Persistent Loss of Hepatitis B Virus Markers in Serum without Cellular Immunity by Combination of Peginterferon and Entecavir Therapy in Humanized Mice

ABSTRACT Nucleot(s)ide analogues and peginterferon (PEG-IFN) treatment are the only approved therapies for chronic hepatitis B virus (HBV) infection. However, complete eradication of the virus, as indicated by persistent loss of hepatitis B surface antigen (HBsAg), is rare among treated patients. This is due to long-term persistence of the HBV genome in infected hepatocytes in the form of covalently closed circular DNA (cccDNA). In this study, we investigated whether administration of a large dose of a nucleoside analogue in combination with PEG-IFN can achieve long-term loss of HBsAg in human hepatocyte chimeric mice. Mice were treated with a high dose of entecavir and/or PEG-IFN for 6 weeks. High-dose combination therapy with both drugs resulted in persistently negative HBV DNA in serum. Although small amounts of HBV DNA and cccDNA (0.1 and 0.01 copy/cell, respectively) remained in the mouse livers, some of the mice remained persistently negative for serum HBV DNA at 13 weeks after cessation of the therapy. Serum HBsAg and hepatitis B core-related antigen (HBcrAg) continued to decrease and eventually became negative at 12 weeks after cessation of the therapy. Analysis of the HBV genome in treated mice showed accumulation of G-to-A hypermutation and CpG III island methylation. Persistent loss of serum HBV DNA and loss of HBV markers by high-dose entecavir and PEG-IFN combination treatment in chimeric mice suggests that control of HBV can be achieved even in the absence of a cellular immune response.

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Interaction between ganciclovir and foscarnet as inhibitors of duck hepatitis B virus replication in vitro.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.5.1180 ◽

1996 ◽

Vol 40 (5) ◽

pp. 1180-1185 ◽

Cited By ~ 7

Author(s):

G Civitico ◽

T Shaw ◽

S Locarnini

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Hbv Dna ◽

Duck Hepatitis ◽

Chronic Hepatitis B Virus ◽

B Virus ◽

Dose Limiting Toxicity

Safe and effective treatments for chronic hepatitis B virus (HBV) infection have yet to be developed. Both ganciclovir (9-[1,3-dihydroxy-2-propoxymethyl]guanine) and foscarnet (trisodium phosphonoformate hexahydrate) are potent inhibitors of hepadnavirus replication when used individually in vitro and in vivo. However, the clinical usefulness of each drug is reduced by dose-limiting toxicity, especially during long-term monotherapy. Here we demonstrate additive inhibition of duck HBV DNA replication in cultures of primary duck hepatocytes congenitally infected with duck HBV by combinations of ganciclovir and foscarnet at low, clinically achievable concentrations. These results suggest that the effects of ganciclovir and foscarnet against HBV may be additive in vivo.

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Association Between Seroclearance of Hepatitis B Surface Antigen and Long-Term Clinical Outcomes of Patients With Chronic Hepatitis B Virus Infection: Systematic Review and Meta-Analysis

Clinical Gastroenterology and Hepatology ◽

10.1016/j.cgh.2020.05.041 ◽

2020 ◽

Cited By ~ 1

Author(s):

Ryan T. Anderson ◽

Hannah S.J. Choi ◽

Oliver Lenz ◽

Marion G. Peters ◽

Harry L.A. Janssen ◽

...

Keyword(s):

Systematic Review ◽

Chronic Hepatitis ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Hepatitis B Surface Antigen ◽

Meta Analysis ◽

Hepatitis B Virus Infection ◽

Chronic Hepatitis B Virus ◽

B Virus

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Understanding the antiviral effects of RNAi-based therapy on chronic hepatitis B infection

10.1101/2020.07.21.215012 ◽

2020 ◽

Author(s):

Sarah Kadelka ◽

Harel Dahari ◽

Stanca M Ciupe

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B Virus ◽

Rna Interference ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Hbv Dna ◽

Term Therapy ◽

Chronic Hepatitis B Virus ◽

B Virus

AbstractReaching hepatitis B surface antigen (HBsAg) loss (called functional cure) with approved treatment with pegylated interferon-α (IFN) and/or nucleos(t)ide analogues (NAs) in chronic hepatitis B virus (HBV) infected patients is suboptimal. The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum HBV DNA, HBsAg and hepatitis B e antigen (HBeAg) in chimpanzees and small animals. A recent clinical study (Heparc-2001) showed reduction of serum HBV DNA, HBeAg and HBsAg in HBeAg-positive patients treated with a single dose of ARC-520 and daily NA (entecavir). To provide insights into HBV dynamics under ARC-520 treatment and its efficacy in blocking HBV DNA, HBsAg, and HBeAg production we developed a a multi-compartmental pharmacokinetic-pharamacodynamic model and calibrated it with measured HBV data. We showed that the time-dependent ARC-520 efficacies in blocking HBsAg and HBeAg are more than 96% effective around day 1, and slowly wane to 50% in 1-4 months. The combined ARC-520 and entecavir effect on HBV DNA is constant over time, with efficacy of more than 99.8%. HBV DNA loss is entecavir mediated and the strong but transient HBsAg and HBeAg decays are solely ARC-520 mediated. We added complexity to the model in order to reproduce current long-term therapy outcomes with NAs by considering the tradeoff between hepatocyte loss and hepatocyte division, and used it to make in-silico long-term predictions for virus, HBsAg and HBeAg titer dynamics. These results may help assess ongoing RNAi drug development for hepatitis B virus infection.Author summaryWith about 300 million persons infected worldwide and 800,000 deaths annually, chronic infection with hepatitis B virus (HBV) is a major public health burden with high endemic areas around the world. Current treatment options focus on removing circulating HBV DNA but are suboptimal in removing hepatitis B s- and e-antigens. ARC-520, a RNA interference drug, had induced substantial hepatitis B s- and e- antigen reductions in animals and patients receiving therapy. We study the effect of ARC-520 on hepatitis B s- and e-antigen decline by developing mathematical models for the dynamics of intracellular and serum viral replication, and compare it to patient HBV DNA, hepatitis B s- and e-antigen data from a clinical trial with one ARC-520 injection and daily nucleoside analogue therapy. We examine biological parameters describing the different phases of HBV DNA, s-antigen and e-antigen decline and rebound after treatment initiation, and estimate treatment effectiveness. Such approach can inform the RNA interference drug therapy.

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