Identification of a quadruple mutation that confers tenofovir resistance in chronic hepatitis B patients

Cited 91 time in webofscience Cited 79 time in scopus
  • Hit : 499
  • Download : 0
DC FieldValueLanguage
dc.contributor.authorPark, Eun-Sookko
dc.contributor.authorLee, Ah Ramko
dc.contributor.authorKim, Doo Hyunko
dc.contributor.authorLee, Jeong-Hoonko
dc.contributor.authorYoo, Jeong-Juko
dc.contributor.authorAhn, Sung Hyunko
dc.contributor.authorSim, Heewooko
dc.contributor.authorPark, Soreeko
dc.contributor.authorKang, Hong Seokko
dc.contributor.authorWon, Juheeko
dc.contributor.authorHa, Yea Nako
dc.contributor.authorShin, Gu-Choulko
dc.contributor.authorKwon, So Youngko
dc.contributor.authorPark, Yong Kwangko
dc.contributor.authorChoi, Byeong-Sunko
dc.contributor.authorBin Lee, Yunko
dc.contributor.authorJeong, Nakcheolko
dc.contributor.authorAn, Yohanko
dc.contributor.authorJu, Young Seokko
dc.contributor.authorYu, Su Jongko
dc.contributor.authorChae, Hee Bokko
dc.contributor.authorYu, Kyung-Sangko
dc.contributor.authorKim, Yoon Junko
dc.contributor.authorYoon, Jung-Hwanko
dc.contributor.authorZoulim, Fabienko
dc.contributor.authorKim, Kyun-Hwanko
dc.date.accessioned2019-06-03T10:25:06Z-
dc.date.available2019-06-03T10:25:06Z-
dc.date.created2019-06-03-
dc.date.created2019-06-03-
dc.date.issued2019-06-
dc.identifier.citationJOURNAL OF HEPATOLOGY, v.70, no.6, pp.1093 - 1102-
dc.identifier.issn0168-8278-
dc.identifier.urihttp://hdl.handle.net/10203/262431-
dc.description.abstractBackground & 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.languageEnglish-
dc.publisherELSEVIER SCIENCE BV-
dc.titleIdentification of a quadruple mutation that confers tenofovir resistance in chronic hepatitis B patients-
dc.typeArticle-
dc.identifier.wosid000467987600013-
dc.identifier.scopusid2-s2.0-85063609690-
dc.type.rimsART-
dc.citation.volume70-
dc.citation.issue6-
dc.citation.beginningpage1093-
dc.citation.endingpage1102-
dc.citation.publicationnameJOURNAL OF HEPATOLOGY-
dc.identifier.doi10.1016/j.jhep.2019.02.006-
dc.contributor.localauthorJu, Young Seok-
dc.contributor.nonIdAuthorPark, Eun-Sook-
dc.contributor.nonIdAuthorLee, Ah Ram-
dc.contributor.nonIdAuthorKim, Doo Hyun-
dc.contributor.nonIdAuthorLee, Jeong-Hoon-
dc.contributor.nonIdAuthorYoo, Jeong-Ju-
dc.contributor.nonIdAuthorAhn, Sung Hyun-
dc.contributor.nonIdAuthorSim, Heewoo-
dc.contributor.nonIdAuthorPark, Soree-
dc.contributor.nonIdAuthorKang, Hong Seok-
dc.contributor.nonIdAuthorWon, Juhee-
dc.contributor.nonIdAuthorHa, Yea Na-
dc.contributor.nonIdAuthorShin, Gu-Choul-
dc.contributor.nonIdAuthorKwon, So Young-
dc.contributor.nonIdAuthorPark, Yong Kwang-
dc.contributor.nonIdAuthorChoi, Byeong-Sun-
dc.contributor.nonIdAuthorBin Lee, Yun-
dc.contributor.nonIdAuthorJeong, Nakcheol-
dc.contributor.nonIdAuthorYu, Su Jong-
dc.contributor.nonIdAuthorChae, Hee Bok-
dc.contributor.nonIdAuthorYu, Kyung-Sang-
dc.contributor.nonIdAuthorKim, Yoon Jun-
dc.contributor.nonIdAuthorYoon, Jung-Hwan-
dc.contributor.nonIdAuthorZoulim, Fabien-
dc.contributor.nonIdAuthorKim, Kyun-Hwan-
dc.description.isOpenAccessN-
dc.type.journalArticleArticle-
dc.subject.keywordAuthorCapsid assembly modulator-
dc.subject.keywordAuthorEntecavir-
dc.subject.keywordAuthorNucleotide analogue-
dc.subject.keywordAuthorCYEI-
dc.subject.keywordAuthorHBV-
dc.subject.keywordAuthorAntivirals-
dc.subject.keywordPlusVIRUS POLYMERASE MUTATIONS-
dc.subject.keywordPlusDISOPROXIL FUMARATE-
dc.subject.keywordPlusREVERSE-TRANSCRIPTASE-
dc.subject.keywordPlusLAMIVUDINE-
dc.subject.keywordPlusTHERAPY-
dc.subject.keywordPlusHBV-
dc.subject.keywordPlusSUSCEPTIBILITY-
dc.subject.keywordPlusREPLICATION-
dc.subject.keywordPlusGUIDELINES-
dc.subject.keywordPlusSELECTION-
Appears in Collection
MSE-Journal Papers(저널논문)
Files in This Item
There are no files associated with this item.
This item is cited by other documents in WoS
⊙ Detail Information in WoSⓡ Click to see webofscience_button
⊙ Cited 91 items in WoS Click to see citing articles in records_button

qr_code

  • mendeley

    citeulike


rss_1.0 rss_2.0 atom_1.0