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Failure to mulple Interferon-free direct anviral therapies: could chronic hepa,s C become incurable? J Vermehren1, J Dietz1, S Susser1, E Scho52, J Schaenberg3, E Zizer4, J Schulze zur Wiesch5, C Antoni6, P Wietzke-Braun7, C Niederau8, S Mauss9, JK Rockstroh10, B Müllhaupt11, RE Stauber12, S Zeuzem1, C Sarrazin1 1Medizinische Klinik 1, Universitätsklinikum Frankfurt, Germany, 2Charité Universitätsmedizin Berlin, Germany, 3Universitätsklinikum Mainz, Germany, 4Universitätsklinikum Ulm, Germany, 5Universitätsklinikum Eppendorf, Hamburg, Germany, 6Universitätsklinikum Mannheim, Germany, 7Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany, 8Kath. Klinikum Oberhausen, Germany, 9Medizinisches Versorgungszentrum, Düsseldorf, Germany, 10Universitätsklinikum Bonn, Germany, 11UniversitätsSpital Zürich, Switzerland, 12Universitätsklinikum Graz, Austria Background & Aim Methods Chronic hepaRs C virus (HCV) infecon is a major health burden, affecRng approximately 71 million people worldwide who are at risk of developing chronic liver disease, cirrhosis and In a large resistance database, clinical and virological data were collected from paents who failed at least two DAA regimens. HCV NS3, NS5A and NS5B amplificaon and populaon- hepatocellular carcinoma.1 Following the introducRon of direct acRng anRviral agents (DAAs), the majority of paents with chronic HCV infecon can now be cured with only 8-12 based sequencing was performed. weeks of anRviral therapy. However, some paents do not achieve a sustained virologic response (SVR), regardless of the HCV genotype and/or DAA treatment involved. For these Retreatment was primarily based on guideline recommendaons, i.e. paents who failed on a regimen containing an NS5A inhibitor were retreated with a protease inhibitor and 2 paents, retreatment opons are limited. sofosbuvir, and paents who failed on a protease inhibitor-based regimen were retreated with an NS5A inhibitor and sofosbuvir. Retreatment may be parRcularly difficult due to the higher prevalence of negave predictors such as cirrhosis, prior treatment with interferon (IFN), and presence of resistance- However, detailed recommendaons for retreatment were also given based on the resistance analysis, where available. associated subsRtuRons (RASs). The aim of the present study was to assess the clinical and virological characterisRcs and retreatment opRons of paents who failed mulRple courses of DAA therapies in a real-world seng. All paents were retreated at the discreRon of the treang physician. Thus, some paents did not receive guideline-recommended and/or resistance-based regimens. Results 1st DAA Treatment (NS5A Inhibitor-based regimens) Resistance Analysis 1 2nd DAA treatment Resistance Analysis 2 3rd DAA treatment Addi,onal paents (not depicted) There were a total of 5 GT1 paents who did Gen Prior IFN not respond to 12 wks. of SMV + SOF, four Age GT Cirrhosis Regimen Duraon Outcome NS3 NS5A NS5B Regimen Duraon Outcome NS3 NS5A NS5B Regimen Duraon Outcome der experience of whom were retreated with LDV/SOF±RBV for 12-24 wks. All experienced relapse F 60 1a yes yes DCV + SOF 24 wks. REL Q80K Q30H, H58D - LDV/SOF + RBV 24 wks. REL Q80K Q30H, H58D - GZR/EBR + SOF + RBV 16 wks. SVR12 thereaer. None have been retreated so far. M 55 1a yes yes LDV/SOF 12 wks. REL NA NA NA PrOD + RBV 24 wks. REL - L31V - GZR/EBR + SOF + RBV 12 wks. SVR12 The remaining SMV + SOF failure paent M 50 1a yes yes LDV/SOF 12 wks. REL - Q30R - LDV/SOF + RBV 24 wks. REL - Q30R - SOF/VEL/VOX 12 wks. pending