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Outcomes of Treatment With Bulevirtide Combined With Pegylated Interferon in Patients With Chronic Hepatitis D
TAKE-HOME MESSAGE
- This phase IIb open-label trial assessed the outcomes of treatment with pegylated interferon (peginterferon) alfa-2a in combination with bulevirtide in patients with chronic hepatitis D. The patients were randomized to receive peginterferon alfa-2a alone for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 μg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. The patients were followed for 48 weeks after the end of the treatment.
- Hepatitis D virus RNA was undetectable in 46% of the patients in the 10-mg bulevirtide plus peginterferon alfa-2a group compared with only 25% of those in the peginterferon alfa-2a group, 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, and 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
In a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear.
METHODS
In this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 μg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 μg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group.
RESULTS
A total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity.
CONCLUSIONS
The combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.).
Additional Info
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Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D
N. Engl. J. Med 2024 Jul 11;391(2)133-143, T Asselah, V Chulanov, P Lampertico, H Wedemeyer, A Streinu-Cercel, V Pântea, S Lazar, G Placinta, GS Gherlan, P Bogomolov, T Stepanova, V Morozov, V Syutkin, O Sagalova, D Manuilov, RC Mercier, L Ye, BL Da, G Chee, AH Lau, A Osinusi, M Bourliere, V Ratziu, S Pol, MN Hilleret, F ZoulimFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
More than 40 years since its discovery, there is no FDA-approved therapy for chronic hepatitis D virus (HDV) infection, the most aggressive form of chronic viral hepatitis. The off-label use of 48-week pegylated interferon-α (pegIFN) therapy is suboptimal in achieving sustained HDV RNA negativity after therapy is completed (approximately 25%), which is comparable to the sustained virological response rate achieved with pegIFN-based therapy for hepatitis C in the early 2000s. Bulevirtide (BLV), an entry inhibitor, was recently approved in Europe as the first direct-acting drug for chronic hepatitis D. Asselah et al conducted a phase 2b open-label trial comparing four treatment arms — (i) pegIFN alone, (ii) pegIFN + 2 mg BLV daily, (iii) pegIFN + 10 mg BLV daily, and (iv) BLV 10 mg daily alone — and reported sustained HDV negativity (ALT normalization) rates of 25% (42%), 26% (38%), 46% (46%), and 12% (22%), respectively, 48 weeks after treatment was completed. PegIFN + 10 mg BLV was superior to BLV alone. The study was not powered to compare the pegIFN + BLV arms with pegIFN alone. Interestingly, most patients who had sustained HDV negativity did not clear hepatitis B surface antigen (HBsAg).
The 46% HDV negativity rate achieved with pegIFN + 10 mg BLV suggests a welcome advance in HDV therapy. In addition, HDV negativity and ALT normalization rates observed at the end of treatment suggest fascinating opportunities to develop response-guided therapy strategies to optimize sustained HDV negativity. Further research could focus on developing response-guided therapy–stopping rules and to identify patients who can reach sustained HDV negativity with longer courses of BLV monotherapy and combination therapy with pegIFN. As HDV packaging and secretion from infected cells relies on HBsAg, achieving sustained HDV negativity without clearing HBsAg may potentially indicate HDV cure.