@article {20341,
	title = {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},
	journal = {BMC Infect DisBMC Infect DisBMC Infect Dis},
	volume = {18},
	number = {1},
	year = {2018},
	note = {1471-2334Colagrossi, LunaHermans, Lucas ESalpini, RominaDi Carlo, DomenicoPas, Suzan DAlvarez, MartaBen-Ari, ZivBoland, GreetBruzzone, BiancaCoppola, NicolaSeguin-Devaux, CaroleDyda, TomaszGarcia, FedericoKaiser, RolfK{\"o}se, SukranKrarup, HenrikLazarevic, IvanaLunar, Maja MMaylin, SarahMicheli, ValeriaMor, OrnaParaschiv, SimonaParaskevis, DimitrosPoljak, MarioPuchhammer-St{\"o}ckl, ElisabethSimon, Fran{\c c}oisStanojevic, MajaStene-Johansen, KathrineTihic, NijazTrimoulet, PascaleVerheyen, JensVince, AdrianaLepej, Snjezana ZidovecWeis, NinaYalcinkaya, T{\"u}layBoucher, Charles A BWensing, Annemarie M JPerno, Carlo FSvicher, ValentinaOrcid: 0000-0002-2377-504xHEPVIR working group of the European Society for translational antiviral research (ESAR)RBAP11YS7K_001/FIRB project/InternationalPB05/InterOmics/InternationalJournal ArticleMulticenter StudyBMC Infect Dis. 2018 Jun 1;18(1):251. doi: 10.1186/s12879-018-3161-2.},
	month = {Jun 1},
	pages = {251},
	edition = {2018/06/03},
	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-na{\"\i}ve 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.},
	keywords = {(Grant No. 4{\textendash}003/2012 (UEFISCDI)), during the conduct of the study. NW received a, *Codon, Terminator, *Drug-resistance, *HBsAg, *Hbv, *Immune-escape, *Mutation, *Stop-codons, 175073), during the conduct of the study. SP received a grant from project BESTHOPE,, 2013), Luxembourg (as outlined in art. 25 of 28th august 1998 law on hospitals, 2016, promoted by EASL and at the 14th European Meeting of HIV \& Hepatitis 2016., Adult, Amino Acid Substitution, Antiviral Agents/*therapeutic use, available, thus approval was deemed unnecessary according the Internal Regulation of, changes on April 20, 2004 {\textquotedblleft}Pharmaceutical Law{\textquotedblright}), Norway (as outlined in the Regional, claims in published maps and institutional affiliations., Clinical Center, Bosnia Erzegovina. In accordance with National Guidelines and/or, comittees of medical and health research ethics in Norway, reference nr 2012/896),, Committee of Sheba Medical Center in Israel, Ethikkommission of the Medical, Croatia, specific national guidelines/legislatives on this issue are currently not, de la Provincia de Granada, Granada, Spain. Director for Research of University, device. Part of the samples derived from our RESINA-cohort which is approved by the, during the conduct of the study, and received fees for advisory board participation,, Dutch Civil Code [WMO] and 7:457 [WGBO]), Denmark (as outlined in the Act on, establishments), Poland (as outlined in the Polish Act from on December 5, 1996, on, ethics {\textquotedblleft}Cologne-16-460{\textquotedblright}. COMPETING INTERESTS: IL received a grant from the Ministry, Europe, Female, France (as outlined in French Public Health Law CSP Art. L 1121{\textendash}1.1), Rumenia (as, from Regulations on Clinical Research, Official Gazette, Number 28617 at Apr 13,, from the legislative decree 211/2003), The Netherlands (as outlined in 7:467 of the, Genotype, grant from The Danish Council for Independent Research (Grant No. 12{\textendash}127,717),, grants from Bristol-Myers Squibb, Gilead, Janssen, MSD and Viiv Healthcare. None of, Hepatitis B Surface Antigens/*genetics/immunology, Hepatitis B virus/*genetics/immunology, Hepatitis B, Chronic/drug therapy/*immunology/virology, Humans, Janssen, MSD and Medivir. AMJW received consultancy fees, travel and/or research, Kapodistrian University of Athens, Athens, Greece. Ethic Committee of the Faculty of, lectures and chairing meetings from Abbvie, Bristol-Myers Squibb, Glaxo Smith Kline,, legislature, approval by Ethic Committee was not necessary since the study was based, Male, Medicine, University of Belgrade, Belgrade, Serbia. Comit{\'e} de Etica de Investigacion, Middle Aged, of Education, Science and Technological Development, Republic of Serbia, (Grant No., of sequences submission, there was no specific requirement concerning retrospective, on a retrospective analysis of anonymized viral sequences obtained for clinical, outlined in leg. 46/2003), Slovenia (as outlined in 26 Direktive 98/44/EC). For, PUBLISHER{\textquoteright}S NOTE: Springer Nature remains neutral with regard to jurisdictional, received educational and research grants from BMS and Gilead, during the conduct of, Research Ethics Review of Health Research Projects), Turkey (as outlined in art. 2, routine practice for the following centers: Italy (as outlined in art. 6 and art. 9, Society for the study of AIDS and STDs, during the conduct of the study. VS and CFP, studies, legislations covered only clinical trials involving drugs or medical, the University Hospital for Infectious Diseases, in Zagreb. For Germany, at the time, these were related to this work. DP received funding by the Hellenic Scientific, this manuscript have been presented in part at the 51st International Liver Congress, this study. The other authors have no conflict of interests. Results reported in, University, Vienna, Austria. Ethical Committee of the Medical School National and, {\textquotedblleft}physician professions and dentists{\textquotedblright} and in art. 37.1 Act of September 6, 2001 with},
	isbn = {1471-2334},
	author = {Colagrossi, L. and Hermans, L. E. and Salpini, R. and Di Carlo, D. and Pas, S. D. and Alvarez, M and Ben-Ari, Z. and Boland, G. and Bruzzone, B. and Coppola, N. and Seguin-Devaux, C. and Dyda, T. and Garcia, F and Kaiser, R and K{\"o}se, S. and Krarup, H. and Lazarevic, I. and Lunar, M. M. and Maylin, S. and Micheli, V. and Mor, O and Paraschiv, S and Paraskevis, D and Poljak, M and Puchhammer-St{\"o}ckl, E and Simon, F. and Stanojevic, M and Stene-Johansen, K. and Tihic, N. and Trimoulet, P. and Verheyen, J. and Vince, A. and Lepej, S. Z. and Weis, N. and Yalcinkaya, T. and Boucher, C A B and Wensing, A M J and Perno, C. F. and Svicher, V.}
}
