Effect of Peg-IFN on the viral kinetics of patients with HDV infection treated with bulevirtide
Selma El Messaoudi,
Ségolène Brichler,
Claire Fougerou-Leurent,
Emmanuel Gordien,
Athenaïs Gerber,
Amal Kortebi,
Garance Lagadic,
Miroslava Subic-Levrero,
Sophie Metivier,
Stanislas Pol,
Anne Minello,
Vlad Ratziu,
Vincent Leroy,
Philippe Mathurin,
Laurent Alric,
Fatoumata Coulibaly,
Jean-Michel Pawlotsky,
Fabien Zoulim,
Victor de Lédinghen,
Jérémie Guedj
Affiliations
Selma El Messaoudi
Université Paris Cité, IAME, Inserm, Paris, France; Corresponding author. Address: Université Paris Cité, IAME, Inserm, 16 rue Henri Huchard, 75018 Paris, France
Ségolène Brichler
National Reference Center for Viral Hepatitis B, C, and D, Department of Clinical Microbiology, Hôpital Avicenne AP-HP, Université Sorbonne Paris Nord, Bobigny, INSERM U955, Créteil, France
National Reference Center for Viral Hepatitis B, C, and D, Department of Clinical Microbiology, Hôpital Avicenne AP-HP, Université Sorbonne Paris Nord, Bobigny, INSERM U955, Créteil, France
Athenaïs Gerber
National Reference Center for Viral Hepatitis B, C, and D, Department of Clinical Microbiology, Hôpital Avicenne AP-HP, Université Sorbonne Paris Nord, Bobigny, INSERM U955, Créteil, France
Department of Hepatology, Hospices Civils de Lyon, INSERM Unit 1052, Université Claude Bernard Lyon 1, France
Sophie Metivier
Department of Hepatology, CHU Rangueil, Toulouse, France
Stanislas Pol
Department of Hepatology, Hôpital Cochin, AP-HP, Université Paris-René Descartes, INSERM U1016, Paris, France
Anne Minello
Department of Hepatology and Gastroenterology, University hospital Dijon, INSERM UMR 1231, France
Vlad Ratziu
Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
Vincent Leroy
Department of Hepatology and Gastroenterology, Centre Hospitalo-Universitaire, INSERM U1209, Université Grenoble Alpes, Grenoble, France
Philippe Mathurin
Service des maladies de l’appareil digestif, Université Lille 2 and Inserm U795, Lille, France
Laurent Alric
Department of Internal Medicine and Digestive Diseases, UMR-152, Toulouse III University, Toulouse, France
Fatoumata Coulibaly
Clinical research department, ANRS Maladies infectieuses émergentes, Paris, France
Jean-Michel Pawlotsky
National Reference Center for Viral Hepatitis B, C, and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Inserm U955, Créteil, France
Fabien Zoulim
Department of Hepatology, Hospices Civils de Lyon, INSERM Unit 1052, Université Claude Bernard Lyon 1, France
Victor de Lédinghen
Centre d'Investigation de la Fibrose Hépatique, Bordeaux University Hospital, Pessac, France; INSERM U1312, Bordeaux University, Bordeaux, France
Jérémie Guedj
Université Paris Cité, IAME, Inserm, Paris, France
Background & Aims: Bulevirtide is a first-in-class entry inhibitor antiviral treatment for chronic hepatitis D. The viral kinetics during bulevirtide therapy and the effect of combining bulevirtide with pegylated-interferon (Peg-IFN) are unknown. Methods: We used mathematical modelling to analyze the viral kinetics in two French observational cohorts of 183 patients receiving bulevirtide with or without Peg-IFN for 48 weeks. Results: The efficacy of bulevirtide in blocking cell infection was estimated to 90.3%, whereas Peg-IFN blocked viral production with an efficacy of 92.4%, albeit with large inter-individual variabilities. The addition of Peg-IFN to bulevirtide was associated with a more rapid virological decline, with a rate of virological response (>2 log of decline or undetectability) at week 48 of 86.9% (95% prediction interval [PI] = [79.7–95.0]), compared with 56.1% (95% PI = [46.4–66.7]) with bulevirtide only. The model was also used to predict the probability to achieve a cure of viral infection, with a rate of 8.8% (95% PI = [3.5–13.2]) with bulevirtide compared with 18.8% (95% PI = [11.6–29.0]) with bulevirtide + Peg-IFN. Mathematical modelling suggests that after 144 weeks of treatment, the rates of viral cure could be 42.1% (95% PI = [33.3–52.6]) with bulevirtide and 66.7% (95% PI = [56.5–76.8]) with bulevirtide + Peg-IFN. Conclusions: In this analysis of real-world data, Peg-IFN strongly enhanced the kinetics of viral decline in patients treated with bulevirtide. Randomized clinical trials are warranted to assess the virological and clinical benefit of this combination, and to identify predictors of poor response to treatment. Impact and implications: Bulevirtide has been approved for chronic HDV infection by regulatory agencies in Europe based on its good safety profile and rapid virological response after treatment initiation, but the optimal duration of treatment and the chance to achieve a sustained virological response remain unknown. The results presented in this study have a high impact for clinicians and investigators as they provide important knowledge on the long-term virological benefits of a combination of Peg-IFN and bulevirtide in patients with CHD. Clinical trials are now warranted to confirm those predictions.
