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Conference Paper: Three-year assessment of entecavir resistance in chronic hepatitis B patients and the mechanism of viral breakthrough by the resistance substitutions

TitleThree-year assessment of entecavir resistance in chronic hepatitis B patients and the mechanism of viral breakthrough by the resistance substitutions
Authors
Issue Date2008
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
Citation
The 59th Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, CA, 31 October - 4 November 2008. In Hepatology, 2008, v. 48 n. Suppl 1, p. 728A-729A How to Cite?
AbstractBackground/Aim: Persistence of lamivudine-resistance (LVDr)mutations in chronic hepatitis B patients who switched to ente-cavir (ETV) is worrisome because LVDr was shown to enhancethe risk of development of the ETV-resistance (ETVr). To assessfrequency of ETVr and the specific substitutions associated with viral breakthrough (BT) during 3-years ETV therapy and exam-ine the mechanism of the BT on the basis of molecular dockingsimulation study using the hepatitis B virus (HBV) polymerasemodel. Methods: One-hundred patients with chronic hepatitis B(45 from Japan, 25 USA, 30 Hong Kong) including 41 LVD-refractory patients and 59 naïve patients were enrolled. Drugresistant substitutions (T184SCGA/ILFM, 184ILFM, S202G,S202C) were assessed by recently developed INNO-LiPA ETVTDF (v3) add-on DR v2 assays. To examine the mechanism ofpossible involvement of the mutations in the drug resistance,three-dimensional (3D) homology for the HBV-RT domain wasmodeled, based on HIV-RT-DNA structure, demonstrating tenta-tive action of ETV against HBV-RT. Results: In 41 LVD-refractorypatients, the ETVr substitutions were present in 2 (cumulativeprevalence: 4.9%) cases at baseline and emerged in 6(14.6%), 10 (24.4%) and 13 (44.8%) cases at weeks 48, 96,and 144, respectively. There was no evidence of ETVr substitu-tions in naïve patients during the 144 weeks period. Eleven(26.8%) of 41 LVD-refractory patients treated with ETV devel-oped BT within 60 to 144 weeks of the therapy. The ETVr sub-stitutions (T184SCGA/ILFM or S202G) were associated withBT (adjusted Odds Ratio [OR] 141.12, 95%CI 6.94-2870.20;OR 201.25, 95%CI 11.22-3608.65, respectively) as revealedby multivariate logistic regression model analysis of the cohortsadjusted by age, gender, “2 log reduction of HBV DNA at 1year” and presence of LVDr (L180M and/or M204V). Molecu-lar docking simulation showed that the triple amino acid sub-stitutions (L180M, M204V, S202G or T184L) within HBV-RTinhibited ETV binding by altering the affinity of the tentativeattachment site (demonstrated by increase in the minimal dis-tance between ETV and the binding site, from 1.28 to 2.23angstrom, and decrease in binding potential from -97 to -86Kcal/mol). Conclusions: INNO-LiPA is useful for early detectionof ETVr. The molecular docking simulation suggested that theETVr could account for the resistance phenotype to ETV in vivo.High and long-term efficacy of ETV was demonstrated in naïvepatients, whereas ADV add-on LVD should be considered as afirst-, or second-line treatment option for LVD-refractory patientsdue to high risk of BT during ETV treatment.
Persistent Identifierhttp://hdl.handle.net/10722/62403
ISSN
2014 Impact Factor: 11.055
2014 SCImago Journal Rankings: 4.310

 

