosed consulting, safety/data monitoring, or travel for Gilead Sciences, AbbVie, Antio Therapeutics, Eiger Biopharmaceutical, Enyo Pharma, GlaxoSmithKline, Johnson & Johnson Healthcare Systems, and Vir Biotechnology. Dr. Zoulim reported consulting or research for multiple pharmaceutical/biotech companies, including Gilead Sciences. Numerous study coauthors declared financial relationships such as consulting, research, or employment with multiple private-sector companies, including Gilead Sciences. Dr. Lok and Dr. Gurakar disclosed no competing interests relevant to their comments.
