<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Colagrossi, L.</style></author><author><style face="normal" font="default" size="100%">Hermans, L. E.</style></author><author><style face="normal" font="default" size="100%">Salpini, R.</style></author><author><style face="normal" font="default" size="100%">Di Carlo, D.</style></author><author><style face="normal" font="default" size="100%">Pas, S. D.</style></author><author><style face="normal" font="default" size="100%">Alvarez, M</style></author><author><style face="normal" font="default" size="100%">Ben-Ari, Z.</style></author><author><style face="normal" font="default" size="100%">Boland, G.</style></author><author><style face="normal" font="default" size="100%">Bruzzone, B.</style></author><author><style face="normal" font="default" size="100%">Coppola, N.</style></author><author><style face="normal" font="default" size="100%">Seguin-Devaux, C.</style></author><author><style face="normal" font="default" size="100%">Dyda, T.</style></author><author><style face="normal" font="default" size="100%">Garcia, F</style></author><author><style face="normal" font="default" size="100%">Kaiser, R</style></author><author><style face="normal" font="default" size="100%">Köse, S.</style></author><author><style face="normal" font="default" size="100%">Krarup, H.</style></author><author><style face="normal" font="default" size="100%">Lazarevic, I.</style></author><author><style face="normal" font="default" size="100%">Lunar, M. M.</style></author><author><style face="normal" font="default" size="100%">Maylin, S.</style></author><author><style face="normal" font="default" size="100%">Micheli, V.</style></author><author><style face="normal" font="default" size="100%">Mor, O</style></author><author><style face="normal" font="default" size="100%">Paraschiv, S</style></author><author><style face="normal" font="default" size="100%">Paraskevis, D</style></author><author><style face="normal" font="default" size="100%">Poljak, M</style></author><author><style face="normal" font="default" size="100%">Puchhammer-Stöckl, E</style></author><author><style face="normal" font="default" size="100%">Simon, F.</style></author><author><style face="normal" font="default" size="100%">Stanojevic, M</style></author><author><style face="normal" font="default" size="100%">Stene-Johansen, K.</style></author><author><style face="normal" font="default" size="100%">Tihic, N.</style></author><author><style face="normal" font="default" size="100%">Trimoulet, P.</style></author><author><style face="normal" font="default" size="100%">Verheyen, J.</style></author><author><style face="normal" font="default" size="100%">Vince, A.</style></author><author><style face="normal" font="default" size="100%">Lepej, S. Z.</style></author><author><style face="normal" font="default" size="100%">Weis, N.</style></author><author><style face="normal" font="default" size="100%">Yalcinkaya, T.</style></author><author><style face="normal" font="default" size="100%">Boucher, C A B</style></author><author><style face="normal" font="default" size="100%">Wensing, A M J</style></author><author><style face="normal" font="default" size="100%">Perno, C. F.</style></author><author><style face="normal" font="default" size="100%">Svicher, V.</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">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</style></title><secondary-title><style face="normal" font="default" size="100%">BMC Infect DisBMC Infect DisBMC Infect Dis</style></secondary-title><alt-title><style face="normal" font="default" size="100%">BMC infectious diseases</style></alt-title><short-title><style face="normal" font="default" size="100%">BMC infectious diseasesBMC infectious diseases</style></short-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">(Grant No. 4–003/2012 (UEFISCDI)), during the conduct of the study. NW received a</style></keyword><keyword><style  face="normal" font="default" size="100%">*Codon, Terminator</style></keyword><keyword><style  face="normal" font="default" size="100%">*Drug-resistance</style></keyword><keyword><style  face="normal" font="default" size="100%">*HBsAg</style></keyword><keyword><style  face="normal" font="default" size="100%">*Hbv</style></keyword><keyword><style  face="normal" font="default" size="100%">*Immune-escape</style></keyword><keyword><style  face="normal" font="default" size="100%">*Mutation</style></keyword><keyword><style  face="normal" font="default" size="100%">*Stop-codons</style></keyword><keyword><style  face="normal" font="default" size="100%">175073), during the conduct of the study. SP received a grant from project BESTHOPE,</style></keyword><keyword><style  face="normal" font="default" size="100%">2013), Luxembourg (as outlined in art. 25 of 28th august 1998 law on hospitals</style></keyword><keyword><style  face="normal" font="default" size="100%">2016, promoted by EASL and at the 14th European Meeting of HIV &amp; Hepatitis 2016.</style></keyword><keyword><style  face="normal" font="default" size="100%">Adult</style></keyword><keyword><style  face="normal" font="default" size="100%">Amino Acid Substitution</style></keyword><keyword><style  face="normal" font="default" size="100%">Antiviral Agents/*therapeutic use</style></keyword><keyword><style  face="normal" font="default" size="100%">available, thus approval was deemed unnecessary according the Internal Regulation of</style></keyword><keyword><style  face="normal" font="default" size="100%">changes on April 20, 2004 “Pharmaceutical Law”), Norway (as outlined in the Regional</style></keyword><keyword><style  face="normal" font="default" size="100%">claims in published maps and institutional affiliations.