Author information

¹From Université de Paris-Cité, Department of Hepatology, Hôpital Beaujon Assistance Publique-Hôpitaux de Paris (AP-HP), Centre de Recherche sur l'Inflammation, INSERM Unité Mixte de Recherche 1149, Clichy (T.A.), Hôpital Saint Joseph, Marseille (M.B.), Sorbonne Université, Hôpital Pitié-Salpêtrière, AP-HP, Pitié-Salpétrière, INSERM Unité Mixte de Recherche S 1138, Centre de Recherche des Cordeliers (V.R.), and Hôpital Cochin, AP-HP, Université Paris-Cité (S.P.), Paris, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble (M.-N.H.), and Hospices Civils de Lyon, Université Claude Bernard Lyon 1, INSERM Unité 1052, Lyon Hepatology Institute, Lyon (F.Z.) - all in France; the Infectious Diseases Department, Sechenov University (V.C.), M.F. Vladimirsky Moscow Regional Research and Clinical Institute (P.B.), the Clinic of Modern Medicine (T.S.), and the Research Institute of Emergency Medicine n.a. N.V. Sklifosovsky (V.S.), Moscow, Medical Company "Hepatolog," Samara (V.M.), and South Ural State Medical University, Chelyabinsk (O.S.) - all in Russia; the Department of Pathophysiology and Transplantation, Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, and CRC "A. M. and A. Migliavacca" Center for Liver Disease, University of Milan - both in Milan (P.L.); Klinik für Gastroenterologie, Hepatologie, und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany (H.W.); Matei Bals National Institute of Infectious Diseases (A.S.-C.), Carol Davila University of Medicine and Pharmacy (A.S.-C., G.S.G.), and Dr. Victor Babes Foundation (G.S.G.), Infectious and Tropical Diseases Hospital (S.L.) - all in Bucharest, Romania; Infectious Clinical Hospital "T. Ciorba" (V.P.) and State University of Medicine and Pharmacy "Nicolae Testemitanu" (G.P.), Chisinau, Moldova; and Gilead Sciences, Foster City, CA (D.M., R.-C.M., L.Y., B.L.D., G.C., A.H.L., A.O.).

Abstract

Background: 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.).