scholarly journals Evaluation of Single and Combination Therapies with Tenofovir Disoproxil Fumarate and EmtricitabineIn Vitroand in a Robust Mouse Model Supporting High Levels of Hepatitis B Virus Replication

2012 ◽  
Vol 56 (12) ◽  
pp. 6186-6191 ◽  
Author(s):  
Raymond F. Schinazi ◽  
Leda Bassit ◽  
Marcia M. Clayton ◽  
Bill Sun ◽  
James J. Kohler ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Combination Therapy ◽  
Virus Replication ◽  
Tenofovir Disoproxil Fumarate ◽  
Hbv Infection ◽  
Experimental Drugs ◽  
Chronic Hepatitis B Virus ◽  
B Virus

ABSTRACTNext-generation therapies for chronic hepatitis B virus (HBV) infection will involve combinations of established and/or experimental drugs. The current study investigated thein vitroandin vivoefficacy of tenofovir disoproxil fumarate (TDF) and/or emtricitabine [(−)-FTC] alone and in combination therapy for HBV infection utilizing the HepAD38 system (human hepatoblastoma cells transfected with HBV). Cellular pharmacology studies demonstrated increased levels of (−)-FTC triphosphate with coincubation of increasing concentrations of TDF, while (−)-FTC had no effect on intracellular tenofovir (TFV) diphosphate levels. Quantification of extracellular HBV by real-time PCR from hepatocytes demonstrated the anti-HBV activity with TDF, (−)-FTC, and their combination. Combination of (−)-FTC with TDF or TFV (ratio, 1:1) had a weighted average combination index of 0.7 for both combination sets, indicating synergistic antiviral effects. No cytotoxic effects were observed with any regimens. Using anin vivomurine model which develops robust HBV viremia in nude mice subcutaneously injected with HepAD38 cells, TDF (33 to 300 mg/kg of body weight/day) suppressed virus replication for up to 10 days posttreatment. At 300 mg/kg/day, (−)-FTC strongly suppressed virus titers to up to 14 days posttreatment. Combination therapy (33 mg/kg/day each drug) sustained suppression of virus titer/ml serum (<1 log10unit from pretreatment levels) at 14 days posttreatment, while single-drug treatments yielded virus titers 1.5 to 2 log units above the initial virus titers. There was no difference in mean alanine aminotransferase values or mean wet tumor weights for any of the groups, suggesting a lack of drug toxicity. TDF–(−)-FTC combination therapy provides more effective HBV suppression than therapy with each drug alone.

scholarly journals Hepatitis B Virus Pre-S Mutants as Biomarkers and Targets for the Development and Recurrence of Hepatocellular Carcinoma

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 945 ◽  
Author(s):  
Chiao-Fang Teng ◽  
Han-Chieh Wu ◽  
Ih-Jen Su ◽  
Long-Bin Jeng
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hbv Infection ◽  
Signal Pathways ◽  
Recurrence Rates ◽  
Chronic Hepatitis B Virus ◽  
B Virus

Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC), the leading cause of cancer-related death worldwide. Despite progress in the prevention and therapy of HCC, high incidence and recurrence rates of HCC remain big threats, resulting in poor patient survival. Effective biomarkers and targets of HCC are therefore urgently needed for better management and to improve patient outcomes. Pre-S mutants have been well demonstrated as HBV oncoproteins that play important roles in HCC development through activation of multiple oncogenic signal pathways in hepatocytes, in vitro and in vivo. The presence of pre-S mutants in patients with chronic HBV infection and HBV-related HCC has been associated with a significantly higher risk of HCC development and recurrence after curative surgical resection, respectively. In this review, we summarize the roles of pre-S mutants as biomarkers for predicting HBV-related HCC development and recurrence, and highlight the pre-S mutants-activated oncogenic signal pathways as potential targets for preventing HBV-related HCC development.

