FRI-217-Safety, antiviral activity, and pharmacokinetics of a novel hepatitis B virus capsid assembly modulator, JNJ-, in Asian and non-Asian patients with chronic hepatitis B

2019 ◽  
Vol 70 (1) ◽  
pp. e489-e490 ◽  
Author(s):  
Jeysen Yogaratnam ◽  
Fabien Zoulim ◽  
Joris Vandenbossche ◽  
Oliver Lenz ◽  
Willem Talloen ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Antiviral Activity ◽  
Chronic Hepatitis B ◽  
Capsid Assembly ◽  
Virus Capsid ◽  
Asian Patients ◽  
B Virus

scholarly journals Hepatitis B virus and site-specific nucleases: effects of genetic modifications in CRISPR/Cas9 on antiviral activity

2019 ◽  
Vol 9 (2) ◽  
pp. 279-287
Author(s):  
A. P. Kostyusheva ◽  
S. A. Brezgin ◽  
D. N. Zarifyan ◽  
D. S. Chistyakov ◽  
V. I. Gegechkory ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Antiviral Activity ◽  
Viral Replication ◽  
Chronic Hepatitis B ◽  
Viral Genome ◽  
Site Specific ◽  
Guide Rnas ◽  
B Virus

Chronic hepatitis B is a severe liver disease caused by persistent infection of hepatitis B virus in human hepatocytes. Chronic hepatitis B is one of the most common diseases in the world. According to recent estimations, more than 250 million people are chronically infected and more than 1 million of people die annually due to consequences of chronic hepatitis B: liver cirrhosis and hepatocellular carcinoma. The key factor of hepatitis B virus persistency is a special form of viral genome called circular covalently closed DNA. Current therapeutics suppress viral replication but have no effect on circular covalently closed DNA as it exists in the nuclei of hepatocytes as a minichromosome and is not accessible for therapeutics. Commonly, viral reactivation occurs after cessation of treatment. Therefore, duration of antiviral treatment is supposed to be indefinitely long. One of the most promising approaches to target circular covalently closed DNA is the technology of site-specific nucleases CRISPR/Cas9 from Streptococcus pyogenes. A short guide RNA recruits an SpCas9 protein to the viral genome and induces generation of DNA double strand breaks. However, there are several limitations of CRISPR/Cas9 hampering translation of this technology into the clinic. First, efficacy of CRISPR/Cas9 needs to be improved. Second, CRISPR/Cas9-mediated off-target mutagenesis represents a menacing problem which has to be addressed. To overcome these limitations, several approaches have been devised to improve CRISPR/Cas9 activity (modification of guide RNAs) and reduce off-target mutagenesis (a Cas9 protein with enhanced specificity, eSpCas9). In this study, we compared antiviral activity of a classic SpCas9 with an eSpCas9 system as well as analyzed effects of gRNAs modification on anti-HBV effects. Here, we demonstrated that SpCas9 has the highest antiviral potency, reducing transcription and replication of HBV over 90%. Hepatitis B virus covalently closed circular DNA declined over 90% post CRISPR/Cas9 transfection. Although it was previously shown that modified guide RNAs increase nucleolytic activity of CRISPR/Cas9, our results indicated that this modification impairs antiviral activity of CRISPR/Cas9. To conclude, CRISPR/Cas9 effectively suppress viral replication and transcription per se. Described modifications do not potentiate antiviral activity of CRISPR/Cas9 system and should not be used for development of future therapeutics. The best strategy to improve CRISPR/Cas9 efficacy is to design new highly effective guide RNAs. 

Pharmacokinetics, safety and tolerability of single- and multiple-ascending doses of JNJ-64530440, a novel hepatitis B virus capsid assembly modulator, in healthy volunteers

2021 ◽  
pp. 135965352110443
Author(s):  
Thomas N Kakuda ◽  
Jeysen Z Yogaratnam ◽  
Christopher Westland ◽  
Edward J Gane ◽  
Christian Schwabe ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Antiviral Activity ◽  
Healthy Volunteers ◽  
Second Generation ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Capsid Assembly ◽  
Virus Capsid ◽  
B Virus

