BMC Infectious Diseases (Jun 2018)

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 Micheli,
  • Orna 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,
  • on behalf of the HEPVIR working group of the European Society for translational antiviral research (ESAR)

DOI
https://doi.org/10.1186/s12879-018-3161-2
Journal volume & issue
Vol. 18, no. 1
pp. 1 – 12

Abstract

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Abstract 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.

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