received ProD+RBV for 24 wks. but experienced virologic breakthrough at week M 60 1a no no LDV/SOF 8 wks. REL - Q30R - PrOD + RBV 12 wks. REL Y56H, D168A Q30R Y448H GZR/EBR + SOF + RBV 12 wks. SVR12 19. This paent had RASs in all 3 targets. He M 68 1a yes no LDV/SOF 12 wks. REL - Q30R - PrOD + RBV 12 wks. REL D168A, R155K Q30R S556G No retreatment was retreated with LDV/SOF+SMV+RBV for 24 wks. with SVR12. F 55 1a yes yes LDV/SOF + RBV 12 wks. REL - - S556G LDV/SOF + RBV 24 wks. REL - M28T, Q30R S556G SMV + SOF + RBV 12 wks. SVR12 M 62 1a yes yes LDV/SOF + RBV 12 wks. REL - Y93C - ProD + SOF + RBV 24 wks. REL R155K M28T, Q30R - SOF/VEL/VOX 12 wks. pending M 57 1a yes yes VEL/SOF 12 wks. REL - Q30R, H58D - PrOD + RBV 12 wks. REL D168V Q30R, H58D - No retreatment DAA regimen according to M 59 1b yes yes LDV/SOF 12 wks. REL - Y93H C316N, S556G SMV + SOF + RBV 24 wks. REL - Y93H C316N, S556G No retreatment guideline recommendaon F 56 1b no yes LDV/SOF 12 wks. REL - Y93H - SMV + SOF + RBV 24 wks. BT - - - No retreatment and/or resistance analysis F 73 1b no yes LDV/SOF 24 wks. REL NA NA NA PrOD 14 wks. discont.* NA NA NA DCV + SOF 24 wks. REL Non-recommended M 55 3a yes yes DCV + SOF 24 wks. NR - Y93H - DCV + SOF + RBV 24 wks. REL - Y93H L159F No retreatment regimen M 53 3a yes yes DCV + SOF 24 wks. REL - Y93H - LDV/SOF 36 wks. REL - Y93H - SOF/VEL/VOX 12 wks. pending Recommended regimen M 46 3a no yes DCV + SOF 12 wks. REL - Y93H - VEL/SOF + RBV 12 wks. REL - Y93H - SOF/VEL/VOX 12 wks. pending but short duraon and/or M 63 3a yes yes DCV + SOF 12 wks. REL - A30K - VEL/SOF + RBV 12 wks. REL - A30K, L31V - No retreatment no RBV added F 56 3a yes yes DCV + SOF + RBV 24 wks. REL NA NA NA LDV/SOF + RBV 24 wks. REL - Y93H - No retreatment M 55 3a yes yes DCV + SOF + RBV 24 wks. REL - Y93H - VEL/SOF + RBV 12 wks. REL - Y93H - No retreatment * disconnued due to side effects M 61 3a yes yes DCV + SOF + RBV 12 wks. REL - Y93H - VEL/SOF + RBV 12 wks. REL - Y93H - No retreatment **plus 20 wks. PEG-IFN/RBV rescue F 66 3a yes yes LDV/SOF 24 wks. REL NA NA NA VEL/SOF 12 wks. REL - Y93H - No retreatment therapy M 39 3a yes yes LDV/SOF 12 wks. REL NA NA NA VEL/SOF 12 wks. REL - Y93H - No retreatment Abbreviaons: • ASV, asunaprevir M 56 4d yes no LDV/SOF + RBV 12 wks. BT - L30R, Y93H SMV + SOF + RBV 12 wks. D168V L30R, Y93C No retreatment 1st DAA Treatment (NS3/4A Inhibitor-based) - REL - • DCV, daclatasvir F 55 4r yes yes LDV/SOF 12 wks. REL L30R, Y93S S282T VEL/SOF + RBV 12 wks. REL - L30R, Y93S - No retreatment • EBR, elbasvir • GZR, grazoprevir st nd rd 1 DAA Treatment (other regimens) Resistance Analysis 1 2 DAA treatment Resistance Analysis 2 3 DAA treatment • IFN, interferon Gen Prior IFN . • LDV, ledipasvir Age GT Cirrhosis Regimen Duraon Outcome NS3 NS5A NS5B Regimen Duraon Outcome NS3 NS5A NS5B Regimen Duraon Outcome • PrOD, paritaprevir/ritonavir, ombitasvir + der experience dasabuvir M 55 1a yes yes PrOD + RBV 12 wks. REL NA NA NA SMV + SOF 12 wks. REL NA NA NA LDV/SOF + RBV 24 wks. REL • RBV, ribavirin M 61 1a no no PrOD + RBV 12 wks. REL Q80K, D168A Q30H, Y93H S556G GZR/EBR + RBV 16 wks. REL pending pending No retreatment • SMV, simeprevir • SOF, sofosbuvir M 56 3a yes yes SOF + RBV 24 wks. REL - - - DCV + SOF + RBV 24 wks. REL - Y93H - No retreatment HCC • VEL, velpatasvir M 56 3a yes no SOF + RBV 24 wks. REL NA NA NA DCV + SOF 24 wks. REL - A30K - No retreatment • VOX, voxilaprevir F 57 3a yes yes SOF + RBV 24 wks. REL - - - DCV + SOF + RBV 24 wks. REL - Y93H - No retreatment HCC • GT, genotype • NA, not available M 52 