Background Pharmacokinetics and safety of JNJ-64530440, a hepatitis B virus capsid assembly modulator producing normal empty capsids (CAM-N), in healthy volunteers were evaluated. Methods This Phase I study (NCT03439488) was a double-blind, randomised, placebo-controlled study. Adults ( n = 10/cohort, five Asian/five non-Asian), randomised 4:1, received single-ascending doses of oral JNJ-64530440 (first- and second-generation formulations) or placebo under fasted (50, 150, 300 and 900 mg) or fed (300, 750, 1,000, 2000 and 4000 mg) conditions. Multiple-ascending doses of 750 or 2000 mg once daily and 750 mg twice daily JNJ-64530440 (second-generation formulation) for 7 days were evaluated. Pharmacokinetic parameters were estimated from plasma concentrations. Safety was assessed throughout. Results Less than dose-proportional increases in maximum plasma concentrations (Cmax) and area under the plasma concentration–time curves (AUCs) were observed across the doses. Mean plasma half-lives ranged from 9.3 to 14.5 h. Cmax and AUC were ∼two fold higher under fed versus fasting conditions and slightly higher in Asians versus Caucasians. JNJ-64530440 doses ≥750 mg achieved plasma levels higher than protein-binding adjusted concentrations demonstrating in vitro antiviral activity. No serious adverse events (AEs), treatment discontinuations or dose-limiting toxicities were seen. AE frequency/severity did not increase with dose. Conclusions Single (up to 4000 mg) and multiple doses (up to 2000 mg for 7 days) of JNJ-64530440 were well tolerated in healthy volunteers. Multiple doses ≥750 mg/day achieved plasma concentrations expected to have antiviral activity that may lower hepatitis B surface antigen. No clinically relevant differences in tolerability or pharmacokinetic parameters were seen between Asians versus Caucasians.

Detection of Hepatitis B Genotypes in HBsAg & HBeAg Carriers

2018 ◽  
Vol 7 (5) ◽  
Author(s):  
Salman Khan ◽  
Molly Madan
Keyword(s):  
Chronic Hepatitis ◽  
Viral Load ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Central Research ◽  
Elisa Kit ◽  
B Virus ◽  
Negative Chronic Hepatitis ◽  
Genotype A

Objective:- Hepatitis B is noteworthy medical issues that may include the late continuation of liver cirrhosis and hepatocellular carcinoma. The present study aimed for the detection and diffrentiation of Hepatitis B virus HBsAg inactive non-replicative carriers, HBeAg-positive inactive replicative carriers, active carriers & HBeAg-negative chronic hepatitis B by Real Time PCR and their genotyping Methods: This research conducted on 245 positive for HBsAg, 118 (48.16 %) were male and 127 (51.84%) were female patients, which was performed in central research station labortory of Microbiology at netaji subhash Chandra Bose subharti Medical College and Hospital, Meerut Between march 2016 to November 2017 The sera were separated and screened for HBsAg by ELISA kit. Positive samples for HBsAg were tested for HBeAg ELISA kit and DNA Viral load then sequenced for genotying Results:. Of the 245 HBsAg Positive case 55 (1.12%) were HBeAg positive. In 16 PCR positive and HBV genotyping, In HBsAg inactive Non-Replicative 37.5% (n=6) genotype-B and 6.25% (n=1) genotype-A, In HBeAg inactive Replicative 12.5% (n=2) genotype-B and 12.5% (n=2) genotype-A and In HBeAg Active Chronic Hepatitis B 18.75% (n=3) genotype-B and 12.5% (n=2) genotype-A were detected Conclusions: Management strategy, using HBsAg, HBeAg and HBV DNA viral load, seems adequate for the confirmation and diffrentiation of Hepatitis B virus inactive, active carriers & HBeAg-negative chronic hepatitis B patients and genotype B was more prevalent in comparission to genotype A. Distribution of carriers & genotypes, help physicians to prescribe proper antiviral/interferon therapy according to current genotyping pattern in this region Keywords: Hepatitis B virus, Carrier State, HBsAg, HBeAg, RT-PCR

scholarly journals rtE218G, a novel hepatitis B virus mutation with resistance to adefovir dipivoxil in patients with chronic hepatitis B

2010 ◽  
Vol 17 ◽  
pp. 66-72 ◽  
Author(s):  
L. J. Liu ◽  
J. H. Wang ◽  
S. C. Du ◽  
J. H. Tian ◽  
R. F. Yang ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Adefovir Dipivoxil ◽  
B Virus
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