title: Prevalence, virology and antiviral drugs susceptibility of hepatitis B virus rtN238H polymerase mutation from 1865 Chinese patients with chronic hepatitis B.
abstract: Amino acid substitutions at positions rtN238T/D of the hepatitis B virus (HBV) polymerase have been reported as potential mutations associated with adefovir (ADV) resistance. In this study, we characterized the prevalence of the rtN238H mutation and determined the susceptibility to LAM and ADV using phenotypic analyzes in vitro. One thousand eight hundred and sixty-five HBsAg-positive patients with chronic HBV (CHB) infection were included in this study. HBV genotypes and reverse transcriptase (RT) mutations were determined by direct sequencing. Replication-competent HBV constructs containing the naturally occurring rtN238H mutation were generated and replication capacity and susceptibility to LAM and ADV in transiently transfected hepatoma cell lines were determined. Among 1865 enrolled HBV infected patients, 8.8% (165/1865) showed mutations in the rtN238 locus (143 males/22 females, 91 treatment-naive, 42 ADV-treated, 16 LAM-treated and 16 ADV+LAM-treated), namely 86% rtN238H (142/165), 5.5% rtN238S (9/165), 5.5% rtN238T (9/165) and 3% rtN238D (5/165). Among the rtN238H mutant strains, there were no significant differences between ADV- or/and LAM- treated patients and treated-naive patients (42% vs. 58%). Compared with wild-type HBV, this mutant displayed an equivalent susceptibility to LAM or ADV in phenotypic assays. Importantly, we found that the incidence rate of rtN238H was higher in HBV genotype B infected patients than HBV genotype C subsets (80.3% vs. 19.7%), even without exogenous selection pressures. As rtN238H did neither impair the viral replication efficiency nor susceptibility to LAM or ADV in vitro, rtN238H likely represents background polymorphisms rather than resistance mutations with clinical implications. The incidence of rtN238H may be associated with HBV genotype.
authors.affiliation: Pediatric Liver Disease Therapy and Research Center, Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China. zhongyanwei@126.com
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Zhong
authors.forename: Jiyun
authors.initials: J
authors.lastname: Lv
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Xing
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.forename: Heling
authors.initials: H
authors.lastname: Su
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D044466:Asian People; D002648:Child; D002675:Child, Preschool; D002681:China; D005260:Female; D005838:Genotype; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D019259:Lamivudine; C053001:adefovir; D012194:RNA-Directed DNA Polymerase; D000225:Adenine