Inhibition of hepatitis B virus replication in vivo by nucleoside analogues and siRNA

2015 ◽  
Vol 41 (08) ◽  
Author(s):  
C Klein ◽  
CT Bock ◽  
H Wedemeyer ◽  
T Wüstefeld ◽  
S Locarnini ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Virus Replication ◽  
Nucleoside Analogues ◽  
B Virus

High prevalence of occult hepatitis C virus infection in patients with chronic hepatitis B virus infection

2013 ◽  
Vol 62 (8) ◽  
pp. 1235-1238 ◽  
Author(s):  
Inmaculada Castillo ◽  
Javier Bartolomé ◽  
Juan Antonio Quiroga ◽  
Vicente Carreño
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatitis B Virus ◽  
Virus Infection ◽  
Hepatitis B ◽  
Hcv Infection ◽  
Hbv Infection ◽  
Chronic Hepatitis B Virus ◽  
B Virus

Hepatitis C virus (HCV) infection in the absence of detectable antibodies against HCV and of viral RNA in serum is called occult HCV infection. Its prevalence and clinical significance in chronic hepatitis B virus (HBV) infection is unknown. HCV RNA was tested for in the liver samples of 52 patients with chronic HBV infection and 21 (40 %) of them were positive for viral RNA (occult HCV infection). Liver fibrosis was found more frequently and the fibrosis score was significantly higher in patients with occult HCV than in negative ones, suggesting that occult HCV infection may have an impact on the clinical course of HBV infection.

scholarly journals Creation of a Six-fingered Artificial Transcription Factor That Represses the Hepatitis B Virus HBx Gene Integrated into a Human Hepatocellular Carcinoma Cell Line

2012 ◽  
Vol 18 (4) ◽  
pp. 378-387 ◽  
Author(s):  
Xinghui Zhao ◽  
Zhanzhong Zhao ◽  
Junwei Guo ◽  
Peitang Huang ◽  
Xudong Zhu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcription Factor ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Line ◽  
Hbv Infection ◽  
Luciferase Reporter ◽  
Artificial Transcription Factor ◽  
Chronic Hepatitis B Virus ◽  
B Virus

Chronic hepatitis B virus (HBV) infection is an independent risk factor for the development of hepatocellular carcinoma (HCC). The HBV HBx gene is frequently identified as an integrant in the chromosomal DNA of patients with HCC. HBx encodes the X protein (HBx), a putative viral oncoprotein that affects transcriptional regulation of several cellular genes. Therefore, HBx may be an ideal target to impede the progression of HBV infection–related HCC. In this study, integrated HBx was transcriptionally downregulated using an artificial transcription factor (ATF). Two three-fingered Cys2-His2 zinc finger (ZF) motifs that specifically recognized two 9-bp DNA sequences regulating HBx expression were identified from a phage-display library. The ZF domains were linked into a six-fingered protein that specified an 18-bp DNA target in the Enhancer I region upstream of HBx. This DNA-binding domain was fused with a Krüppel-associated box (KRAB) transcriptional repression domain to produce an ATF designed to downregulate HBx integrated into the Hep3B HCC cell line. The ATF significantly repressed HBx in a luciferase reporter assay. Stably expressing the ATF in Hep3B cells resulted in significant growth arrest, whereas stably expressing the ATF in an HCC cell line lacking integrated HBx (HepG2) had virtually no effect. The targeted downregulation of integrated HBx is a promising novel approach to inhibiting the progression of HBV infection–related HCC.

Discovery of novel hepatitis B virus (HBV) antivirals and analysis of mechanisms of action of HBV-targeting agents

2017 ◽  
Author(s):  
◽  
Andrew Douglas Huber
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Treatment Options ◽  
Mechanisms Of Action ◽  
Hbv Infection ◽  
Viral Inhibition ◽  
University Of Missouri ◽  
Chronic Hepatitis B Virus ◽  
B Virus

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Chronic hepatitis B virus (HBV) infection leads to liver disease, cirrhosis, and hepatocellular carcinoma. Globally, an estimated 50% of all hepatocellular carcinoma cases are linked to chronic HBV infection. More than 240 million people are chronically infected, and there are 0.5-1 million deaths per year due to HBVrelated liver conditions. HBV treatment options rarely cure infections and are associated with adverse side effects that often outweigh the potential benefits of treatment. New treatments, therefore, are highly desired for HBV therapy. Towards this goal, we have developed novel compounds targeting two viral targets and assessed the mechanisms of action by which these compounds act. We have developed systems for the discovery and evaluation of compounds that inhibit 2 distinct steps in the HBV life cycle. Using these systems, we have developed potent inhibitors of HBV replication that have potential to become clinically used HBV drugs. Furthermore, we have used our methods to evaluate which properties of these compounds are likely to result in better viral inhibition. The work described in this thesis has led to at least 2 new compound groups for potential use as HBV antivirals and provides insight into mechanisms by which potent antivirals can be achieved.

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