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 journalArticle

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

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Lamivudine
Genotype
Mutation
Hepatitis B Surface Antigens
RNA-Directed DNA Polymerase
Immune System Diseases
Cluster Analysis
Disease Progression
Therapeutics
Multivariate Analysis
Logistic Models
Regression Analysis

Keywords

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

ASJC Scopus subject areas

  • Hepatology

Cite this

The profile of mutational clusters associated with lamivudine resistance can be constrained by HBV genotypes. / Svicher, Valentina; Gori, Caterina; Trignetti, Maria; Visca, Michela; Micheli, Valeria; Bernassola, Martina; Salpini, Romina; Gubertini, Guido; Longo, Roberta; Niero, Fosca; Ceccherini-Silberstein, Francesca; De Sanctis, Giuseppe Maria; Spanò, Alberto; Cappiello, Giuseppina; Perno, Carlo Federico.

In: Journal of Hepatology, Vol. 50, No. 3, 03.2009, p. 461-470.

Research output: Contribution to journalArticle

Svicher, V, Gori, C, Trignetti, M, Visca, M, Micheli, V, Bernassola, M, Salpini, R, Gubertini, G, Longo, R, Niero, F, Ceccherini-Silberstein, F, De Sanctis, GM, Spanò, A, Cappiello, G & Perno, CF 2009, 'The profile of mutational clusters associated with lamivudine resistance can be constrained by HBV genotypes', Journal of Hepatology, vol. 50, no. 3, pp. 461-470. https://doi.org/10.1016/j.jhep.2008.07.038
Svicher, Valentina ; Gori, Caterina ; Trignetti, Maria ; Visca, Michela ; Micheli, Valeria ; Bernassola, Martina ; Salpini, Romina ; Gubertini, Guido ; Longo, Roberta ; Niero, Fosca ; Ceccherini-Silberstein, Francesca ; De Sanctis, Giuseppe Maria ; Spanò, Alberto ; Cappiello, Giuseppina ; Perno, Carlo Federico. / The profile of mutational clusters associated with lamivudine resistance can be constrained by HBV genotypes. In: Journal of Hepatology. 2009 ; Vol. 50, No. 3. pp. 461-470.
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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.",
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T1 - The profile of mutational clusters associated with lamivudine resistance can be constrained by HBV genotypes

AU - Svicher, Valentina

AU - Gori, Caterina

AU - Trignetti, Maria

AU - Visca, Michela

AU - Micheli, Valeria

AU - Bernassola, Martina

AU - Salpini, Romina

AU - Gubertini, Guido

AU - Longo, Roberta

AU - Niero, Fosca

AU - Ceccherini-Silberstein, Francesca

AU - De Sanctis, Giuseppe Maria

AU - Spanò, Alberto

AU - Cappiello, Giuseppina

AU - Perno, Carlo Federico

PY - 2009/3

Y1 - 2009/3

N2 - 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.

AB - 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.

KW - HBV genotype

KW - Immune escape mutant

KW - LMV resistance

KW - Mutational clusters

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