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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- Publisher Website: 10.1128/AAC.01061-09
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| Title | Mechanism of entecavir resistance of hepatitis B virus with viral breakthrough as determined by long-term clinical assessment and molecular docking simulation | ||||||
|---|---|---|---|---|---|---|---|
| Authors | Mukaide, M2 7 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 Date | 2010 | ||||||
| Publisher | American Society for Microbiology. | ||||||
| Citation | Antimicrobial Agents And Chemotherapy, 2010, v. 54 n. 2, p. 882-889 [How to Cite?] DOI: http://dx.doi.org/10.1128/AAC.01061-09 | ||||||
| Abstract | The 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. | ||||||
| ISSN | 0066-4804 2011 Impact Factor: 4.841 2011 SCImago Journal Rankings: 0.486 | ||||||
| DOI | http://dx.doi.org/10.1128/AAC.01061-09 | ||||||
| ISI Accession Number ID | WOS:000273860600041
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. | ||||||
| PubMed Central ID | PMC2812155 | ||||||
| References | References in Scopus |
| dc.contributor.author | Mukaide, M | ||||||
|---|---|---|---|---|---|---|---|
| dc.contributor.author | Tanaka, Y | ||||||
| dc.contributor.author | ShinI, T | ||||||
| dc.contributor.author | Yuen, MF | ||||||
| dc.contributor.author | Kurbanov, F | ||||||
| dc.contributor.author | Yokosuka, O | ||||||
| dc.contributor.author | Sata, M | ||||||
| dc.contributor.author | Karino, Y | ||||||
| dc.contributor.author | Yamada, G | ||||||
| dc.contributor.author | Sakaguchi, K | ||||||
| dc.contributor.author | Orito, E | ||||||
| dc.contributor.author | Inoue, M | ||||||
| dc.contributor.author | Baqai, S | ||||||
| dc.contributor.author | Lai, CL | ||||||
| dc.contributor.author | Mizokami, M | ||||||
| dc.date.accessioned | 2011-08-18T08:43:49Z | ||||||
| dc.date.available | 2011-08-18T08:43:49Z | ||||||
| dc.date.issued | 2010 | ||||||
| dc.description.abstract | The 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.nature | Link_to_subscribed_fulltext | ||||||
| dc.identifier.citation | Antimicrobial 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.doi | http://dx.doi.org/10.1128/AAC.01061-09 | ||||||
| dc.identifier.epage | 889 | ||||||
| dc.identifier.hkuros | 174328 | ||||||
| dc.identifier.isi | WOS:000273860600041
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.issn | 0066-4804 2011 Impact Factor: 4.841 2011 SCImago Journal Rankings: 0.486 | ||||||
| dc.identifier.issue | 2 | ||||||
| dc.identifier.openurl | | ||||||
| dc.identifier.pmcid | PMC2812155 | ||||||
| dc.identifier.pmid | 19933798 | ||||||
| dc.identifier.scopus | eid_2-s2.0-75749138479 | ||||||
| dc.identifier.spage | 882 | ||||||
| dc.identifier.uri | http://hdl.handle.net/10722/137117 | ||||||
| dc.identifier.volume | 54 | ||||||
| dc.language | eng | ||||||
| dc.publisher | American Society for Microbiology. | ||||||
| dc.publisher.place | United States | ||||||
| dc.relation.ispartof | Antimicrobial Agents and Chemotherapy | ||||||
| dc.relation.references | References in Scopus | ||||||
| dc.rights | Antimicrobial Agents and Chemotherapy. Copyright © American Society for Microbiology. | ||||||
| dc.subject.mesh | Adult | ||||||
| dc.subject.mesh | Antiviral Agents - pharmacology - therapeutic use | ||||||
| dc.subject.mesh | Drug Resistance, Viral - genetics | ||||||
| dc.subject.mesh | Guanine - analogs and derivatives - pharmacology - therapeutic use | ||||||
| dc.subject.mesh | Hepatitis B virus - drug effects - genetics - physiology | ||||||
| dc.title | Mechanism of entecavir resistance of hepatitis B virus with viral breakthrough as determined by long-term clinical assessment and molecular docking simulation | ||||||
| dc.type | Article |
Author Affiliations
- Okayama University Medical School
- SRL, Inc.
- Alameda County Medical Center
- Nagoya Daini Red Cross Hospital
- Kurume University School of Medicine
- The University of Hong Kong
- Nagoya City University Graduate School of Medical Sciences
- Sapporo Kosei Hospital
- National Cancer Center Tokyo
- Kawasaki Medical College
- Japan Konodai Hospital
- Chiba University