Colagrossi, Luna, Hermans, Lucas E., Salpini, Romina ORCID: 0000-0002-2488-2082, Di Carlo, Domenico ORCID: 0000-0002-8324-4873, Pas, Suzan D., Alvarez, Marta, Ben-Ari, Ziv, Boland, Greet, Bruzzone, Bianca, Coppola, Nicola, Seguin-Devaux, Carole ORCID: 0000-0003-0636-5222, Dyda, Tomasz, Garcia, Federico ORCID: 0000-0001-7611-781X, Kaiser, Rolf, Kose, Sukran, Krarup, Henrik, Lazarevic, Ivana ORCID: 0000-0001-6795-1378, Lunar, Maja M., Maylin, Sarah, Micheli, Valeria, Mor, Orna, Paraschiv, Simona, Paraskevis, Dimitros, Poljak, Mario, Puchhammer-Stoeckl, Elisabeth, Simon, Francois, Stanojevic, Maja, Stene-Johansen, Kathrine, Tihic, Nijaz, Trimoulet, Pascale, Verheyen, Jens, Vince, Adriana, Lepej, Snjezana Zidovec, Weis, Nina ORCID: 0000-0002-3133-2724, Yalcinkaya, Tulay, Boucher, Charles A. B., Wensing, Annemarie M. J., Perno, Carlo F. and Svicher, Valentina (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. BMC Infect. Dis., 18. LONDON: BIOMED CENTRAL LTD. ISSN 1471-2334

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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)side 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 sl195M, sl196S, and sE164D (resulting from drug-resistance mutation rtM204 V, rtM204l, 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%Cl]: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-naive patients (29.5% vs 21. 2%, P= 0.032). Strong correlation was observed between sP120T and rtM204l/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%Cl]: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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Colagrossi, LunaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hermans, Lucas E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Salpini, RominaUNSPECIFIEDorcid.org/0000-0002-2488-2082UNSPECIFIED
Di Carlo, DomenicoUNSPECIFIEDorcid.org/0000-0002-8324-4873UNSPECIFIED
Pas, Suzan D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alvarez, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ben-Ari, ZivUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boland, GreetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruzzone, BiancaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coppola, NicolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seguin-Devaux, CaroleUNSPECIFIEDorcid.org/0000-0003-0636-5222UNSPECIFIED
Dyda, TomaszUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia, FedericoUNSPECIFIEDorcid.org/0000-0001-7611-781XUNSPECIFIED
Kaiser, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kose, SukranUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krarup, HenrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lazarevic, IvanaUNSPECIFIEDorcid.org/0000-0001-6795-1378UNSPECIFIED
Lunar, Maja M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maylin, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Micheli, ValeriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mor, OrnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paraschiv, SimonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paraskevis, DimitrosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poljak, MarioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Puchhammer-Stoeckl, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simon, FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stanojevic, MajaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stene-Johansen, KathrineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tihic, NijazUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trimoulet, PascaleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Verheyen, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vince, AdrianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lepej, Snjezana ZidovecUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weis, NinaUNSPECIFIEDorcid.org/0000-0002-3133-2724UNSPECIFIED
Yalcinkaya, TulayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boucher, Charles A. B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wensing, Annemarie M. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perno, Carlo F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Svicher, ValentinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-185041
DOI: 10.1186/s12879-018-3161-2
Journal or Publication Title: BMC Infect. Dis.
Volume: 18
Date: 2018
Publisher: BIOMED CENTRAL LTD
Place of Publication: LONDON
ISSN: 1471-2334
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HEPATITIS-B-VIRUS; SURFACE-ANTIGEN; CLINICAL-IMPLICATIONS; LAMIVUDINE THERAPY; POSITIVE MOTHERS; GENE; REACTIVATION; VACCINATION; PROTEIN; REPLICATIONMultiple languages
Infectious DiseasesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18504

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