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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Hepatitis B virus rtCYE/rtCYEI mutations may contribute limited tenofovir resistance: Analysis of a large sample of Chinese patients
Lan-Lan Si, Zhen-Ping Fan, Wen-Hui Liu, Rong-Juan Chen, Xue-Yuan Chen, Dong Ji, Le Li, Chun Chen, Hao Liao, Jun Wang, Dong-Ping Xu, Jun Zhao, Yan Liu
Lan-Lan Si, Graduate School, Guangzhou Medical University, Guangzhou 511436, Guangdong Province, China
Lan-Lan Si, Rong-Juan Chen, Xue-Yuan Chen, Le Li, Hao Liao, Jun Wang, Dong-Ping Xu, Yan Liu, Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China
Zhen-Ping Fan, Department of The Fifth Cadre Health Care, The Second Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing 100039, China
Wen-Hui Liu, Department of Gastroenterology, The Second Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing 100853, China
Dong Ji, Chun Chen, Jun Zhao, Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
Co-first authors: Lan-Lan Si and Zhen-Ping Fan.
Co-corresponding authors: Jun Zhao and Yan Liu.
Author contributions: Liu Y and Zhao J substantially contributed to the conception and design of the work, played important and indispensable roles in the article as the co-corresponding authors; Si LL, Fan ZP, and Liu WH contributed to the acquisition, analysis, and interpretation of study data; Chen RJ, Chen XY, Ji D, Li Le, Chen C, Liao H and Wang J participated in the collection of patient samples and clinical information analysis; Xu DP, Si LL, Chen RJ, Zhao J, and Liu Y contributed to drafting the manuscript or revising it critically for important intellectual content; all authors reviewed and approved the final version of the manuscript.
Supported by The National Natural Science Foundation of China, No. 82470632.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Beijing 302 Hospital (Approved Number: FRM-EC-018-02-V2.0).
Conflict-of-interest statement: All authors declare that they have no competing interests.
Data sharing statement: The clinical patient data are not publicly available due to privacy protection restrictions, but can be accessed upon request by contacting the corresponding author (
liuyan5360@163.com) and submitting a research proposal following approval by the Ethics Committee.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Yan Liu, PhD, Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, No. 100 Xisihuan Middle Road, Beijing 100039, China.
liuyan5360@163.com
Received: March 31, 2025
Revised: May 9, 2025
Accepted: July 16, 2025
Published online: August 27, 2025
Processing time: 149 Days and 20.3 Hours
BACKGROUND
Whether rtS106C+H126Y+D134E/rtS106C+H126Y+D134E+L269I (rtCYE/rtCYEI) mutations in the hepatitis B virus (HBV) reverse-transcriptase (RT) region are associated with tenofovir disoproxil fumarate (TDF) resistance is controversial.
AIM
To evaluate the presence of the rtCYE/rtCYEI mutations in a large cohort of Chinese patients with chronic HBV infection.
METHODS
A total of 28236 patients who underwent drug resistance testing at the Fifth Medical Center of Chinese PLA General Hospital from 2007 to 2019 were enrolled. All patients received nucleoside/nucleotide analogues (NAs) therapy, and serum samples were collected for sequence analysis of the HBV RT domain with mutation analysis.
RESULTS
The detection rates of a single mutation of rtS106C, rtH126Y, rtD134E, and rtL269I were 8.21%, 3.20%, 2.55% and 61.49% in 23718 genotype C patients, and 1.31%, 1.76%, 0.21%, and 92.33% in 4266 genotype B patients, respectively. The combined mutations of rtCYE/rtCYEI were only detected in 12 genotype C patients, accounting for 0.042% of all patients. These 12 patients had received NA treatments except TDF before testing. Among them, 6 patients had coexisting rtCYE/rtCYEI and lamivudine-resistance mutations, and 2 patients had coexisting rtCYE/rtCYEI and adefovir-resistance mutations. Compared with the wild-type (WT) strain, the replication capacity of rtCYE/rtCYEI mutants from representative patients decreased by 41.1%-71.8%, and TDF susceptibility reduced by less than 2-fold, but rtCYEI+rtA181V/N236T mutants exhibited a 6.2-/9.9-fold decrease in TDF susceptibility. Molecular modeling showed that rtCYE/rtCYEI mutants had a slight decrease in binding energy to TDF compared to the WT strain. In the clinic, emergence of the rtCYE/rtCYEI mutations was not specifically associated with TDF treatment.
CONCLUSION
HBV rtCYE/rtCYEI mutations have a limited effect on TDF susceptibility and are not sufficient to cause TDF resistance.
Core Tip: Whether rtS106C+H126Y+D134E/rtS106C+H126Y+D134E+L269I (rtCYE/rtCYEI) mutations in the reverse-transcriptase region of hepatitis B virus (HBV) are associated with tenofovir resistance is controversial. The present study investigated many nucleoside/nucleotide analogues (NAs)-treated Chinese patients, focusing on the relationship between rtCYE/rtCYEI mutations and tenofovir resistance. We confirmed that rtCYE/rtCYEI mutations were rare (0.042%) in NAs-treated chronic HBV-infected patients and could appear in tenofovir treatment-naïve patients and remain sensitive to tenofovir. The effect of rtCYE/rtCYEI mutations on tenofovir susceptibility was limited. This study extends the current knowledge related to HBV resistance, which helps to explain the controversy and has clinical implications for resistance management.
