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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

TitleMechanism of entecavir resistance of hepatitis B virus with viral breakthrough as determined by long-term clinical assessment and molecular docking simulation
Authors
Issue Date2010
PublisherAmerican Society for Microbiology.
Citation
Antimicrobial Agents And Chemotherapy, 2010, v. 54 n. 2, p. 882-889 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/137117
ISSN
2014 Impact Factor: 4.476
2014 SCImago Journal Rankings: 2.005
PubMed Central ID
ISI Accession Number ID
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.

References

 

DC FieldValueLanguage
dc.contributor.authorMukaide, Men_HK
dc.contributor.authorTanaka, Yen_HK
dc.contributor.authorShinI, Ten_HK
dc.contributor.authorYuen, MFen_HK
dc.contributor.authorKurbanov, Fen_HK
dc.contributor.authorYokosuka, Oen_HK
dc.contributor.authorSata, Men_HK
dc.contributor.authorKarino, Yen_HK
dc.contributor.authorYamada, Gen_HK
dc.contributor.authorSakaguchi, Ken_HK
dc.contributor.authorOrito, Een_HK
dc.contributor.authorInoue, Men_HK
dc.contributor.authorBaqai, Sen_HK
dc.contributor.authorLai, CLen_HK
dc.contributor.authorMizokami, Men_HK
dc.date.accessioned2011-08-18T08:43:49Z-
dc.date.available2011-08-18T08:43:49Z-
dc.date.issued2010en_HK
dc.identifier.citationAntimicrobial Agents And Chemotherapy, 2010, v. 54 n. 2, p. 882-889en_HK
dc.identifier.issn0066-4804en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137117-
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.en_HK
dc.languageeng-
dc.publisherAmerican Society for Microbiology.-
dc.relation.ispartofAntimicrobial Agents and Chemotherapyen_HK
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 simulationen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0066-4804&volume=54&issue=2&spage=882&epage=889&date=2009&atitle=Mechanism+of+entecavir+resistance+of+hepatitis+B+virus+with+viral+breakthrough+as+determined+by+long-term+clinical+assessment+and+molecular+docking+simulation-
dc.identifier.emailYuen, MF:mfyuen@hkucc.hku.hken_HK
dc.identifier.emailLai, CL:hrmelcl@hku.hken_HK
dc.identifier.authorityYuen, MF=rp00479en_HK
dc.identifier.authorityLai, CL=rp00314en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1128/AAC.01061-09en_HK
dc.identifier.pmid19933798en_HK
dc.identifier.pmcidPMC2812155-
dc.identifier.scopuseid_2-s2.0-75749138479en_HK
dc.identifier.hkuros174328-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-75749138479&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume54en_HK
dc.identifier.issue2en_HK
dc.identifier.spage882en_HK
dc.identifier.epage889en_HK
dc.identifier.isiWOS:000273860600041-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridMukaide, M=6701669224en_HK
dc.identifier.scopusauthoridTanaka, Y=35235708000en_HK
dc.identifier.scopusauthoridShinI, T=6602524170en_HK
dc.identifier.scopusauthoridYuen, MF=7102031955en_HK
dc.identifier.scopusauthoridKurbanov, F=7003649588en_HK
dc.identifier.scopusauthoridYokosuka, O=7103382578en_HK
dc.identifier.scopusauthoridSata, M=35355942700en_HK
dc.identifier.scopusauthoridKarino, Y=7003525051en_HK
dc.identifier.scopusauthoridYamada, G=35351929600en_HK
dc.identifier.scopusauthoridSakaguchi, K=35412434400en_HK
dc.identifier.scopusauthoridOrito, E=7006161634en_HK
dc.identifier.scopusauthoridInoue, M=8889234100en_HK
dc.identifier.scopusauthoridBaqai, S=36670818500en_HK
dc.identifier.scopusauthoridLai, CL=7403086396en_HK
dc.identifier.scopusauthoridMizokami, M=7103318255en_HK

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