DC Field | Value | Language |
---|---|---|
dc.contributor.author | Park, Eun-Sook | ko |
dc.contributor.author | Lee, Ah Ram | ko |
dc.contributor.author | Kim, Doo Hyun | ko |
dc.contributor.author | Lee, Jeong-Hoon | ko |
dc.contributor.author | Yoo, Jeong-Ju | ko |
dc.contributor.author | Ahn, Sung Hyun | ko |
dc.contributor.author | Sim, Heewoo | ko |
dc.contributor.author | Park, Soree | ko |
dc.contributor.author | Kang, Hong Seok | ko |
dc.contributor.author | Won, Juhee | ko |
dc.contributor.author | Ha, Yea Na | ko |
dc.contributor.author | Shin, Gu-Choul | ko |
dc.contributor.author | Kwon, So Young | ko |
dc.contributor.author | Park, Yong Kwang | ko |
dc.contributor.author | Choi, Byeong-Sun | ko |
dc.contributor.author | Bin Lee, Yun | ko |
dc.contributor.author | Jeong, Nakcheol | ko |
dc.contributor.author | An, Yohan | ko |
dc.contributor.author | Ju, Young Seok | ko |
dc.contributor.author | Yu, Su Jong | ko |
dc.contributor.author | Chae, Hee Bok | ko |
dc.contributor.author | Yu, Kyung-Sang | ko |
dc.contributor.author | Kim, Yoon Jun | ko |
dc.contributor.author | Yoon, Jung-Hwan | ko |
dc.contributor.author | Zoulim, Fabien | ko |
dc.contributor.author | Kim, Kyun-Hwan | ko |
dc.date.accessioned | 2019-06-03T10:25:06Z | - |
dc.date.available | 2019-06-03T10:25:06Z | - |
dc.date.created | 2019-06-03 | - |
dc.date.created | 2019-06-03 | - |
dc.date.issued | 2019-06 | - |
dc.identifier.citation | JOURNAL OF HEPATOLOGY, v.70, no.6, pp.1093 - 1102 | - |
dc.identifier.issn | 0168-8278 | - |
dc.identifier.uri | http://hdl.handle.net/10203/262431 | - |
dc.description.abstract | 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. Eleven HBV clones harboring a series of mutations in the reverse transcriptase gene were constructed by site-directed mutagenesis. Drug susceptibility of each clone was determined by Southern blot analysis and real-time PCR. The relative frequency of mutants was evaluated by ultra-deep sequencing and clonal analysis. Results: Five mutations (rtS106C [C], rtH126Y [Y], rtD134E [E], rtM204I/V, and rtL269I [I]) were commonly found in viral isolates from 2 patients. The novel mutations C, Y, and E were associated with drug resistance. In assays for drug susceptibility, the IC50 value for wild-type HBV was 3.8 +/- 0.6 mu M, whereas the IC50 values for CYE and CYEI mutants were 14.1 +/- 1.8 and 58.1 +/- 0.9 mu M, respectively. The IC90 value for wild-type HBV was 30 +/- 0.5 mu M, whereas the IC90 values for CYE and CYEI mutants were 185 +/- 0.5 and 790 +/- 0.2 mu M, respectively. Both tenofovir-resistant mutants and wild-type HBV had similar susceptibility to the capsid assembly modulator NVR 3-778 (IC50 < 0.4 mu M vs. IC50 = 0.4 mu M, respectively). Conclusions: Our study reveals that the quadruple (CYEI) mutation increases the amount of tenofovir required to inhibit HBV by 15.3-fold in IC50 and 26.3-fold in IC90. These results demonstrate that tenofovir-resistant HBV mutants can emerge, although the genetic barrier is high. Lay summary: Tenofovir is the most potent nucleotide analogue for the treatment of chronic hepatitis B virus infection and there has been no hepatitis B virus mutation that confers > 10-fold resistance to tenofovir up to 8 years. Herein, we identified, for the first time, a quadruple mutation that conferred 15.3-fold (IC50) and 26.3-fold (IC90) resistance to tenofovir in 2 patients who experienced viral breakthrough during tenofovir treatment. (C) 2019 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. | - |