3a no no SOF + RBV 24 wks. REL - - - DCV + SOF 12 wks. REL - Y93H - SOF/VEL/VOX + RBV 12 wks. pending • wks., weeks M 64 3a no no SOF + RBV 24 wks. REL NA NA NA VEL/SOF 12 wks. NR - A30K, Y93H - SOF/VEL/VOX + RBV 12 wks. pending References: M 44 3a yes yes SOF + RBV 24 wks. REL NA NA NA VEL/SOF 12 wks. REL - Y93H - No retreatment 1. WHO Factsheet HCV 2017 2. Bourlière et al. NEJM 2017 M 55 3a yes yes SOF + RBV 24 wks. REL - Y93H - VEL/SOF + RBV 24 wks. REL - Y93H - No retreatment F 55 3a yes no SOF + RBV 24 wks. REL - A30K - VEL/SOF + RBV 12 wks. REL - A30K - No retreatment Disclosures: JV received speaking and/or consulng fees from M 76 1b yes yes DCV + ASV** 12 wks. REL - L31M - SMV + SOF + RBV 12 wks. REL D168Y L31M, Y93H - LDV/SOF + RBV 24 wks. SVR12 Abbo5, AbbVie, BMS, Gilead, Medtronic, Merck/MSD, and Roche. Disclosures from other authors can be found in the Conclusion abstract book. • Importantly, treatment failure was even observed in paents in whom the best-available retreatment opon was chosen • Contact: The majority of pa,ents who did not respond to mul,ple DAA therapies • Some paents who do not respond to multargeted rescue therapies may never be cured were male (76%) and had cirrhosis (79%) [email protected] Acknowledgements: • University Hospitals: C. Antoni, R. Vogelmann, M. Ebert (Mannheim, DE); J. Backhus, T. Seufferlein (Ulm, DE); J. Balavoine, E. Giostra (Genf, CH); C. Berg (Tübingen, DE); M. Cornberg, H. Wedemeyer, M. Manns (Hannover, DE); A. De Go5ardi (Bern, CH); R. Esteban (Barcelona, ES); T. Discher , E. Roeb (Gießen, DE); M. Gress (Marburg, DE); R. Günther (Kiel, DE); A. Herrmann, A. Stallmach (Jena. DE); D. Hoffmann (TU, München); H. Klinker (Würzburg, DE); A. Kodal (Lübeck, DE); F. Lammert (Homburg); M. Löbermann (Rostock, DE); A. Lohse (Hamburg, DE); P. Malfertheiner (Magdeburg, DE); D. Resistance tes,ng was performed in 71% of pa,ents aJer the first failed Moradpour (Lausanne, CH); C. Moreno (Brüssel, BE); C Neumann-Haefelin ; R. Thimme (Freiburg, DE); L. Reinhardt, V.
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    The Great Trail in Alberta Le Grand Sentier d’Alberta This marks the connection of Alberta’s section of The Great Trail of Canada in honour of Canada’s 150th anniversary Ceci marque le raccordement du Grand Sentier à travers d’Alberta pour le 150e anniversaire de la Confédération of Confederation in 2017. canadienne en 2017. À partir d’où vous êtes, vous pouvez entreprendre l’un des voyages les plus beaux et les plus diversifiés du monde. From where you are standing, you can embark upon one of the most magnificent and diverse journeys in the world. Que vous vous dirigiez vers l’est, l’ouest, le nord ou le sud, Le Grand Sentier du Canada — créé par le sentier Whether heading east, west, north or south, The Great Trail—created by Trans Canada Trail (TCT) and its partners— Transcanadien (STC) et ses partenaires — vous offre ses multiples beautés naturelles ainsi que la riche histoire et offers all the natural beauty, rich history and enduring spirit of our land and its peoples. l’esprit qui perdure de notre pays et des gens qui l’habitent. Launched in 1992, just after Canada’s 125th anniversary of Confederation The Great Trail was conceived by a group of Lancé en 1992, juste après le 125e anniversaire de la Confédération du Canada, Le Grand Sentier a été conçu, par un visionary and patriotic individuals as a means to connect Canadians from coast to coast to coast. groupe de visionnaires et de patriotes, comme le moyen de relier les Canadiens d’un océan aux deux autres.
