scholarly journals ATI-2173, a Novel Liver-Targeted Non-Chain-Terminating Nucleotide for Hepatitis B Virus Cure Regimens

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Katherine E. Squires ◽  
Douglas L. Mayers ◽  
Gregory R. Bluemling ◽  
Alexander A. Kolykhalov ◽  
David B. Guthrie ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Small Subset ◽  
Resistance Mutations ◽  
Skeletal Myopathy ◽  
B Virus ◽  
Inhibitor Resistance ◽  
Hbv Model

ABSTRACT ATI-2173 is a novel liver-targeted molecule designed to deliver the 5′-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5′-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of treatment. However, long-term clevudine treatment was found to exhibit reversible skeletal myopathy in a small subset of patients and was subsequently discontinued from development. ATI-2173 was designed by modifying clevudine with a 5′-phosphoramidate to deliver the 5′-monophosphate to the liver. Bypassing the first phosphorylation step of clevudine, the 5′-monophosphate is converted to the active 5′-triphosphate in the liver. ATI-2173 is a selective inhibitor of HBV with an anti-HBV 50% effective concentration (EC50) of 1.31 nM in primary human hepatocytes, with minimal to no toxicity in hepatocytes, skeletal muscle, liver, kidney, bone marrow, and cardiomyocytes. ATI-2173 activity was decreased by viral polymerase mutations associated with entecavir, lamivudine, and adefovir resistance, but not capsid inhibitor resistance mutations. A single oral dose of ATI-2173 demonstrated 82% hepatic extraction, no food effect, and greatly reduced peripheral exposure of clevudine compared with equimolar oral dosing of clevudine. Despite reduced plasma clevudine exposure, liver concentrations of the 5′-triphosphate were equivalent following ATI-2173 versus clevudine administration. By selectively delivering the 5′-monophosphate to the liver, while retaining the unique anti-HBV activity of the 5′-triphosphate, ATI-2173 may provide an improved pharmacokinetic profile for clinical use, reducing systemic exposure of clevudine and potentially eliminating skeletal myopathy.

scholarly journals Frequency of Hepatitis B Virus Resistance Mutations in Women Using Tenofovir Gel as Pre-Exposure Prophylaxis

Viruses ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 569
Author(s):  
Cheryl Baxter ◽  
Sinaye Ngcapu ◽  
Jason T Blackard ◽  
Eleanor A Powell ◽  
Patricia K Penton ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Systemic Exposure ◽  
Resistance Mutations ◽  
Dosing Regimen ◽  
Hbv Genotype ◽  
B Virus ◽  
Tenofovir Gel ◽  
Exposure Prophylaxis ◽  
The Impact

Intermittent use of a single antiretroviral agent in the presence of a replicating virus could potentially increase the development of antiviral resistance. The pericoital, before-and-after sex, dosing regimen used in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 tenofovir gel trial meant that women who were infected with hepatitis B virus (HBV) were exposed intermittently to tenofovir during their participation. The impact of this dosing regimen on HBV resistance was assessed by amplification of the HBV polymerase region from 37 stored plasma samples of women who were HBV surface antigen positive. All samples belonged to HBV genotype A. None of the known tenofovir resistance mutations (M240V/I, L180M, A194T, V214A, N238T) were identified in any individuals. While it is reassuring that no resistance mutations were found among women using topical tenofovir, the rapidly expanding access to oral tenofovir-containing HIV pre-exposure prophylaxis (PrEP), with higher systemic exposure to the drug, makes monitoring for potential HBV drug resistance important.

scholarly journals Characterization of antiviral resistance mutations among the Eastern Indian Hepatitis B virus infected population

2013 ◽  
Vol 10 (1) ◽  
pp. 56 ◽  
Author(s):  
Rajesh Panigrahi ◽  
Avik Biswas ◽  
Binay Krishna De ◽  
Sekhar Chakrabarti ◽  
Runu Chakravarty
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Antiviral Resistance ◽  
Resistance Mutations ◽  
Infected Population ◽  
B Virus

scholarly journals Coevolution analysis of amino-acids reveals diversified drug-resistance solutions in viral sequences: a case study of hepatitis B virus

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Elin Teppa ◽  
Francesca Nadalin ◽  
Christophe Combet ◽  
Diego Javier Zea ◽  
Laurent David ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Coevolution Analysis ◽  
B Virus ◽  
Compensatory Mutations ◽  
Viral Sequences

Abstract The study of mutational landscapes of viral proteins is fundamental for the understanding of the mechanisms of cross-resistance to drugs and the design of effective therapeutic strategies based on several drugs. Antiviral therapy with nucleos(t)ide analogues targeting the hepatitis B virus (HBV) polymerase protein (Pol) can inhibit disease progression by suppression of HBV replication and makes it an important case study. In HBV, treatment may fail due to the emergence of drug-resistant mutants. Primary and compensatory mutations have been associated with lamivudine resistance, whereas more complex mutational patterns are responsible for resistance to other HBV antiviral drugs. So far, all known drug-resistance mutations are located in one of the four Pol domains, called reverse transcriptase. We demonstrate that sequence covariation identifies drug-resistance mutations in viral sequences. A new algorithmic strategy, BIS2TreeAnalyzer, is designed to apply the coevolution analysis method BIS2, successfully used in the past on small sets of conserved sequences, to large sets of evolutionary related sequences. When applied to HBV, BIS2TreeAnalyzer highlights diversified viral solutions by discovering thirty-seven positions coevolving with residues known to be associated with drug resistance and located on the four Pol domains. These results suggest a sequential mechanism of emergence for some mutational patterns. They reveal complex combinations of positions involved in HBV drug resistance and contribute with new information to the landscape of HBV evolutionary solutions. The computational approach is general and can be applied to other viral sequences when compensatory mutations are presumed.

