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Modelling HDV kinetics under 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

JHEP Reports

February 2024

 [Full Text[Pubmed]

Abstract

Background and aim: Bulevirtide (BLV) was recently approved for the treatment of compensated chronic hepatitis D virus (HDV) infection in Europe in 2020. Understanding of the effect of the entry inhibitor BLV on HDV-host dynamics is in its infancy.

Methods: Participants were 18 HDV patients under nucleos(t)ide analogue treatment for hepatitis B with compensated cirrhosis and clinically significant portal hypertension (CSPH) who 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 [interquartile, 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 4 main HDV kinetic patterns: monophasic, MP (n=2), biphasic, BP (n=10), flat-partial response, FPR (n=4), and non-responder, NR (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 blocks ∼100% 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 had a non-MP HDV decline pattern. Moreover, modeling explained ALT normalization without a change in HBsAg based on a noncytolytic 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 HDV treatment with the entry blocker Bulevirtide (BLV) provides a novel window into the dynamics of HDV RNA, ALT. 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.

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