  • Listdpcampsbyteamno.Pdf

    Listdpcampsbyteamno.Pdf

    Land Geallieerde Zone Team nr Location teams Camp Germany American zone, District no. 5 Team 1 Füssen Germany French Zone, Northern district Team 2 Landstuhl Germany American zone, District no. 3 Team 3 Bamberg Giessen (Verdun Kaserne) Germany American zone, District no. 1 Team … Schwäbisch Gmünd Motor pool, Hardt-Kaserne (Polish), Germany British zone, Westfalen region Team 5 Hagen Germany British zone, Westfalen region Team 6 Paderborn Germany British zone, Westfalen region Team 7 Haltern am See Germany British zone, North Rhine region Team 8 Duisdorf Euskirchen Camp Germany American zone, District no. 2 Team 9 Darmstadt Germany American zone, District no. 2 Team 10 Giessen Berg Kaserne Germany British zone, Westfalen region Team 11 Greven Germany British zone, North Rhine region Team 12 Dorsten Doistein Camp Germany British zone, Hannover region Team 13 Hameln Germany French Zone, Northern district Team 14 Wittlich Germany French Zone, Northern district Team 15 Lebach Sammellager für ausländische Arbeiter Kaserne Lebach Germany French Zone, Northern district Team 15 Trier-Kemmel Germany British zone, North Rhine region Team 16 Düsseldorf Germany French Zone, Northern district Team 17 Landstuhl Germany French Zone, Northern district Team 18 Baumholder Germany French Zone, Northern district Team 19 Trier Germany French Zone, Northern district Team 20 Koblenz Germany American zone, District no. 5 Team 21 Augsburg Germany British zone, Westfalen region Team 22 Melle Germany American zone, District no. 1 Team 23 Mannheim Germany British zone, North Rhine region Team 25 Köln Germany French Zone, Northern district Team 26 Homburg Germany American zone, District no. 2 Team 27 Hanau Germany American zone, District no.
  • Westfälische Bibliographie Zur Geschichte, Landes- Kunde Und Volkskunde

    Westfälische Bibliographie Zur Geschichte, Landes- Kunde Und Volkskunde

    Bertram Haller Westfälische Bibliographie zur Geschichte, Landes- kunde und Volkskunde Vierter Band: Register Materialien der Historischen Kommission für Westfalen Band 2 Bertram Haller Westfälische Bibliographie zur Geschichte, Landeskunde und Volkskunde Vierter Band: Register Materialien der Historischen Kommission für Westfalen Band 2 © 2013 Historische Kommission für Westfalen, Landschaftsverband Westfalen-Lippe Historische Kommission für Westfalen Geschäftsstelle Postanschrift: Salzstraße 38 (Erbdrostenhof) Historische Kommission für Westfalen 48143 Münster Landschaftsverband Westfalen-Lippe Telefon (0251) 591–4720 48133 Münster Fax (0251) 591–5871 Email: [email protected] www.historische-kommission.lwl.org Einleitung In Westfalen war durch eine gemeinsame Initiative der Historischen Kommission und des Ver- eins für Geschichte und Altertumskunde Westfalens im Jahre 1936 ein lange gehegter Plan einer retrospektiven Bibliographie für Westfalen durch Alois Bömer, den ehemaligen Direktor der Universitätsbibliothek Münster, und durch Hermann Degering, den pensionierten Direktor der Handschriftenabteilung der Preußischen Staatsbibliothek Berlin, mit der „Westfälischen Bibliographie zur Geschichte, Landeskunde und Volkskunde“ in Angriff genommen und bis 1944 in die Tat umgesetzt worden. Sie umfaßt die Literatur von etwa 1800 bis 1940. Nach dem Tod von Hermann Degering 1942 und Alois Bömer 1944 lag diese Bibliographie als Ma- nuskript vor. Von 1955 bis 1990 wurde ihr Text von Rudolf Schetter, Johannes Bauermann, Helmut Müller und Bertram Haller bearbeitet, ergänzt und zum Druck gebracht. Eine Arbeit, für die von Bömer und Degering keinerlei Vorarbeit vorlag, war die Anfertigung eines alphabetischen Gesamtregisters. Dieses ist das Werk in erster Linie von Rudolf Schetter. Rudolf Schetter hatte bereits 1945 die Bearbeitung der Bibliographie und ihres Registers nach den damals gültigen Kriterien übernommen. Diese Kriterien entsprechen heute nicht mehr den modernen Anforderungen.
  • DZIF Annual Report 2019

    DZIF Annual Report 2019

    GERMAN CENTER FOR INFECTION RESEARCH Annual Report 2019 1 Cover image: Blood meal served on a cotton swab. Mosquitoes are not only annoying, but also sometimes dangerous pests. Through their saliva they can transmit various viruses and other pathogens such as malaria parasites. ANNUAL REPORT 2019 The DZIF at a glance The German Center for Infection Research (DZIF) coordinates and oversees the strategic planning of translational infection research within Germany. Its mission is to translate results from basic biomedical research into clinical research. 35 DZIF research centres work concertedly against the global threat of infectious diseases. Table of contents Editorial ............................................................................................................................................................................. 3 About the DZIF ............................................................................................................................................................. 4 Science – Translation in focus Emerging Infections ................................................................................................................................................. 6 Tuberculosis ................................................................................................................................................................... 8 Malaria .............................................................................................................................................................................