The profile of mutational clusters associated with lamivudine resistance can be constrained by HBV genotypes

Valentina Svicher, Caterina Gori, Maria Trignetti, Michela Visca, Valeria Micheli, Martina Bernassola, Romina Salpini, Guido Gubertini, Roberta Longo, Fosca Niero, Francesca Ceccherini-Silberstein, Giuseppe Maria De Sanctis, Alberto Spanò, Giuseppina Cappiello, Carlo Federico Perno

Research output: Contribution to journalArticlepeer-review

Abstract

Background/Aims: 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.

Original languageEnglish
Pages (from-to)461-470
Number of pages10
JournalJournal of Hepatology
Volume50
Issue number3
DOIs
Publication statusPublished - Mar 2009

Keywords

  • HBV genotype
  • Immune escape mutant
  • LMV resistance
  • Mutational clusters

ASJC Scopus subject areas

  • Hepatology

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