title: Pre-existing YMDD mutants in treatment-naïve patients with chronic hepatitis B are not selected during lamivudine therapy.
abstract: Although the rate at which mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of hepatitis B virus polymerase form is high during prolonged lamivudine (LAM) therapy, these mutations sometimes occur naturally in treatment-naïve patients with chronic hepatitis B. The prevalence of natural YMDD mutants differs geographically, and its clinical significance during LAM therapy is unknown. This study aimed to investigate whether pre-existing YMDD mutants were selected during LAM therapy. It included 14 treatment-naïve patients who were treated with LAM for at least 9 months. LAM resistance was evaluated before and at 3-month intervals during treatment. Mutations were analyzed by direct sequencing, restriction fragment mass polymorphism (RFMP) assays, and a single-step multiplex polymerase chain reaction (PCR) test using dual-priming oligonucleotide (DPO) primers. DPO-based multiplex PCR showed two YMDD mutations in two patients before LAM therapy; rtM204V and rtL180M + rtM204V/I. Further, two patients had an rtL180M mutation without an accompanying rtM204V/I mutation. No mutant was detected in any patient by direct sequencing or the RFMP assay before LAM therapy. A virological response was observed at 3 months in all patients with pre-existing YMDD mutants. All mutations disappeared after 3 months of LAM therapy, and during the follow-up period, no re-emergence was detected by any of the three methods. Further, the viral load was suppressed optimally. In conclusion, pre-existing YMDD mutants were cleared early during the course of LAM therapy, which produced a consistent virological response, and the mutants were not selected by LAM therapy.
authors.affiliation: Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea.
authors.forename: Sae Hwan
authors.initials: SH
authors.lastname: Lee
authors.forename: Hong Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: In-Seon
authors.initials: IS
authors.lastname: Byun
authors.forename: Soung Won
authors.initials: SW
authors.lastname: Jeong
authors.forename: Sang Gyune
authors.initials: SG
authors.lastname: Kim
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Jang
authors.forename: Young Seok
authors.initials: YS
authors.lastname: Kim
authors.forename: Boo Sung
authors.initials: BS
authors.lastname: Kim
mesh_terms: D000328:Adult; D020816:Amino Acid Motifs / Q000235:genetics; D000998:Antiviral Agents / Q000627:therapeutic use; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012150:Polymorphism, Restriction Fragment Length; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D012641:Selection, Genetic; D019562:Viral Load; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D019259:Lamivudine; D012194:RNA-Directed DNA Polymerase