HBV: clinical implications beyond drug resistance Jens Verheyen - - PowerPoint PPT Presentation
HBV: clinical implications beyond drug resistance Jens Verheyen Institut fr Virologie Universittsklinikum Essen What can be more interesting than resistance profiles? M204I/V A181T/V N236T T128I V191I Adefovir Lamivudin adefovir
Institut für Virologie Universitätsklinikum Essen
M204I/V Lamivudin telbivudin M204I/V+ L180C/M+ I169T+ T184AGIS+ S202GI+ M250V entecavir A181T/V Adefovir lamivudin N236T adefovir T128I V191I A194T V207I Q215S L229MVFW Complex resistance profiles
Nguyen, T. and Locarnini, S. (2009) Nat. Rev. Gastroenterol. Hepatol. doi:10.1038
HBV isolates carrying mutations M204I/V: n=60 Prevalence of HBsAg stop codons: n=7 (12%) Clonal analysis of HBV isolates carrying stop codons (n=7): aditional stop codons n=2 HBV isolates carrying two stop codons: n=2 Mutation A181T does not always lead to a stop codon at position HBsAg 172
Y Q G M L P L P T C T T G S T G T P K T S I V T A C P Q P C G N M S F C C P P G T C K D C N T T F K Y P S I W L I C S W A A D L
98-
S
G145R
105L 109R/V/H/I *110M/R/H/I/V *114R 117T 118K/R/S/P 119R 120A/E/LP/Q/S/T/R 121S/Y 123A/N 124R/Y *126N/S/V/I/T *127R/S/T 128V 129H/K/P/R 130D/R *131D/I/S 132A/P 133I/L/T/V *134H/N/R/S/V 137R/S/W/Y 139S 140S 141E/I/R 142L/R/S *143L/P 144A/E/G 145A/K/L/R 146D/S 147S/T * Positions with genotypic specific polymorphisms
Schaefer et al., 2004
=> 22 of 60 (36.7 %) HBV isolates carried HBsAg mutations previously related to immune escape
Assay A
Differences between two quantitative HBsAg assays in detection in vitro expressed HBsAg => Measuring quantitative HBsAg with two different assays might feign quantitative changes
Assay B
10 20 30 40 50 60 70 HBsAg concentration in cell supernatant (IU/mL) HBsAg mutants Architect Elisa
Promoter Strep-Tec HBsAg HBsAg mutations correlated with occult HBV infection (Svicher et al.):
acute hepatitis (85%) chronic hepatitis (15%) complications: liver cirrhoses hepatocellular carcinoma
Mutations accumulating in hepatocellular carcinoma (HCC): (Valentina Svicher / Romina Salpini)
acute hepatitis (85%) chronic hepatitis (15%) complications: liver cirrhoses hepatocellular carcinoma
HBV related immune diseases
PAN: systemic vasculitis (medium-sized and small muscular arteries)
HBV and PAN: 30% (8%) HBV and PAN: acute or chronic HBV infection. HBV-PAN pathophysiology: immune-complex deposits or viral replication
HBV infected patients with polyarteritis nodosa: n=24 GT-A (n=15), GT-D (n=8), HBV GT-E (n=1) HBV GT-D isolates: n=4 sp-I88V/LHB-I84M/A3105G, sp-H90P/LHB-T87P/A3112C, sp-H100R/LHB-T97A/A3142G HBV isolates: n=12 RT-R41K/SHB-D33N GT-A: n=5, GT-D: n=6, GT-E: n=1 Mutations accumulating in HBV PAN isolates:
HBV pathogenesis (HBsAg stop codons) HBV immune escape (HBsAg) HBV: Viral factors and PAN HBV: Viral factors and HCC HBV detection escape
Bastian Beggel MPI for Informatics, Saarbrücken Thomas Lengauer Andreas Erhardt Klinik für Gastroenterologie Hepatologie und Infektiologie Heinrich Heine Universität Düsseldorf Hauke Niekamp Institut für Medizinische Virologie, Andreas Geipel Justus-Liebig-Universität Gießen Dieter Glebe Valentina Svicher Department of Experimental Medicine and Surgery Valeria Cento Institut of Virology, University of Rome Tor Vergata Romina Slpini Carlo Perno
Institute of Virology, University of Cologne
Maria Neumann-Fraune Elena Knops Nadine Lübke Eugen Schülter Claudia Müller Dörte Hammerschmidt Monika Timmen-Wego Saleta Sierra-Aragon Eva Heger Finja Schweitzer Rolf Kaiser Herbert Pfister