DC FieldValueLanguage
dc.contributor.authorTanaka, Y-
dc.contributor.authorMukaide, M-
dc.contributor.authorYuen, RMF-
dc.contributor.authorShin, IT-
dc.contributor.authorOrito, E-
dc.contributor.authorKurbanov, F-
dc.contributor.authorFukai, K-
dc.contributor.authorYokosuka, O-
dc.contributor.authorSata, M-
dc.contributor.authorIde, T-
dc.contributor.authorKarino, Y-
dc.contributor.authorYamada, G-
dc.contributor.authorSakaguchi, K-
dc.contributor.authorInoue, M-
dc.contributor.authorGish, RG-
dc.contributor.authorLai, CL-
dc.contributor.authorMizokami, M-
dc.date.accessioned2010-07-13T04:00:30Z-
dc.date.available2010-07-13T04:00:30Z-
dc.date.issued2008-
dc.identifier.citationThe 59th Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, CA, 31 October - 4 November 2008. In Hepatology, 2008, v. 48 n. Suppl 1, p. 728A-729A-
dc.identifier.issn0270-9139-
dc.identifier.urihttp://hdl.handle.net/10722/62403-
dc.description.abstractBackground/Aim: Persistence of lamivudine-resistance (LVDr)mutations in chronic hepatitis B patients who switched to ente-cavir (ETV) is worrisome because LVDr was shown to enhancethe risk of development of the ETV-resistance (ETVr). To assessfrequency of ETVr and the specific substitutions associated with viral breakthrough (BT) during 3-years ETV therapy and exam-ine the mechanism of the BT on the basis of molecular dockingsimulation study using the hepatitis B virus (HBV) polymerasemodel. Methods: One-hundred patients with chronic hepatitis B(45 from Japan, 25 USA, 30 Hong Kong) including 41 LVD-refractory patients and 59 naïve patients were enrolled. Drugresistant substitutions (T184SCGA/ILFM, 184ILFM, S202G,S202C) were assessed by recently developed INNO-LiPA ETVTDF (v3) add-on DR v2 assays. To examine the mechanism ofpossible involvement of the mutations in the drug resistance,three-dimensional (3D) homology for the HBV-RT domain wasmodeled, based on HIV-RT-DNA structure, demonstrating tenta-tive action of ETV against HBV-RT. Results: In 41 LVD-refractorypatients, the ETVr substitutions were present in 2 (cumulativeprevalence: 4.9%) cases at baseline and emerged in 6(14.6%), 10 (24.4%) and 13 (44.8%) cases at weeks 48, 96,and 144, respectively. There was no evidence of ETVr substitu-tions in naïve patients during the 144 weeks period. Eleven(26.8%) of 41 LVD-refractory patients treated with ETV devel-oped BT within 60 to 144 weeks of the therapy. The ETVr sub-stitutions (T184SCGA/ILFM or S202G) were associated withBT (adjusted Odds Ratio [OR] 141.12, 95%CI 6.94-2870.20;OR 201.25, 95%CI 11.22-3608.65, respectively) as revealedby multivariate logistic regression model analysis of the cohortsadjusted by age, gender, “2 log reduction of HBV DNA at 1year” and presence of LVDr (L180M and/or M204V). Molecu-lar docking simulation showed that the triple amino acid sub-stitutions (L180M, M204V, S202G or T184L) within HBV-RTinhibited ETV binding by altering the affinity of the tentativeattachment site (demonstrated by increase in the minimal dis-tance between ETV and the binding site, from 1.28 to 2.23angstrom, and decrease in binding potential from -97 to -86Kcal/mol). Conclusions: INNO-LiPA is useful for early detectionof ETVr. The molecular docking simulation suggested that theETVr could account for the resistance phenotype to ETV in vivo.High and long-term efficacy of ETV was demonstrated in naïvepatients, whereas ADV add-on LVD should be considered as afirst-, or second-line treatment option for LVD-refractory patientsdue to high risk of BT during ETV treatment.-
dc.languageeng-
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/-
dc.relation.ispartofHepatology-
dc.rightsHepatology. Copyright © John Wiley & Sons, Inc.-
dc.rightsSpecial Statement for Preprint only Before publication: 'This is a preprint of an article accepted for publication in [The Journal of Pathology] Copyright © ([year]) ([Pathological Society of Great Britain and Ireland])'. After publication: the preprint notice should be amended to follows: 'This is a preprint of an article published in [include the complete citation information for the final version of the Contribution as published in the print edition of the Journal]' For Cochrane Library/ Cochrane Database of Systematic Reviews, add statement & acknowledgement : ‘This review is published as a Cochrane Review in the Cochrane Database of Systematic Reviews 20XX, Issue X. Cochrane Reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the Review.’ Please include reference to the Review and hyperlink to the original version using the following format e.g. Authors. Title of Review. Cochrane Database of Systematic Reviews 20XX, Issue #. Art. No.: CD00XXXX. DOI: 10.1002/14651858.CD00XXXX (insert persistent link to the article by using the URL: http://dx.doi.org/10.1002/14651858.CD00XXXX) (This statement should refer to the most recent issue of the Cochrane Database of Systematic Reviews in which the Review published.)-
dc.titleThree-year assessment of entecavir resistance in chronic hepatitis B patients and the mechanism of viral breakthrough by the resistance substitutions-
dc.typeConference_Paper-
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0270-9139&volume=48&issue=Suppl 1&spage=728A&epage=&date=2008&atitle=Three-year+assessment+of+entecavir+resistance+in+chronic+hepatitis+B+patients+and+the+mechanism+of+viral+breakthrough+by+the+resistance+substitutionsen_HK
dc.identifier.emailYuen, RMF: mfyuen@hkucc.hku.hk-
dc.identifier.emailLai, CL: hrmelcl@hku.hk-
dc.identifier.authorityYuen, RMF=rp00479-
dc.identifier.authorityLai, CL=rp00314-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/hep.22644-
dc.identifier.hkuros161369-
dc.identifier.volume48-
dc.identifier.issueSuppl 1-
dc.identifier.spage728A-
dc.identifier.epage729A-
dc.publisher.placeUnited States-

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