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

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 (t 1/2) 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 t 1/2 = 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. Chronic hepatitis B virus (HBV) and hepatitis D virus (HDV) co-infection affects an estimated 15-40 million persons worldwide 1,2 and is the most aggressive form of viral hepatitis 3. Therapy with pegylated interferon-α2a (pegIFN) is suboptimal in controlling HDV infection 4,5 and no other therapies are approved for the treatment of HDV. HDV requires hepatitis B surface antigen (HBsAg) for assembly and release. While the large isoform (L-HBsAg) is not requisite for HDV assembly and release, it is necessary for infectivity 6. Drugs that directly target HDV and reduce HDV levels are in development 7 , however the only anti-HBV treatment that affects HBsAg production is the nucleic acid polymer (NAP) REP 2139-Ca, which is accompanied by declines in both HBsAg and HDV RNA 8-11. Therefore, analyzing antiviral response during REP 2139-Ca monotherapy provides a unique opportunity to examine HBsAg production and clearance rates in HBV/HDV co-infected patients and to obtain a deeper understanding of REP 2139-Ca mode of action and efficacy against HDV. The aim of this study was to analyze the kinetics of HBV DNA, HBsAg, ALT and HDV RNA during REP 2139-Ca monotherapy and investigate the dynamics of HDV RNA and HBsAg using mathematical modelling.

Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection

“…There is a wide range of estimates for the free virus clearance rate in serum: as low as 0.69 per day 25,33,57 ; and as high as 21.7 per day 58 ; we search the entire 0 < c < 100 parameter space. The decay rate of HBsAg is bounded between 0 < d S < 200 per day, containing previous estimates ranging between 0.057 to 0.58 per day 59,60 . In previous modeling work 44,61 HBeAg decay rate d E was set to 0.3 per day.…”

One‐quarter of chronic hepatitis D patients reach HDV‐RNA decline or undetectability during the natural course of the disease

“…In a study analysing HDV-RNA kinetics during REP 2139-Ca treatment, the mathematical model predicted that both HDV-RNA and HBsAg would decline after 25.3(20.3-32.7) days. The HDV blocking efficacy of peg-IFN was estimated at 96.2% (93.0%-99.8%), whereas the corresponding blocking efficacy under REP 2139-Ca was 99.7% (95.9%-99.8%) 26. HDV-RNA decline, so the performance of multivariate analysis was not well suited.…”

A Mathematical Analysis of HDV Genotypes: From Molecules to Cells

“…Future work relating to mathematical modeling of HDV genotypes is to address HDV viral kinetics across the different genotypes by a simple differential equation model [57,58], which can be solved by standard mathematical software such as Matlab without the need for a sophisticated numerical solution as in, for example, [59,60], where the model is nonlinear. Some parameter values can be fixed based on [61], while others are estimated for each patient according to each participant's viral kinetics.…”