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Entecavir-resistant hepatitis B virus decreases surface antigenicity: A full genome and functional characterization.

Published on Mar 25, 2020in Liver International5.542
· DOI :10.1111/LIV.14446
Soree Park8
Estimated H-index: 8
(Konkuk University),
Eun-Sook Park11
Estimated H-index: 11
(Konkuk University)
+ 9 AuthorsJeong-Hoon Lee24
Estimated H-index: 24
(SNU: Seoul National University)
Abstract
BACKGROUND & AIM: Since polymerase and surface genes overlap in hepatitis B virus (HBV), an antiviral-induced mutation in the polymerase gene may alter the surface antigenicity in patients with chronic hepatitis B (CHB), but this possibility has not been clearly confirmed. This study aimed to determine the drug susceptibility and surface antigenicity of the patient-derived mutants. PATIENTS AND METHODS: Full-length HBV genomes isolated from four entecavir-resistant CHB patients were cloned and sequenced. Around 10 clones of full-length HBV obtained from each patient were analyzed and registered in the NCBI GenBank. Representative clones were further characterized by in vitro drug susceptibility and surface antigenicity assays. RESULTS: The rtL180M+rtM204V mutations were common among all the clones analyzed. Additionally, the ETV-resistance mutations rtT184A/L, rtS202G, and rtM250V were found among three patients. Most of the ETV-resistant mutants had amino acid alterations within the known epitopes recognized by T- and B-cells in the HBV surface and core antigens. The in vitro drug susceptibility assay showed that all tested clones were resistant to ETV treatment. However, they were all susceptible to ADV and TDF. More importantly, the rtI169T mutation in the RT domain, led to the sF161L mutation in the overlapping S gene, which decreased in surface antigenicity. CONCLUSIONS: The ETV-resistance mutations can affect the antigenicity of the HBsAg proteins due to changes in the overlapping sequence of this surface antigen. Thus, the apparent decline or disappearance of HBsAg needs to be interpreted cautiously in patients with previous or current antiviral-resistance mutations.
  • References (46)
  • Citations (1)
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References46
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#1Eun-Sook Park (Konkuk University)H-Index: 11
#2Ah Ram Lee (Konkuk University)H-Index: 7
Last. Kyun-Hwan Kim (Konkuk University)H-Index: 22
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Background & Aims Tenofovir disoproxil fumarate (TDF) is one the most potent nucleot(s)ide analogues for treating chronic hepatitis B virus (HBV) infection. Phenotypic resistance caused by genotypic resistance to TDF has not been reported. This study aimed to characterize HBV mutations that confer tenofovir resistance. Methods Two patients with viral breakthrough during treatment with TDF-containing regimens were prospectively enrolled. The gene encoding HBV reverse transcriptase was sequenced. ...
5 CitationsSource
#1Mehrangiz Dezhbord (Yonsei University)H-Index: 2
#2Soo Young Lee (Yonsei University)H-Index: 22
Last. Wang-Shick Ryu (Yonsei University)H-Index: 19
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Abstract Despite the utmost importance of cccDNA in HBV biology, the mechanism by which cccDNA synthesis is regulated is not completely understood. Here we explored HepG2-NTCP cell line and performed a time-course HBV infection experiment (up to 30 days) to follow the conversion of the input viral DNA into cccDNA. We found that a protein-free RC DNA (PF-RC DNA) become detectable as early as 12 h post infection (hpi) prior to the detection of cccDNA, which become evident only at 2–3 dpi. Intrigui...
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: The clinical practice guideline for the management of chronic hepatitis B (CHB) was originally enacted in 2004 by the Korean Association for the Study of the Liver in order to provide medical practitioners with specific medical information regarding CHB to help them facilitate their understanding of the disease and treatment of the infected patients. Other than an update on the treatment of antiviral resistance in 2014, which is a partial revision, the guidelines for the treatment of chronic h...
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#2Anna S.F. LokH-Index: 44
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#1Pietro LamperticoH-Index: 43
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Summary Hepatitis B virus (HBV) infection remains a global public health problem with changing epidemiology due to several factors including vaccination policies and migration. This Clinical Practice Guideline presents updated recommendations for the optimal management of HBV infection. Chronic HBV infection can be classified into five phases: (I) HBeAg-positive chronic infection, (II) HBeAg-positive chronic hepatitis, (III) HBeAg-negative chronic infection, (IV) HBeAg-negative chronic hepatitis...
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Summary Background Entecavir (ETV) and tenofovir disoproxil fumarat (TDF) are the two first-line therapies recommended in the treatment of chronic hepatitis B because of having potent antiviral effect and high genetic barriers against resistance. We aimed to compare efficacy of these drugs and to evaluate predictors of viral suppression. Methods This multicenter retrospective study was conducted in nucleos(t)ide analogue-naive chronic hepatitis B (CHB) patients from different 6 centers. Results ...
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#1Md. Golzar Hossain (Osaka University)H-Index: 4
#2Keiji Ueda (Osaka University)H-Index: 23
Mutation in the hepatitis B virus surface antigen (HBsAg) may affect the efficiency of diagnostic immunoassays or success of vaccinations using HBsAg. Thus, antigenicity and immunogenicity analyses of the mutated HBsAg are necessary to develop novel diagnostic tools and efficient vaccinations. Here, the in vitro antigenicity of three wild-type HBsAg open reading frames (ORFs) (adr4, W1S [subtype adr] and W3S [subtype adr]) isolated from clinically infected patients and nineteen synthesized singl...
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#1Menglin ShanH-Index: 1
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BACKGROUND: Drug-resistant HBV mutants frequently arise during nucleoside/nucleotide analogue (NA) therapy, while the resistance mutations on polymerase also have consequent changes in the S protein. The enrichment of immune-escape mutations was negatively correlated with hepatitis B surface antigen (HBsAg) clearance under NA therapy. This study aims to characterize the variability of HBV polymerase and surface antigen in patients with virological breakthrough under NA therapy. METHODS: From 201...
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#1Doo Hyun KimH-Index: 9
#2Hong Seok KangH-Index: 8
Last. Kyun-Hwan KimH-Index: 22
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Approximately 350 million people are estimated to be persistently infected with hepatitis B virus (HBV) worldwide. HBV maintains persistent infection by employing covalently closed circular DNA (cccDNA), a template for all HBV RNAs. Chronic hepatitis B (CHB) patients are currently treated with nucleos(t)ide analogs such as lamivudine, adefovir, entecavir, and tenofovir. However, these treatments rarely cure CHB because they are unable to inhibit cccDNA transcription and inhibit only a late stage...
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