title: The profile of mutational clusters associated with lamivudine resistance can be constrained by HBV genotypes.
abstract: OBJECTIVE
  To investigate the different clusters of mutations associated with lamivudine resistance in HBV genotypes D and A.
  
  
  METHODS
  HBV reverse transcriptase sequences of 89 HBV-infected patients failing lamivudine treatment were analyzed. The association of mutations with HBV genotypes was assessed by Chi-Squared test and multivariate logistic regression analysis. Covariate analysis was based on hierarchical clustering.
  
  
  RESULTS
  In genotype A, the rtM204V (prevalence: 68.2%) was the main sign of lamivudine failure. Multivariate analysis confirmed that genotype A is the only predictor for rtM204V emergence (OR: 14.5 [95% CI: 1.3-158], P=0.02). Covariate analysis showed that rtM204V clusters with rtL180M, rtL229V (corresponding to sF220L in the HBsAg), and, interestingly, with HBsAg mutation sS207N (bootstrap=0.95). Both sF220L and sS207N co-localized in the fourth transmembrane HBsAg domain. In contrast, in genotype D the primary mutations rtM204V and rtM204I occurred with similar prevalence (39.1% versus 45.3%, P=0.47), and showed a distinct pattern of compensatory mutations. rtM204V clusters with mutations localized in the RT-B domain (rtV173L, rtL180M, and rtT184A/S) (bootstrap=0.94), while rtM204I clusters with mutations localized in the RT-A domain (rtS53N, rtT54Y, and rtL80I/V) (bootstrap=0.96) (without associations with HBsAg specific mutations).
  
  
  CONCLUSIONS
  HBV genotype plays an important role in driving RT evolution under lamivudine treatment, and thus can be relevant for therapeutic sequencing, immunological response and disease progression.
authors.affiliation: Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Svicher
authors.forename: Caterina
authors.initials: C
authors.lastname: Gori
authors.forename: Maria
authors.initials: M
authors.lastname: Trignetti
authors.forename: Michela
authors.initials: M
authors.lastname: Visca
authors.forename: Valeria
authors.initials: V
authors.lastname: Micheli
authors.forename: Martina
authors.initials: M
authors.lastname: Bernassola
authors.forename: Romina
authors.initials: R
authors.lastname: Salpini
authors.forename: Guido
authors.initials: G
authors.lastname: Gubertini
authors.forename: Roberta
authors.initials: R
authors.lastname: Longo
authors.forename: Fosca
authors.initials: F
authors.lastname: Niero
authors.forename: Francesca
authors.initials: F
authors.lastname: Ceccherini-Silberstein
authors.forename: Giuseppe Maria
authors.initials: GM
authors.lastname: De Sanctis
authors.forename: Alberto
authors.initials: A
authors.lastname: Spanò
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Cappiello
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000627:therapeutic use; D001219:Aspartate Aminotransferases / Q000097:blood; D016000:Cluster Analysis; D017931:DNA Primers; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D015658:HIV Infections / Q000150:complications; D006515:Hepatitis B virus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012194:RNA-Directed DNA Polymerase / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D017931:DNA Primers; D004279:DNA, Viral; D019259:Lamivudine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D012194:RNA-Directed DNA Polymerase