Role of hepatitis B virus genetic barrier in drug-resistance and immune-escape development

Valentina Svicher, Valeria Cento, Romina Salpini, Fabio Mercurio, Maria Fraune, Bastian Beggel, Yue Han, Caterina Gori, Linda Wittkop, Ada Bertoli, Valeria Micheli, Guido Gubertini, Roberta Longo, Sara Romano, Michela Visca, Valentina Gallinaro, Nicoletta Marino, Francesco Mazzotta, Giuseppe Maria De Sanctis, Hervè FleuryPascale Trimoulet, Mario Angelico, Giuseppina Cappiello, Xin Xin Zhang, Jens Verheyen, Francesca Ceccherini-Silberstein, Carlo Federico Perno

Research output: Contribution to journalArticlepeer-review


Background: Impact of hepatitis B virus genetic barrier, defined as the number and type of nucleotide substitutions required to overcome drug/immune selective pressure, on drug-resistance/immune-escape development is unknown. Methods: Genetic barrier was calculated according to Van de Vijver (2006) in 3482 hepatitis B virus-reverse transcriptase/HBV surface antigen sequences from 555 drug-naïve patients and 2927 antiviral-treated patients infected with hepatitis B virus genotypes A-G. Results: Despite high natural variability, genetic barrier for drug-resistance development is identical amongst hepatitis B virus genotypes, but varies according to drug-resistance mutation type. Highest genetic barrier is found for secondary/compensatory mutations (e.g. rtL80I/V-rtL180M-rtV173L), whilst most primary mutations (including rtM204V-rtA181T/V-rtI169T-rtA194T) are associated with low genetic barrier. An exception is rtM204I, which can derive from a transition or a transversion. Genotypes A and G are more prone to develop immune/diagnostic-escape mutations sT114R and sG130N. Vaccine-escape associated sT131N-mutation is a natural polymorphism in both A and G genotypes. Conclusion: Genetic barrier and reverse transcriptase/HBV surface antigen overlapping can synergistically influence hepatitis B virus drug-resistance/immune-escape development. The different immune-escape potential of specific hepatitis B virus genotypes could have important clinical consequences in terms of disease progression, vaccine strategies and correct HBV surface antigen detection.

Original languageEnglish
Pages (from-to)975-983
Number of pages9
JournalDigestive and Liver Disease
Issue number12
Publication statusPublished - Dec 2011


  • Drug resistance
  • Genetic barrier
  • Immune escape
  • RT/HBsAg overlapping

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology


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