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

doi:10.1016/j.jhepr.2023.100966

Modelling HDV kinetics under the entry inhibitor bulevirtide suggests the existence of two HDV-infected cell populations

JHEP Rep. 2023 Nov 15;6(2):100966. doi: 10.1016/j.jhepr.2023.100966. eCollection 2024 Feb.

Affiliations

¹ The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
² Department of Information Science, Bar-Ilan University, Ramat Gan, Israel.
³ Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁴ Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Virology Unit, Milan, Italy.
⁵ CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Abstract

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 t_1/2 = 13 days) and slow HDV clearing (median t_1/2 = 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.

Keywords: ALT; Bulevirtide; HBsAg; HDV RNA; mathematical modeling.