PMID- 22398037 OWN - NLM STAT- MEDLINE DCOM- 20120725 LR - 20131121 IS - 1873-5967 (Electronic) IS - 1386-6532 (Linking) VI - 54 IP - 1 DP - 2012 May TI - The rtL229 substitutions in the reverse transcriptase region of hepatitis B virus (HBV) polymerase are potentially associated with lamivudine resistance as a compensatory mutation. PG - 66-72 LID - 10.1016/j.jcv.2012.02.003 [doi] AB - BACKGROUND: It remains unclear whether hepatitis B virus (HBV) reverse-transcriptase (RT) rtL229 substitutions influence HBV drug resistance. OBJECTIVE: The study was to investigate the association of HBV rtL229 substitutions with viral resistance to lamivudine (LAM). STUDY DESIGN: Entire HBV RT genes were amplified by nested PCR and sequenced from sera of 6000 nucleos(t)ide analog-experienced patients with chronic HBV infection. The incidence and clinic relevance of rtL229 substitutions were analyzed. Replication-competent viral amplicons which harbored HBV genomes of wild-type, rtM204I, or rtM204I in conjunction with various rtL229 substitutions (rtL229F/W/M/V) were constructed. The amplicons were transfected into HepG2 cells for phenotyping of replication capacity and susceptibility to nucleos(t)ide analogs. RESULTS: The rtL229 substitutions were detected in 6.57% (394/6000) of patients. Individual substitution incidences were 2.77%, 0.97%, 0.83% and 0.55% for rtL229V, rtL229F, rtL229M and rtL229W, respectively. The incidence of rtL229 substitutions was significantly higher in LAM-experienced patients (341/4220, 8.1%) than in LAM-naive patients (53/1780, 3.0%), and were independently associated with genotypic LAM resistance (77.9% vs. 21.2%, OR 8.806, 95%CI 6.345-12.223) and low viral replication (HBV DNA <1000IU/mL) (4.60% vs. 24.2%, OR 0.478, 95%CI 0.254-0.898). Representative cases follow-up showed that rtL229F developed subsequent to rtM204I emergence during LAM treatment and regressed with rtM204I after LAM withdrawal. Functionally, rtL229F did not confer reduced susceptibility to LAM, but could restore replication capacity of rtM204I strain. CONCLUSION: The rtL229 substitutions were potentially associated with LAM resistance in Chinese patients and rtL229F had characteristics of a compensatory mutation of rtM204I mutant. CI - Copyright (c) 2012 Elsevier B.V. All rights reserved. FAU - Ji, Dong AU - Ji D AD - Institute of Infectious Diseases and Liver Failure Research Center, Beijing 302 Hospital, Beijing 100039, China. FAU - Liu, Yan AU - Liu Y FAU - Li, Le AU - Li L FAU - Xu, Zhihui AU - Xu Z FAU - Si, Lan-Lan AU - Si LL FAU - Dai, Jiu-Zeng AU - Dai JZ FAU - Li, Xiaodong AU - Li X FAU - Wang, Lin AU - Wang L FAU - Yao, Zengtao AU - Yao Z FAU - Xin, Shao-Jie AU - Xin SJ FAU - Chen, Guo-Feng AU - Chen GF FAU - Xu, Dongping AU - Xu D LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120306 PL - Netherlands TA - J Clin Virol JT - Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology JID - 9815671 RN - 0 (Antiviral Agents) RN - 0 (Gene Products, pol) RN - 0 (P protein, Hepatitis B virus) RN - 2T8Q726O95 (Lamivudine) SB - IM MH - Adult MH - *Amino Acid Substitution MH - Antiviral Agents/*pharmacology MH - Cell Line MH - China MH - *Drug Resistance, Viral MH - Female MH - Gene Products, pol/*genetics MH - Hepatitis B/virology MH - Hepatitis B virus/*drug effects/genetics/isolation & purification/physiology MH - Hepatocytes/virology MH - Humans MH - Lamivudine/*pharmacology MH - Male MH - Middle Aged MH - *Mutation, Missense MH - Virus Replication EDAT- 2012/03/09 06:00 MHDA- 2012/07/26 06:00 CRDT- 2012/03/09 06:00 PHST- 2011/11/16 00:00 [received] PHST- 2012/01/23 00:00 [revised] PHST- 2012/02/06 00:00 [accepted] PHST- 2012/03/09 06:00 [entrez] PHST- 2012/03/09 06:00 [pubmed] PHST- 2012/07/26 06:00 [medline] AID - S1386-6532(12)00052-2 [pii] AID - 10.1016/j.jcv.2012.02.003 [doi] PST - ppublish SO - J Clin Virol. 2012 May;54(1):66-72. doi: 10.1016/j.jcv.2012.02.003. Epub 2012 Mar 6.