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Article: Mechanism of entecavir resistance of hepatitis B virus with viral breakthrough as determined by long-term clinical assessment and molecular docking simulation
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TitleMechanism of entecavir resistance of hepatitis B virus with viral breakthrough as determined by long-term clinical assessment and molecular docking simulation
 
AuthorsMukaide, M7 2
Tanaka, Y7
ShinI, T7
Yuen, MF6
Kurbanov, F7
Yokosuka, O12
Sata, M5
Karino, Y8
Yamada, G10
Sakaguchi, K1
Orito, E4
Inoue, M9
Baqai, S3
Lai, CL6
Mizokami, M11
 
Issue Date2010
 
PublisherAmerican Society for Microbiology.
 
CitationAntimicrobial Agents And Chemotherapy, 2010, v. 54 n. 2, p. 882-889 [How to Cite?]
DOI: http://dx.doi.org/10.1128/AAC.01061-09
 
AbstractThe mechanism by which entecavir resistance (ETVr) substitutions of hepatitis B virus (HBV) can induce breakthrough (BT) during ETV therapy is largely unknown. We conducted a cross-sectional study of 49 lamivudine (LVD)-refractory patients and 59 naïve patients with chronic hepatitis B. BT was observed in 26.8% of the LVD-refractory group during weeks 60 to 144 of ETV therapy. A line probe assay revealed ETVr substitutions only in the LVD-refractory group, i.e., in 4.9% of patients at baseline, increasing to 14.6%, 24.4%, and 44.8% at weeks 48, 96, and 144, respectively. Multivariate logistic regression analysis adjusted for age, gender, HBV DNA levels, and LVD resistance (LVDr) (L180M and M204V, but not M204I) indicated that T184 substitutions and S202G (not S202C) were a significant factor for BT (adjusted odds ratio [OR], 141.12, and 95% confidence interval [CI], 6.94 to 2,870.20; OR, 201.25, and 95% CI, 11.22 to 3608.65, respectively). Modeling of HBV reverse transcriptase (RT) by docking simulation indicated that a combination of LVDr and ETVr (T184L or S202G) was characterized by a change in the direction of the D205 residue and steric conflict in the binding pocket of ETV triphosphate (ETV-TP), by significantly longer minimal distances (2.2 Å and 2.1 Å), and by higher potential energy (-117 and -99.8 Kcal/mol) for ETV-TP compared with the wild type (1.3 Å; -178 Kcal/mol) and LVDr substitutions (1.5 Å; -141 Kcal/mol). Our data suggest that the low binding affinity of ETV-TP for the HBV RT, involving conformational change of the binding pocket of HBV RT by L180M, M204V plus T184L, and S202G, could induce BT. Copyright © 2010, American Society for Microbiology. All Rights Reserved.
 
ISSN0066-4804
2012 Impact Factor: 4.565
2012 SCImago Journal Rankings: 1.963
 
DOIhttp://dx.doi.org/10.1128/AAC.01061-09
 
PubMed Central IDPMC2812155
 
ISI Accession Number IDWOS:000273860600041
Funding AgencyGrant Number
Ministry of Health, Labor, and Welfare of Japan
Ministry of Education, Culture, Sports, and Science
Funding Information:

This work was supported in part by a grant-in-aid from the Ministry of Health, Labor, and Welfare of Japan and a grant-in-aid from the Ministry of Education, Culture, Sports, and Science. We thank Kenichi Fukai, Graduate School of Medicine, Chiba University, Chiba, Japan; Tatsuya Ide, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan; Debbie Hana Yi, Department of Emergency Medicine, New York-Presbyterian Hospital Columbia/Cornell, New York, NY; and Robert G. Gish, California Pacific Medical Center, San Francisco, CA, for their help throughout this work.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorMukaide, M
 
