Failure to mulple Interferon-free direct anviral therapies: could chronic hepas C become incurable? J Vermehren1, J Dietz1, S Susser1, E Scho2, 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 hepas C virus (HCV) infecon is a major health burden, affecng 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 introducon of direct acng anviral agents (DAAs), the majority of paents with chronic HCV infecon can now be cured with only 8-12 based sequencing was performed. weeks of anviral 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 parcularly 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 substuons (RASs). The aim of the present study was to assess the clinical and virological characteriscs and retreatment opons of paents who failed mulple courses of DAA therapies in a real-world seng. All paents were retreated at the discreon 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 Addional 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 Abbo, 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 paents who did not respond to mulple 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 Goardi (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 tesng was performed in 71% of paents aer the first failed Moradpour (Lausanne, CH); C. Moreno (Brüssel, BE); C Neumann-Haefelin ; R. Thimme (Freiburg, DE); L. Reinhardt, V. Ellenrieder (Göngen, DE); J. Schaenberg, M. Sprinzl, P. Galle (Mainz, DE); J. Schmidt (Münster, DE); E. Scho, H.-J. Epple (Berlin); J Siebler (Erlangen); R. Stauber (Graz, A); M. Steckstor, W. Schmiegel (Bochum, DE); W. Stremmel (Heidelberg); B. Strey (Duisburg), K. Tomasiewicz (Lublin, PL); C. Trautwein (Aachen, DE), R. Zachoval (LMU, München, DE). Academic Hospitals: W. Angeli, (Kempten, DE); S. Beckebaum (Essen, DE); C. Doberauer (Köln, DE); K. Ende (Erfurt, DE); A. Erhardt (Wuppertal, DE); A. Garrido-Lüneburg (Bad Oeynhausen, DE); H. Garinger (Steyr, A); D. Genné (Biel, CH), M. Gschwantler (Vienna, A), F. Gundling (München, DE); C. Hartmann (Esslingen, DE); T. Heyer (Düren, DE), C. Hirschi (Luzern, CH); S. Kanzler (Schweinfurt, DE); N. Kordecki (Lingen, DE); M. Kraus (Altöng-Burghausen, DE); U. Kullig (Dresden, DE); L. Magenta, B. Terziroli Berea-Piccoli (Locarno, CH); M. Menges (Schwäbisch Hall, DE); L. Mohr (Lahr); K. Muehlenberg (Regensburg); C. Niederau (Oberhausen, DE); B. Paulweber (Salzburg, A); A. Petrides (Bochum, DE); R. Piso (Olten, CH); W. Rambach (Bad Kissingen); M. Reiser (Marl, DE); B. Riecken (Ludwigsburg, DE); J. Roth (Lauterbach, DE); R. Schöfl, A. Maieron (Linz, A); A. Schneider (Korbach, DE); M. Schuchmann (Konstanz, DE); U. Schulten-Baumer (Eggenfelden, DE); A. Seelhoff (Berlin, DE); D. Semela (St. Gallen, CH), A. Sch (Würzburg, DE); C. Vollmer, J. Brückner (Augsburg, DE); J. Ungemach (Frankfurt, DE); E. Walter (Villingen-Schwenningen, DE); A. Weber (Nürnberg, DE); T. Winzer (Bad course of DAA therapy. Despite this, retreatment was not consistently Hersfeld, DE). Local study sites (private pracces), Germany: W. Abels (Nürnberg); M. Adler (Braunschweig); F. Audebert (Regenburg); C. Baermann (Freiburg); E. Bästlein (Köln); R. Barth (Nürnberg); K. Barthel (Leipzig); K. Baumgartl (Pfungstadt); W. Becker (München); J. Benninger (Regensburg); T. Beyer (Rosenheim); A. Bodtländer (Frankfurt); G. Böhm (Ludwigshafen); U. Bohr (Berlin); N. Börner (Mainz); H.R. Bruch (Bonn); N. Busch (Würselen); O. Burkhard (Worms); C. Chirca (Bad Reichenhall); A. Dienethal (Frankfurt); P.Dietel (Leipzig); F. Dreher (Roenburg); P. Een (Minden); U. Ehrle (Pfungstadt); F. Emke (Osnabrück); J. Fischer (München); U. Fischer (Aalen); D. Frederking; B. Frick (Darmstadt); B. Gantke B. (Düsseldorf); P. Geyer (Fulda); T. Glaunsinger (Berlin);F. Goebel (München); U. Göbel (Cobus); R. Graf (Leutkirch); M. Herder (Urbach): T. Heuchel (Chemnitz); S. Heuer (Bielefeld); R. Heyne (Berlin); K:-H: Höffl (Traunstein); W.P. Hofmann (Berlin), F. Holst (Marburg); H. Hörster (Mönchengladbach); C. John (Berlin); M. Jung (München); B. Kallinowski (Schwetzingen); W. Kerzel (Forchheim); P. Khaykin (Frankfurt); M. Klarhof (Elingen); B. Knapp (Siegen); U. Knevels (Unna); A. Körfer (Peine); A. Köster supported by „Deutsches Zentrum (Friedrichshafen); B. Künzig (Waiblingen); A. Langekamp (Kassel); M. Liman (Bad Saulgau); H. Löhr (Wiesbaden); L. Ludwig (Dornstadt); U. Lutz (Singen); P. Maurer (Bühl); C. Mayer (Marburg); V. Meister (Vechta); D. Moritzen (Bielefeld); M. Mroß (Berlin); M. Mundlos (Verden); U. Naumann (Berlin); O. Nehls (Stugart); K. Ningel (Nürngen); A. Oelmann (Paderborn); H. Olejnik (Goch);E. Pascher (Herrieden); A. Philipp (Recklinghausen); M. Pilcher (Stugart); F. Polzien (Braunschweig); R. Raddant (Geldern); M. Riedel (Köln); S. Rietzler (Albstadt Ebingen); A. Rump (Freiburg); C. Sick (Bremen); J. tailored to the RASs detected Schmidtler-von Fabris (Stadtbergen); L. Schneider (Fürth); J. Schwenzer (Berlin); T. Seidel (Weimar); G. Seitel (Karlsruhe); K. Simon (Leverkusen); D. Stähler (Köln); H. Steffens (Berlin); B. Strey (Duisburg); K. Svensson (Bremen); W. Tacke (Königstein); K. Teubner (Sugart); J. Thieringer (Frankfurt); U. Trappe (Hamm); J. Ullrich (Krefeld); S. Usadel (Freiburg); A. von Lucadou (Nürnberg):, M. Werheid-Dobers (Bergisch-Gladbach); E. Zehnter (Dortmund). für Infektionsforschung (DZIF)“