Combination Therapy Looks Promising for Hepatitis D

The combination of the antiviral bulevirtide (Hepcludex) plus pegylated interferon alfa-2a was superior to bulevirtide monotherapy for chronic hepatitis delta (HDV) infection, a multinational phase 2b open-label study in Europe found.

The combination resulted in higher rates of HDV RNA suppression levels at 24 weeks after end of treatment, especially at a higher, 10-mg dose of bulevirtide, according to researchers led by Tarik Asselah, MD, PhD, a professor of medicine and hepatology at Hôpital Beaujon, APHP, Clichy, France, and the University of Paris.

“This response appeared to be maintained from 24 to 48 weeks after the end of treatment — a finding that supports the concept that sustained undetectable HDV RNA for at least 1 year after treatment is possible in patients with chronic hepatitis D who have been treated with a finite duration of therapy of at least 96 weeks, including 48 weeks of peginterferon alfa-2a therapy,” the investigators wrote in The New England Journal of Medicine.

“As of today, there is no approved treatment for chronic HDV infection in the United States. Pegylated interferon alfa-2a, which is not approved for treatment of HDV, is the only option recommended by US treatment guidelines,” said study corresponding author Fabien Zoulim, MD, PhD, a hepatologist at the Lyon Hepatology Institute and a professor of medicine at the University of Lyon in France, in comments to GI & Hepatology News. “Bulevirtide 2 mg is approved for treating chronic HDV and compensated liver disease, and both bulevirtide and peginterferon are recommended options by the European treatment guidelines.”

The study found that most patients with undetectable HDV RNA levels during treatment-free follow-up showed no reduction in HepB surface antigen (HBsAg), suggesting an undetectable HDV RNA level can be achieved and sustained without HBsAg loss, the authors wrote.

While very small numbers in the combo groups and the higher-dose bulevirtide arm cleared HBsAg, “the study was not powered to evaluate the HBsAg response,” Dr Zoulim said.

HDV is a defective virus that requires HBsAg for assembly and propagation, the authors noted. It affects as many as 20 million persons worldwide, and as the most severe form of chronic viral hepatitis, is associated with 2-6 times the risk of hepatocellular carcinoma and 2-3 times the risk of death associated with HBV monoinfection.

Though not common in the United States, it affects an estimated 10 to 20 million people worldwide (J Hepatol. 2020 Apr. doi: 10.1016/j.jhep.2020.04.008). One US database study found HepD in 4.6% of patients with HepB infection.

Commenting on the study but not a participant in it, Ahmet O. Gurakar, MD, AGAF, a professor of medicine in the sections of gastroenterology and hepatology at Johns Hopkins School of Medicine in Baltimore, Maryland, said the study findings look promising for the future treatment of HepD, but cautioned that it will be “a slow process to get approval for combination therapy with bulevirtide since the FDA has previously said it needs to see more studies. The findings need to be confirmed in larger groups, but it’s difficult to recruit enough patients in the United States for a trial since hepatitis D is not common in this country — it’s more common in the Mediterranean basin Eastern European populations.”

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.”

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. 

This article originally appeared on MDedge.com, part of the Medscape Professional Network.