Modelling HDV kinetics under the entry inhibitor bulevirtide suggests the existence of two HDV-infected cell populations
Louis Shekhtman,
Scott J. Cotler,
Elisabetta Degasperi,
Maria Paola Anolli,
Sara Colonia Uceda Renteria,
Dana Sambarino,
Marta Borghi,
Riccardo Perbellini,
Floriana Facchetti,
Ferruccio Ceriotti,
Pietro Lampertico,
Harel Dahari
Affiliations
Louis Shekhtman
The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA; Department of Information Science, Bar-Ilan University, Ramat Gan, Israel
Scott J. Cotler
The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA
Elisabetta Degasperi
Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Maria Paola Anolli
Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Sara Colonia Uceda Renteria
Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Virology Unit, Milan, Italy
Dana Sambarino
Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Marta Borghi
Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Riccardo Perbellini
Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Floriana Facchetti
Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Ferruccio Ceriotti
Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Virology Unit, Milan, Italy
Pietro Lampertico
Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; CRC “A. M. and A. Migliavacca” Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Corresponding authors. Addresses: Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via F. Sforza 35 - 20122 Milan, Italy; Tel.: +39-0255035432; (P. Lampertico), or The Program for Experimental & Theoretical Modeling, Division of Hepatology, Stritch School of Medicine, Loyola University Chicago, 2160 S. First Ave., Maywood, IL, USA 60153; Tel.: +1-708-216-4682; (H. Dahari)
Harel Dahari
The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA; Corresponding authors. Addresses: Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via F. Sforza 35 - 20122 Milan, Italy; Tel.: +39-0255035432; (P. Lampertico), or The Program for Experimental & Theoretical Modeling, Division of Hepatology, Stritch School of Medicine, Loyola University Chicago, 2160 S. First Ave., Maywood, IL, USA 60153; Tel.: +1-708-216-4682; (H. Dahari)
Background & Aims: Bulevirtide (BLV) was approved for the treatment of compensated chronic hepatitis D virus (HDV) infection in Europe in 2020. However, research into the effects of the entry inhibitor BLV on HDV-host dynamics is in its infancy. Methods: Eighteen patients with HDV under nucleos(t)ide analogue treatment for hepatitis B, with compensated cirrhosis and clinically significant portal hypertension, received BLV 2 mg/day. HDV RNA, alanine aminotransferase (ALT), and hepatitis B surface antigen (HBsAg) were measured at baseline, weeks 4, 8 and every 8 weeks thereafter. A mathematical model was developed to account for HDV, HBsAg and ALT dynamics during BLV treatment. Results: Median baseline HDV RNA, HBsAg, and ALT were 4.9 log IU/ml [IQR: 4.4-5.8], 3.7 log IU/ml [IQR: 3.4-3.9] and 106 U/L [IQR: 81-142], respectively. During therapy, patients fit into four main HDV kinetic patterns: monophasic (n = 2), biphasic (n = 10), flat-partial response (n = 4), and non-responder (n = 2). ALT normalization was achieved in 14 (78%) patients at a median of 8 weeks (range: 4-16). HBsAg remained at pre-treatment levels. Assuming that BLV completely (∼100%) blocks HDV entry, modeling indicated that two HDV-infected cell populations exist: fast HDV clearing (median t1/2 = 13 days) and slow HDV clearing (median t1/2 = 44 days), where the slow HDV-clearing population consisted of ∼1% of total HDV-infected cells, which could explain why most patients exhibited a non-monophasic pattern of HDV decline. Moreover, modeling explained ALT normalization without a change in HBsAg based on a non-cytolytic loss of HDV from infected cells, resulting in HDV-free HBsAg-producing cells that release ALT upon death at a substantially lower rate compared to HDV-infected cells. Conclusion: The entry inhibitor BLV provides a unique opportunity to understand HDV, HBsAg, ALT, and host dynamics. Impact and implications: Mathematical modeling of hepatitis D virus (HDV) treatment with the entry inhibitor bulevirtide (BLV) provides a novel window into the dynamics of HDV RNA and alanine aminotransferase. Kinetic data from patients treated with BLV monotherapy can be explained by hepatocyte populations with different basal HDV clearance rates and non-cytolytic clearance of infected cells. While further studies are needed to test and refine the kinetic characterization described here, this study provides a new perspective on viral dynamics, which could inform evolving treatment strategies for HDV.