</style></keyword><keyword><style  face="normal" font="default" size="100%">Clinical Center, Bosnia Erzegovina. In accordance with National Guidelines and/or</style></keyword><keyword><style  face="normal" font="default" size="100%">comittees of medical and health research ethics in Norway, reference nr 2012/896),</style></keyword><keyword><style  face="normal" font="default" size="100%">Committee of Sheba Medical Center in Israel, Ethikkommission of the Medical</style></keyword><keyword><style  face="normal" font="default" size="100%">Croatia, specific national guidelines/legislatives on this issue are currently not</style></keyword><keyword><style  face="normal" font="default" size="100%">de la Provincia de Granada, Granada, Spain. Director for Research of University</style></keyword><keyword><style  face="normal" font="default" size="100%">device. Part of the samples derived from our RESINA-cohort which is approved by the</style></keyword><keyword><style  face="normal" font="default" size="100%">during the conduct of the study, and received fees for advisory board participation,</style></keyword><keyword><style  face="normal" font="default" size="100%">Dutch Civil Code [WMO] and 7:457 [WGBO]), Denmark (as outlined in the Act on</style></keyword><keyword><style  face="normal" font="default" size="100%">establishments), Poland (as outlined in the Polish Act from on December 5, 1996, on</style></keyword><keyword><style  face="normal" font="default" size="100%">ethics “Cologne-16-460”. COMPETING INTERESTS: IL received a grant from the Ministry</style></keyword><keyword><style  face="normal" font="default" size="100%">Europe</style></keyword><keyword><style  face="normal" font="default" size="100%">Female</style></keyword><keyword><style  face="normal" font="default" size="100%">France (as outlined in French Public Health Law CSP Art. L 1121–1.1), Rumenia (as</style></keyword><keyword><style  face="normal" font="default" size="100%">from Regulations on Clinical Research, Official Gazette, Number 28617 at Apr 13,</style></keyword><keyword><style  face="normal" font="default" size="100%">from the legislative decree 211/2003), The Netherlands (as outlined in 7:467 of the</style></keyword><keyword><style  face="normal" font="default" size="100%">Genotype</style></keyword><keyword><style  face="normal" font="default" size="100%">grant from The Danish Council for Independent Research (Grant No. 12–127,717),</style></keyword><keyword><style  face="normal" font="default" size="100%">grants from Bristol-Myers Squibb, Gilead, Janssen, MSD and Viiv Healthcare. None of</style></keyword><keyword><style  face="normal" font="default" size="100%">Hepatitis B Surface Antigens/*genetics/immunology</style></keyword><keyword><style  face="normal" font="default" size="100%">Hepatitis B virus/*genetics/immunology</style></keyword><keyword><style  face="normal" font="default" size="100%">Hepatitis B, Chronic/drug therapy/*immunology/virology</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Janssen, MSD and Medivir. AMJW received consultancy fees, travel and/or research</style></keyword><keyword><style  face="normal" font="default" size="100%">Kapodistrian University of Athens, Athens, Greece. Ethic Committee of the Faculty of</style></keyword><keyword><style  face="normal" font="default" size="100%">lectures and chairing meetings from Abbvie, Bristol-Myers Squibb, Glaxo Smith Kline,</style></keyword><keyword><style  face="normal" font="default" size="100%">legislature, approval by Ethic Committee was not necessary since the study was based</style></keyword><keyword><style  face="normal" font="default" size="100%">Male</style></keyword><keyword><style  face="normal" font="default" size="100%">Medicine, University of Belgrade, Belgrade, Serbia. Comité de Etica de Investigacion</style></keyword><keyword><style  face="normal" font="default" size="100%">Middle Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">of Education, Science and Technological Development, Republic of Serbia, (Grant No.</style></keyword><keyword><style  face="normal" font="default" size="100%">of sequences submission, there was no specific requirement concerning retrospective</style></keyword><keyword><style  face="normal" font="default" size="100%">on a retrospective analysis of anonymized viral sequences obtained for clinical</style></keyword><keyword><style  face="normal" font="default" size="100%">outlined in leg. 46/2003), Slovenia (as outlined in 26 Direktive 98/44/EC). For</style></keyword><keyword><style  face="normal" font="default" size="100%">PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional</style></keyword><keyword><style  face="normal" font="default" size="100%">received educational and research grants from BMS and Gilead, during the conduct of</style></keyword><keyword><style  face="normal" font="default" size="100%">Research Ethics Review of Health Research Projects), Turkey (as outlined in art. 2</style></keyword><keyword><style  face="normal" font="default" size="100%">routine practice for the following centers: Italy (as outlined in art. 6 and art. 9</style></keyword><keyword><style  face="normal" font="default" size="100%">Society for the study of AIDS and STDs, during the conduct of the study. VS and CFP</style></keyword><keyword><style  face="normal" font="default" size="100%">studies, legislations covered only clinical trials involving drugs or medical</style></keyword><keyword><style  face="normal" font="default" size="100%">the University Hospital for Infectious Diseases, in Zagreb. For Germany, at the time</style></keyword><keyword><style  face="normal" font="default" size="100%">these were related to this work. DP received funding by the Hellenic Scientific</style></keyword><keyword><style  face="normal" font="default" size="100%">this manuscript have been presented in part at the 51st International Liver Congress</style></keyword><keyword><style  face="normal" font="default" size="100%">this study. The other authors have no conflict of interests. Results reported in</style></keyword><keyword><style  face="normal" font="default" size="100%">University, Vienna, Austria. Ethical Committee of the Medical School National and</style></keyword><keyword><style  face="normal" font="default" size="100%">“physician professions and dentists” and in art. 37.1 Act of September 6, 2001 with</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2018</style></year><pub-dates><date><style  face="normal" font="default" size="100%">Jun 1</style></date></pub-dates></dates><number><style face="normal" font="default" size="100%">1</style></number><edition><style face="normal" font="default" size="100%">2018/06/03</style></edition><volume><style face="normal" font="default" size="100%">18</style></volume><pages><style face="normal" font="default" size="100%">251</style></pages><isbn><style face="normal" font="default" size="100%">1471-2334</style></isbn><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">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 &lt; 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.</style></abstract><accession-num><style face="normal" font="default" size="100%">29859062</style></accession-num><notes><style face="normal" font="default" size="100%">1471-2334Colagrossi, LunaHermans, Lucas ESalpini, RominaDi Carlo, DomenicoPas, Suzan DAlvarez, MartaBen-Ari, ZivBoland, GreetBruzzone, BiancaCoppola, NicolaSeguin-Devaux, CaroleDyda, TomaszGarcia, FedericoKaiser, RolfKöse, SukranKrarup, HenrikLazarevic, IvanaLunar, Maja MMaylin, SarahMicheli, ValeriaMor, OrnaParaschiv, SimonaParaskevis, DimitrosPoljak, MarioPuchhammer-Stöckl, ElisabethSimon, FrançoisStanojevic, MajaStene-Johansen, KathrineTihic, NijazTrimoulet, PascaleVerheyen, JensVince, AdrianaLepej, Snjezana ZidovecWeis, NinaYalcinkaya, TülayBoucher, 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.</style></notes><custom2><style face="normal" font="default" size="100%">PMC5984771</style></custom2><auth-address><style face="normal" font="default" size="100%">Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy.Virology, Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands.Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands.Servicio de Microbiología, Hospital San Cecilio, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada, Granada, Spain.Liver Disease Centre, Sheba Medical Centre, Ramat Gan, Israel.Hygiene Unit, IRCCS AOU San Martino - IST, Genoa, Italy.Malattie Infettive, Seconda Università degli studi di Napoli, Naples, Italy.Laboratory of Retrovirology, CRP-Santé, Luxembourg, Luxembourg.Molecular Diagnostics Laboratory, Hospital of Infectious Diseases, Warsaw, Poland.Institute of Virology, University of Cologne, Cologne, Germany.Izmir Tepecik Education and Research Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Izmir, Turkey.Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark.Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.Service de Microbiologie, University Paris Diderot, Hôpital Saint Louis, Paris, France.L. Sacco Hospital, Milan, Italy.National HIV Reference Laboratory, Central Virology Laboratory, Ministry of Health, Tel Hashomer, Ramat Gan, Israel.Molecular Diagnostics Laboratory, National Institute for Infectious Diseases &quot;Matei Bals&quot;, Bucharest, Romania.National Retrovirus Reference Centre, Department of Hygiene, Epidemiology and Medical Statistics, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.Department for Virology, Medical University of Vienna, Vienna, Austria.Department of Virology, Norwegian Institute of Public Health, Oslo, Norway.Institute of Microbiology, Polyclinic for Laboratory Diagnostics, University Clinical Centre Tuzla, Tuzla, Bosnia and Herzegovina.Virology Laboratory, Centre Hospitalier Régional et Université &quot;Victor Segalen&quot;, Bordeaux, France.Institute of Virology, University-Hospital, University Duisburg-Essen, Essen, Germany.University of Zagreb School of Medicine and University Hospital for Infectious Diseases, Zagreb, Croatia.Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark.Refik Saydam National Public Health Agency, Ankara, Turkey.Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy. cf.perno@uniroma2.it.Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy. valentina.svicher@uniroma2.it.</style></auth-address><remote-database-provider><style face="normal" font="default" size="100%">NLM</style></remote-database-provider></record></records></xml>