dc.language | English | - |
dc.publisher | ELSEVIER SCIENCE BV | - |
dc.title | Identification of a quadruple mutation that confers tenofovir resistance in chronic hepatitis B patients | - |
dc.type | Article | - |
dc.identifier.wosid | 000467987600013 | - |
dc.identifier.scopusid | 2-s2.0-85063609690 | - |
dc.type.rims | ART | - |
dc.citation.volume | 70 | - |
dc.citation.issue | 6 | - |
dc.citation.beginningpage | 1093 | - |
dc.citation.endingpage | 1102 | - |
dc.citation.publicationname | JOURNAL OF HEPATOLOGY | - |
dc.identifier.doi | 10.1016/j.jhep.2019.02.006 | - |
dc.contributor.localauthor | Ju, Young Seok | - |
dc.contributor.nonIdAuthor | Park, Eun-Sook | - |
dc.contributor.nonIdAuthor | Lee, Ah Ram | - |
dc.contributor.nonIdAuthor | Kim, Doo Hyun | - |
dc.contributor.nonIdAuthor | Lee, Jeong-Hoon | - |
dc.contributor.nonIdAuthor | Yoo, Jeong-Ju | - |
dc.contributor.nonIdAuthor | Ahn, Sung Hyun | - |
dc.contributor.nonIdAuthor | Sim, Heewoo | - |
dc.contributor.nonIdAuthor | Park, Soree | - |
dc.contributor.nonIdAuthor | Kang, Hong Seok | - |
dc.contributor.nonIdAuthor | Won, Juhee | - |
dc.contributor.nonIdAuthor | Ha, Yea Na | - |
dc.contributor.nonIdAuthor | Shin, Gu-Choul | - |
dc.contributor.nonIdAuthor | Kwon, So Young | - |
dc.contributor.nonIdAuthor | Park, Yong Kwang | - |
dc.contributor.nonIdAuthor | Choi, Byeong-Sun | - |
dc.contributor.nonIdAuthor | Bin Lee, Yun | - |
dc.contributor.nonIdAuthor | Jeong, Nakcheol | - |
dc.contributor.nonIdAuthor | Yu, Su Jong | - |
dc.contributor.nonIdAuthor | Chae, Hee Bok | - |
dc.contributor.nonIdAuthor | Yu, Kyung-Sang | - |
dc.contributor.nonIdAuthor | Kim, Yoon Jun | - |
dc.contributor.nonIdAuthor | Yoon, Jung-Hwan | - |
dc.contributor.nonIdAuthor | Zoulim, Fabien | - |
dc.contributor.nonIdAuthor | Kim, Kyun-Hwan | - |
dc.description.isOpenAccess | N | - |
dc.type.journalArticle | Article | - |
dc.subject.keywordAuthor | Capsid assembly modulator | - |
dc.subject.keywordAuthor | Entecavir | - |
dc.subject.keywordAuthor | Nucleotide analogue | - |
dc.subject.keywordAuthor | CYEI | - |
dc.subject.keywordAuthor | HBV | - |
dc.subject.keywordAuthor | Antivirals | - |
dc.subject.keywordPlus | VIRUS POLYMERASE MUTATIONS | - |
dc.subject.keywordPlus | DISOPROXIL FUMARATE | - |
dc.subject.keywordPlus | REVERSE-TRANSCRIPTASE | - |
dc.subject.keywordPlus | LAMIVUDINE | - |
dc.subject.keywordPlus | THERAPY | - |
dc.subject.keywordPlus | HBV | - |
dc.subject.keywordPlus | SUSCEPTIBILITY | - |
dc.subject.keywordPlus | REPLICATION | - |
dc.subject.keywordPlus | GUIDELINES | - |
dc.subject.keywordPlus | SELECTION | - |
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