dc.contributor.authorTanaka, Y
 
dc.contributor.authorShinI, T
 
dc.contributor.authorYuen, MF
 
dc.contributor.authorKurbanov, F
 
dc.contributor.authorYokosuka, O
 
dc.contributor.authorSata, M
 
dc.contributor.authorKarino, Y
 
dc.contributor.authorYamada, G
 
dc.contributor.authorSakaguchi, K
 
dc.contributor.authorOrito, E
 
dc.contributor.authorInoue, M
 
dc.contributor.authorBaqai, S
 
dc.contributor.authorLai, CL
 
dc.contributor.authorMizokami, M
 
dc.date.accessioned2011-08-18T08:43:49Z
 
dc.date.available2011-08-18T08:43:49Z
 
dc.date.issued2010
 
dc.description.abstractThe mechanism by which entecavir resistance (ETVr) substitutions of hepatitis B virus (HBV) can induce breakthrough (BT) during ETV therapy is largely unknown. We conducted a cross-sectional study of 49 lamivudine (LVD)-refractory patients and 59 naïve patients with chronic hepatitis B. BT was observed in 26.8% of the LVD-refractory group during weeks 60 to 144 of ETV therapy. A line probe assay revealed ETVr substitutions only in the LVD-refractory group, i.e., in 4.9% of patients at baseline, increasing to 14.6%, 24.4%, and 44.8% at weeks 48, 96, and 144, respectively. Multivariate logistic regression analysis adjusted for age, gender, HBV DNA levels, and LVD resistance (LVDr) (L180M and M204V, but not M204I) indicated that T184 substitutions and S202G (not S202C) were a significant factor for BT (adjusted odds ratio [OR], 141.12, and 95% confidence interval [CI], 6.94 to 2,870.20; OR, 201.25, and 95% CI, 11.22 to 3608.65, respectively). Modeling of HBV reverse transcriptase (RT) by docking simulation indicated that a combination of LVDr and ETVr (T184L or S202G) was characterized by a change in the direction of the D205 residue and steric conflict in the binding pocket of ETV triphosphate (ETV-TP), by significantly longer minimal distances (2.2 Å and 2.1 Å), and by higher potential energy (-117 and -99.8 Kcal/mol) for ETV-TP compared with the wild type (1.3 Å; -178 Kcal/mol) and LVDr substitutions (1.5 Å; -141 Kcal/mol). Our data suggest that the low binding affinity of ETV-TP for the HBV RT, involving conformational change of the binding pocket of HBV RT by L180M, M204V plus T184L, and S202G, could induce BT. Copyright © 2010, American Society for Microbiology. All Rights Reserved.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationAntimicrobial Agents And Chemotherapy, 2010, v. 54 n. 2, p. 882-889 [How to Cite?]
DOI: http://dx.doi.org/10.1128/AAC.01061-09
 
dc.identifier.doihttp://dx.doi.org/10.1128/AAC.01061-09
 
dc.identifier.epage889
 
dc.identifier.hkuros174328
 
dc.identifier.isiWOS:000273860600041
Funding AgencyGrant Number
Ministry of Health, Labor, and Welfare of Japan
Ministry of Education, Culture, Sports, and Science
Funding Information:

This work was supported in part by a grant-in-aid from the Ministry of Health, Labor, and Welfare of Japan and a grant-in-aid from the Ministry of Education, Culture, Sports, and Science. We thank Kenichi Fukai, Graduate School of Medicine, Chiba University, Chiba, Japan; Tatsuya Ide, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan; Debbie Hana Yi, Department of Emergency Medicine, New York-Presbyterian Hospital Columbia/Cornell, New York, NY; and Robert G. Gish, California Pacific Medical Center, San Francisco, CA, for their help throughout this work.

 
dc.identifier.issn0066-4804
2012 Impact Factor: 4.565
2012 SCImago Journal Rankings: 1.963
 
dc.identifier.issue2
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC2812155
 
dc.identifier.pmid19933798
 
dc.identifier.scopuseid_2-s2.0-75749138479
 
dc.identifier.spage882
 
dc.identifier.urihttp://hdl.handle.net/10722/137117
 
dc.identifier.volume54
 
dc.languageeng
 
dc.publisherAmerican Society for Microbiology.
 
dc.publisher.placeUnited States
 
dc.relation.ispartofAntimicrobial Agents and Chemotherapy
 
dc.relation.referencesReferences in Scopus
 
dc.rightsAntimicrobial Agents and Chemotherapy. Copyright © American Society for Microbiology.
 
dc.subject.meshAdult
 
dc.subject.meshAntiviral Agents - pharmacology - therapeutic use
 
dc.subject.meshDrug Resistance, Viral - genetics
 
dc.subject.meshGuanine - analogs and derivatives - pharmacology - therapeutic use
 
dc.subject.meshHepatitis B virus - drug effects - genetics - physiology
 
dc.titleMechanism of entecavir resistance of hepatitis B virus with viral breakthrough as determined by long-term clinical assessment and molecular docking simulation
 
dc.typeArticle
 
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Author Affiliations
  1. Okayama University Medical School
  2. SRL, Inc.
  3. Alameda County Medical Center
  4. Nagoya Daini Red Cross Hospital
  5. Kurume University School of Medicine
  6. The University of Hong Kong
  7. Nagoya City University Graduate School of Medical Sciences
  8. Sapporo Kosei Hospital
  9. National Cancer Center Tokyo
  10. Kawasaki Medical College
  11. Japan Konodai Hospital
  12. Chiba University