Hepatitis B virus genotype C encoding resistance mutations that emerge during adefovir dipivoxil therapy: in vitro replication phenotype

2012 ◽  
Vol 7 (2) ◽  
pp. 443-450 ◽  
Author(s):  
Wenpeng Li ◽  
Nadia Warner ◽  
Vitina Sozzi ◽  
Lilly Yuen ◽  
Danni Colledge ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Adefovir Dipivoxil ◽  
Resistance Mutations ◽  
Virus Genotype ◽  
In Vitro Replication ◽  
B Virus ◽  
Genotype C

scholarly journals Use of Massively Parallel Ultradeep Pyrosequencing To Characterize the Genetic Diversity of Hepatitis B Virus in Drug-Resistant and Drug-Naive Patients and To Detect Minor Variants in Reverse Transcriptase and Hepatitis B S Antigen

2008 ◽  
Vol 83 (4) ◽  
pp. 1718-1726 ◽  
Author(s):  
Mariacarmela Solmone ◽  
Donatella Vincenti ◽  
Mattia Carlo Felice Prosperi ◽  
Alessandro Bruselles ◽  
Giuseppe Ippolito ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Reverse Transcriptase ◽  
Direct Sequencing ◽  
Relative Sensitivity ◽  
Massively Parallel ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
B Virus ◽  
Drug Naïve

ABSTRACT Direct population sequencing and reverse hybridization (line probe assay [LiPA])-based methods are the most common methods for detecting hepatitis B virus (HBV) drug resistance mutations, although only mutations present in viral quasispecies with a prevalence of ≥20% can be detected by sequencing, and only known mutations are detected by LiPA. Massively parallel ultradeep pyrosequencing (UDPS; GS FLX platform) was used to analyze HBV quasispecies in reverse transcriptase (RT) and hepatitis B S antigen (HBsAg) from five drug-naive patients and eight drug-resistant patients. Eight primer pairs were used to obtain partially overlapping amplicons, covering the RT gene from codons 1 to 288 and the complete overlapping HBsAg sequence. A 1% mutation frequency was selected as the cutoff based on an error rate estimated on plasmid DNA. This technology enabled simultaneous analysis of between 2,852 and 18,016 clonally amplified fragments from each patient. The results indicate that UDPS has a relative sensitivity much higher than both direct sequencing and LiPA. In addition, the UDPS results are quantitative, allowing establishment of the relative frequency of both known mutations and novel substitutions. Some of the detected RT substitutions led to changes also in HBsAg. On the whole, genotype D presented a higher heterogeneity than genotype A. Considering the high quantity of information that can be provided by a single test from one patient, the short turnaround time, the information on substitution frequency, and the detection of rare variants, there are strong advantages conferred by UDPS, and the new method could play a relevant role in the clinical management of HBV infection and therapy.

scholarly journals Hepatitis B virus genotypes and resistance mutations in patients under long term lamivudine therapy: characterization of genotype G in Brazil

2008 ◽  
Vol 8 (1) ◽  
pp. 11 ◽  
Author(s):  
Marcelle Bottecchia ◽  
Francisco J.D. Souto ◽  
Kycia M.R. O ◽  
Marcia Amendola ◽  
Carlos E Brandao ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Resistance Mutations ◽  
Lamivudine Therapy ◽  
B Virus ◽  
Virus Genotypes

scholarly journals Efficacies of Entecavir against Lamivudine-Resistant Hepatitis B Virus Replication and Recombinant Polymerases In Vitro

2002 ◽  
Vol 46 (8) ◽  
pp. 2525-2532 ◽  
Author(s):  
S. Levine ◽  
D. Hernandez ◽  
G. Yamanaka ◽  
S. Zhang ◽  
R. Rose ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cross Resistance ◽  
Wild Type ◽  
Resistance Mutations ◽  
Hbv Replication ◽  
B Virus ◽  
Inhibition Studies

ABSTRACT Entecavir (ETV) is a potent and selective inhibitor of hepatitis B virus (HBV) replication in vitro and in vivo that is currently in clinical trials for the treatment of chronic HBV infections. A major limitation of the current HBV antiviral therapy, lamivudine (3TC), is the emergence of drug-resistant HBV in a majority of treated patients due to specific mutations in the nucleotide binding site of HBV DNA polymerase (HBV Pol). To determine the effects of 3TC resistance mutations on inhibition by ETV triphosphate (ETV-TP), a series of in vitro studies were performed. The inhibition of wild-type and 3TC-resistant HBV Pol by ETV-TP was measured using recombinant HBV nucleocapsids, and compared to that of 3TC-TP. These enzyme inhibition studies demonstrated that ETV-TP is a highly potent inhibitor of wild-type HBV Pol and is 100- to 300-fold more potent than 3TC-TP against 3TC-resistant HBV Pol. Cell culture assays were used to gauge the potential for antiviral cross-resistance of 3TC-resistant mutants to ETV. Results demonstrated that ETV inhibited the replication of 3TC-resistant HBV, but 20- to 30-fold higher concentrations were required. To gain further perspective regarding the potential therapeutic use of ETV, its phosphorylation was examined in hepatoma cells treated with extracellular concentrations representative of drug levels in plasma in ETV-treated patients. At these concentrations, intracellular ETV-TP accumulated to levels expected to inhibit the enzyme activity of both wild-type and 3TC-resistant HBV Pol. These findings are predictive of potent antiviral activity of ETV against both wild-type and 3TC-resistant HBV.

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