Lucas Etienne Hermans1, Valentina Svicher2, Suzan Diepstraten Pas3, Romina Salpini2, Marta Alvarez4, Ziv Ben Ari5, Greet Boland6, Bianca Bruzzone7, Nicola Coppola8, Carole Seguin-Devaux9, Tomasz Dyda10, Federico Garcia4, Rolf Kaiser11, Sukran Köse12, Henrik Krarup13, Ivana Lazarevic14, Maja M Lunar15, Sarah Maylin16, Valeria Micheli17, Orna Mor18, Simona Paraschiv19, Dimitrios Paraskevis20, Mario Poljak15, Elisabeth Puchhammer-Stöckl21, François Simon16, Maja Stanojevic14, Kathrine Stene-Johansen22, Nijaz Tihic23, Pascale Trimoulet24, Jens Verheyen25, Adriana Vince26, Nina Weis27, Tülay Yalcinkaya28, Snjezana Zidovec Lepej26, Carlo Perno2, Charles A B Boucher3, Annemarie M J Wensing6. 1. Department of Medical Microbiology, University Medical Centre Utrecht Department of Virology, Erasmus Medical Centre, Rotterdam, The Netherlands. 2. Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Italy. 3. Department of Virology, Erasmus Medical Centre, Rotterdam, The Netherlands. 4. Servicio de Microbiología, Hospital San Cecilio, Instituto de Investigación Biosanitaria ibs. GRANADA, Hospitales Universitarios de Granada, Spain. 5. Liver Disease Centre, Sheba Medical Centre, Ramat Gan, Israel. 6. Department of Medical Microbiology, University Medical Centre Utrecht. 7. Hygiene Unit, IRCCS AOU San Martino - IST, Genoa. 8. Malattie Infettive, Seconda Università degli studi di Napoli, Naples, Italy. 9. Laboratory of Retrovirology, CRP-Santé, Luxembourg. 10. Molecular Diagnostics Laboratory, Hospital of Infectious Diseases, Warsaw, Poland. 11. Institute of Virology, University of Cologne, Germany. 12. Clinic of Infectious Diseases and Clinical Microbiology, Izmir Tepecik Education and Research Hospital, Turkey. 13. Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Denmark. 14. Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Serbia. 15. Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Slovenia. 16. Service de Microbiologie, University Paris Diderot, Hôpital Saint Louis, France. 17. Lugi Sacco Hospital, Milan, Italy. 18. National HIV Reference Laboratory, Central Virology Laboratory, Ministry of Health, Tel Hashomer, Ramat Gan, Israel. 19. Molecular Diagnostics Laboratory, National Institute for Infectious Diseases Matei Bals, Bucharest, Romania. 20. National Retrovirus Reference Centre, Department of Hygiene, Epidemiology and Medical Statistics, Faculty of Medicine, National and Kapodistrian University of Athens, Greece. 21. Department for Virology, Medical University of Vienna, Austria. 22. Department of Virology, Norwegian Institute of Public Health, Oslo, Norway. 23. Institute of Microbiology, Polyclinic for Laboratory Diagnostics, University Clinical Centre Tuzla, Bosnia and Herzegovina. 24. Virology Laboratory, Centre Hospitalier Régional et Université Victor Segalen, Bordeaux, France. 25. Institute of Virology, University-Hospital, University Duisburg-Essen, Germany. 26. University of Zagreb School of Medicine and University Hospital for Infectious Diseases "Dr Fran Mihaljevic", Croatia. 27. Department of Infectious Diseases, Copenhagen University Hospital, Denmark. 28. Refik Saydam National Public Health Agency, Ankara, Turkey.
Abstract
BACKGROUND: European guidelines recommend treatment of chronic hepatitis B virus infection (CHB) with the nucleos(t)ide analogs (NAs) entecavir or tenofovir. However, many European CHB patients have been exposed to other NAs, which are associated with therapy failure and resistance. The CAPRE study was performed to gain insight in prevalence and characteristics of NA resistance in Europe. METHODS: A survey was performed on genotypic resistance testing results acquired during routine monitoring of CHB patients with detectable serum hepatitis B virus DNA in European tertiary referral centers. RESULTS: Data from 1568 patients were included. The majority (73.8%) were exposed to lamivudine monotherapy. Drug-resistant strains were detected in 52.7%. The most frequently encountered primary mutation was M204V/I (48.7%), followed by A181T/V (3.8%) and N236T (2.6%). In patients exposed to entecavir (n = 102), full resistance was present in 35.3%. Independent risk factors for resistance were age, viral load, and lamivudine exposure (P < .001). CONCLUSIONS: These findings support resistance testing in cases of apparent NA therapy failure. This survey highlights the impact of exposure to lamivudine and adefovir on development of drug resistance and cross-resistance. Continued use of these NAs needs to be reconsidered at a pan-European level.
BACKGROUND: European guidelines recommend treatment of chronic hepatitis B virus infection (CHB) with the nucleos(t)ide analogs (NAs) entecavir or tenofovir. However, many European CHB patients have been exposed to other NAs, which are associated with therapy failure and resistance. The CAPRE study was performed to gain insight in prevalence and characteristics of NA resistance in Europe. METHODS: A survey was performed on genotypic resistance testing results acquired during routine monitoring of CHB patients with detectable serum hepatitis B virus DNA in European tertiary referral centers. RESULTS: Data from 1568 patients were included. The majority (73.8%) were exposed to lamivudine monotherapy. Drug-resistant strains were detected in 52.7%. The most frequently encountered primary mutation was M204V/I (48.7%), followed by A181T/V (3.8%) and N236T (2.6%). In patients exposed to entecavir (n = 102), full resistance was present in 35.3%. Independent risk factors for resistance were age, viral load, and lamivudine exposure (P < .001). CONCLUSIONS: These findings support resistance testing in cases of apparent NA therapy failure. This survey highlights the impact of exposure to lamivudine and adefovir on development of drug resistance and cross-resistance. Continued use of these NAs needs to be reconsidered at a pan-European level.
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Authors: 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 Journal: BMC Infect Dis Date: 2018-06-01 Impact factor: 3.090
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