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©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
Natural YMDD-motif mutants affect clinical course of lamivudine in chronic hepatitis B
You-Wen Tan, Yun Ye, Guo-Hong Ge, Wei Zhao, Jian-He Gan, Yun Zhao, Zhi-Lin Niu, Dong-Jun Zhang, Li Chen, Xue-Jun Yu, Li-Jun Yang
You-Wen Tan, Yun Ye, Guo-Hong Ge, Li Chen, Xue-Jun Yu, Li-Jun Yang, Department of Liver Diseases, the Third Hospital of Zhenjiang Affiliated to Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
Wei Zhao, Department of Infectious Diseases, the No. 2 Hospital of Nanjing, Nanjing 210003, Jiangsu Province, China
Jian-He Gan, Department of Infectious Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu Province, China
Yun Zhao, Department of Infectious Diseases, the Affiliated Hospital of Yangzhou University, Yangzhou 225001, Jiangsu Province, China
Zhi-Lin Niu, Department of Infectious Diseases, the People’s Hospital of Wujiang, Nantong University School of Medicine, Suzhou 215006, Jiangsu Province, China
Dong-Jun Zhang, Department of Infectious Diseases, the People’s Hospital of Danyang, Nantong University School of Medicine, Nantong 212502, Jiangsu Province, China
Author contributions: Tan YW, Ye Y and Ge GH performed the majority of the experiments; Chen L, Yu XJ and Yang LJ provided analytical tools and were involved in editing the manuscript; Zhao W, Gan JH, Zhao Y, Niu ZL and Zhang DJ provided all of the human material and provided financial support for this work; Tan YW designed the study and wrote the manuscript.
Supported by Zhenjiang Municipal Science and Technology Commission, No. SH2009016.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. You-Wen Tan, Associate Professor, Department of Liver Diseases, the Third Hospital of Zhenjiang Affiliated to Jiangsu University, No. 300, Daijiamen, Runzhou Distinct, Zhenjiang 212000, Jiangsu Province, China. tyw915@sina.com
Telephone: +86-511-88925605 Fax: +86-511-88970779
Received: July 3, 2014
Peer-review started: July 3, 2014
First decision: August 6, 2014
Revised: August 25, 2014
Accepted: October 15, 2014
Article in press: October 15, 2014
Published online: February 21, 2015
AIM: To investigate the prevalence of nature tyrosine-methionine-aspartic acid-aspartic acid motif mutations in chronic hepatitis B (CHB) patients and to evaluate the efficacy of lamivudine.
METHODS: A total of 1268 CHB patients were recruited from the outpatient and inpatient departments of six centers. Tyrosine-methionine-aspartic acid-aspartic acid (YMDD) mutations were analyzed using the hepatitis B virus (HBV) drug resistance line probe assay. Forty voluntary patients were selected from those with positive or negative natural YMDD mutations to undergo treatment with lamivudine.
RESULTS: YMDD mutations were detected in 288 (22.71%) of the 1268 CHB patients. Multivariate analysis revealed that the patients’ HBV DNA level (P = 0.0282) and hepatitis B e antigen status (P = 0.0133) were also associated with natural YMDD mutations. The rates of normalization of alanine aminotransferase levels and HBV DNA nondetection at 6, 24, 36, and 48 wk were compared between the patients with natural YMDD mutations and those without, and the differences were not significant. However, there was a significant difference in the cumulative emergence rates of virological breakthrough at 48 wk in the patients with natural YMDD mutations and those without (32.5% vs 12.5%, P = 0.032).
CONCLUSION: Naturally occurring YMDD mutations are detectable in a large proportion of CHB patients; breakthrough hepatitis tended to occur in patients with natural YMDD mutations.
Core tip: Although tyrosine-methionine-aspartic acid-aspartic acid (YMDD) motif mutation is considered to occur secondary to the use of lamivudine, it has become increasingly apparent that YMDD mutations exist in nature. A total of 1268 chronic hepatitis B (CHB) patients were recruited from six centers. YMDD mutations were detected using Inno-Lipa hepatitis B virus (HBV) drug resistance line probe assay in 288 (22.71%) of the 1268 CHB patients. Our study demonstrated that lamivudine therapy was well tolerated by Chinese CHB patients with natural YMDD mutations and led to reductions in transaminase levels and HBV-DNA loss. However, breakthrough hepatitis tended to occur in patients with natural YMDD mutations.
