Immune-escape mutations and stop-codons in HBsAg develop in a large proportion of patients with chronic HBV infection exposed to anti-HBV drugs in Europe

Luna Colagrossi, Lucas E. Hermans, Romina Salpini, Domenico Di Carlo, Suzan D. Pas, Marta Alvarez, Ziv Ben-Ari, Greet Boland, Bianca Bruzzone, Nicola Coppola, Carole Seguin-Devaux, Tomasz Dyda, Federico Garcia, Rolf Kaiser, Sukran Köse, Henrik Krarup, Ivana Lazarevic, Maja M. Lunar, Sarah Maylin, Valeria MicheliOrna Mor, Simona Paraschiv, Dimitros Paraskevis, Mario Poljak, Elisabeth Puchhammer-Stöckl, François Simon, Maja Stanojevic, Kathrine Stene-Johansen, Nijaz Tihic, Pascale Trimoulet, Jens Verheyen, Adriana Vince, Snjezana Zidovec Lepej, Nina Weis, Tülay Yalcinkaya, Charles A.B. Boucher, Annemarie M.J. Wensing, Carlo F. Perno*, Valentina Svicher, HEPVIR working group of the European Society for translational antiviral research (ESAR)

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

37 Citations (Scopus)


Background: HBsAg immune-escape mutations can favor HBV-transmission also in vaccinated individuals, promote immunosuppression-driven HBV-reactivation, and increase fitness of drug-resistant strains. Stop-codons can enhance HBV oncogenic-properties. Furthermore, as a consequence of the overlapping structure of HBV genome, some immune-escape mutations or stop-codons in HBsAg can derive from drug-resistance mutations in RT. This study is aimed at gaining insight in prevalence and characteristics of immune-associated escape mutations, and stop-codons in HBsAg in chronically HBV-infected patients experiencing nucleos(t)ide analogues (NA) in Europe. Methods: This study analyzed 828 chronically HBV-infected European patients exposed to ≥ 1 NA, with detectable HBV-DNA and with an available HBsAg-sequence. The immune-associated escape mutations and the NA-induced immune-escape mutations sI195M, sI196S, and sE164D (resulting from drug-resistance mutation rtM204 V, rtM204I, and rtV173L) were retrieved from literature and examined. Mutations were defined as an aminoacid substitution with respect to a genotype A or D reference sequence. Results: At least one immune-associated escape mutation was detected in 22.1% of patients with rising temporal-trend. By multivariable-analysis, genotype-D correlated with higher selection of ≥ 1 immune-associated escape mutation (OR[95%CI]:2.20[1.32-3.67], P = 0.002). In genotype-D, the presence of ≥ 1 immune-associated escape mutations was significantly higher in drug-exposed patients with drug-resistant strains than with wild-type virus (29.5% vs 20.3% P = 0.012). Result confirmed by analysing drug-naïve patients (29.5% vs 21.2%, P = 0.032). Strong correlation was observed between sP120T and rtM204I/V (P < 0.001), and their co-presence determined an increased HBV-DNA. At least one NA-induced immune-escape mutation occurred in 28.6% of patients, and their selection correlated with genotype-A (OR[95%CI]:2.03[1.32-3.10],P = 0.001). Finally, stop-codons are present in 8.4% of patients also at HBsAg-positions 172 and 182, described to enhance viral oncogenic-properties. Conclusions: Immune-escape mutations and stop-codons develop in a large fraction of NA-exposed patients from Europe. This may represent a potential threat for horizontal and vertical HBV transmission also to vaccinated persons, and fuel drug-resistance emergence.

Original languageEnglish
Article number251
JournalBMC Infectious Diseases
Issue number1
Publication statusPublished - 1 Jun 2018


  • Drug-resistance
  • HBV
  • HBsAg
  • Immune-escape
  • Stop-codons


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