Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg

Louis Shekhtman, Scott J. Cotler, Leeor Hershkovich, Susan L. Uprichard, Michel Bazinet, Victor Pantea, Valentin Cebotarescu, Lilia Cojuhari, Pavlina Jimbei, Adalbert Krawczyk, Ulf Dittmer, Andrew Vaillant, Harel Dahari

SCIENTIFIC REPORTS

April 2020

Abstract

Hepatitis D virus (HDV) requires hepatitis B surface antigen (HBsAg) for its assembly and release. Current HBV treatments are only marginally effective against HDV because they fail to inhibit HBsAg production/secretion. However, monotherapy with the nucleic acid polymer REP 2139-Ca is accompanied by rapid declines in both HBsAg and HDV RNA. We used mathematical modeling to estimate HDV-HBsAg-host parameters and to elucidate the mode of action and efficacy of REP 2139-Ca against HDV in 12 treatment-naive HBV/HDV co-infected patients. The model accurately reproduced the observed decline of HBsAg and HDV, which was simultaneous. Median serum HBsAg half-life (t1/2) was estimated as 1.3 [0.9-1.8] days corresponding to a pretreatment production and clearance of ~10^8 [10^7.7-10^8.3] IU/day. The HDV-infected cell loss was estimated to be 0.052 [0.035-0.074] days-1 corresponding to an infected cell t1/2=13.3 days. The efficacy of blocking HBsAg and HDV production were 98.2 [94.5-99.9]% and 99.7 [96.0-99.8]%, respectively. In conclusion, both HBsAg production and HDV replication are effectively inhibited by REP 2139-Ca. Modeling HBsAg kinetics during REP 2139-Ca monotherapy indicates a short HBsAg half-life (1.3 days) suggesting a rapid turnover of HBsAg in HBV/HDV co-infection.

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Loyola University Medical Center

Department of Medicine

Division of Hepatology

2160 S. First Ave
Mulcahy Center, Rm 1610

Maywood, IL 60153, USA

Email: hdahari@luc.edu

Phone: 708-216-4682

Fax: 708-216-6299