title: Lamivudine-resistance mutations can be selected even at very low levels of hepatitis B viraemia.
abstract: OBJECTIVE
  To investigate lamivudine (LAM)-resistance profiles of hepatitis B virus (HBV) at the early stages of virological breakthrough (serum HBV-DNA 12-345IU/ml) or when HBV-DNA is undetectable.
  
  
  METHODS
  Sixty-four HBV-mono-infected patients were enrolled: 25 had virological breakthrough with serum HBV-DNA ranging from 12 to 345IU/ml during first-line LAM-monotherapy; 24 were on LAM-monotherapy, and 15 were on LAM+adefovir dipivoxil (ADV) with undetectable serum HBV-DNA (<12IU/ml).
  
  
  RESULTS
  HBV-reverse transcriptase was successfully sequenced in 22 (88.0%) LAM-treated patients with HBV-DNA between 12 and 345IU/ml, and in 12 (30.8%) patients receiving LAM (±ADV) with HBV-DNA<12IU/ml. Drug-resistance mutations were observed in 17 (77.2%) LAM-treated patients with virological breakthrough: 8 M204V, 7 M204I, 1 M204I/V, and 1 A181T. One or ≥2 compensatory mutations were found in 10 (58.8%) and in 4 (23.5%) patients. Drug-resistance mutations were present also in patients with undetectable serum HBV-DNA: M204I was detected in 2 patients receiving LAM-monotherapy, and V84M in 1 patient receiving LAM+ADV.
  
  
  CONCLUSIONS
  Overall findings support the existence of drug-resistance mutations even at very low levels of viral replication. The persistence of low-level HBV replication and consequent drug-resistance emergence should be considered when choosing therapeutic strategies.
authors.affiliation: University of Rome Tor Vergata, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Svicher
authors.forename: Claudia
authors.initials: C
authors.lastname: Alteri
authors.forename: Caterina
authors.initials: C
authors.lastname: Gori
authors.forename: Romina
authors.initials: R
authors.lastname: Salpini
authors.forename: Fabbio
authors.initials: F
authors.lastname: Marcuccilli
authors.forename: Ada
authors.initials: A
authors.lastname: Bertoli
authors.forename: Roberta
authors.initials: R
authors.lastname: Longo
authors.forename: Martina
authors.initials: M
authors.lastname: Bernassola
authors.forename: Valentina
authors.initials: V
authors.lastname: Gallinaro
authors.forename: Sara
authors.initials: S
authors.lastname: Romano
authors.forename: Michela
authors.initials: M
authors.lastname: Visca
authors.forename: Antonella
authors.initials: A
authors.lastname: Ursitti
authors.forename: Marcello
authors.initials: M
authors.lastname: Feasi
authors.forename: Valeria
authors.initials: V
authors.lastname: Micheli
authors.forename: Mario
authors.initials: M
authors.lastname: Angelico
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cassola
authors.forename: Giustino
authors.initials: G
authors.lastname: Parruti
authors.forename: Guido
authors.initials: G
authors.lastname: Gubertini
authors.forename: Giuseppe Maria
authors.initials: GM
authors.lastname: De Sanctis
authors.forename: Francesca
authors.initials: F
authors.lastname: Ceccherini-Silberstein
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Cappiello
authors.forename: Alberto
authors.initials: A
authors.lastname: Spanò
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology*; D004279:DNA, Viral; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D063065:Organophosphonates / Q000494:pharmacology; D019562:Viral Load; D014766:Viremia
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D019259:Lamivudine; D000225:Adenine; C106812:adefovir dipivoxil