Identification of a quadruple mutation that confers tenofovir resistance in chronic hepatitis B patients
- Authors
- Park, Eun-Sook; Lee, Ah Ram; Kim, Doo Hyun; Lee, Jeong-Hoon; Yoo, Jeong-Ju; Ahn, Sung Hyun; Sim, Heewoo; Park, Soree; Kang, Hong Seok; Won, Juhee; Ha, Yea Na; Shin, Gu-Choul; Kwon, So Young; Park, Yong Kwang; Choi, Byeong-Sun; Lee, Yun Bin; Jeong, Nakcheol; An, Yohan; Ju, Young Seok; Yu, Su Jong; Chae, Hee Bok; Yu, Kyung-Sang; Kim, Yoon Jun; Yoon, Jung-Hwan; Zoulim, Fabien; Kim, Kyun-Hwan
- Issue Date
- Jun-2019
- Publisher
- Elsevier BV
- Keywords
- Capsid assembly modulator; Entecavir; Nucleotide analogue; CYEI; HBV; Antivirals
- Citation
- Journal of Hepatology, v.70, no.6, pp 1093 - 1102
- Pages
- 10
- Journal Title
- Journal of Hepatology
- Volume
- 70
- Number
- 6
- Start Page
- 1093
- End Page
- 1102
- URI
- https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/4511
- DOI
- 10.1016/j.jhep.2019.02.006
- ISSN
- 0168-8278
1600-0641
- 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.
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