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1. Long-term persistence of HCV resistance-associated substitutions after DAA treatment failure

Author

Julia Dietz, Beat Müllhaupt, Peter Buggisch, Christiana Graf, Kai-Henrik Peiffer, Katrin Matschenz, Jörn M. Schattenberg, Christoph Antoni, Stefan Mauss, Claus Niederau, Thomas Discher, Janina Trauth, Georg Dultz, Julian Schulze zur Wiesch, Felix Piecha, Hartwig Klinker, Tobias Müller, Thomas Berg, Christoph Neumann-Haefelin, Christoph P. Berg, Stefan Zeuzem, Christoph Sarrazin, J. Balavoine, E. Giostra, M. Berning, J. Hampe, A. Canbay, W. Steckstor, W. Schmiegel, N.H. Brockmeyer, A. De Gottardi, A. Rauch, N. Semmo, J. Fischer, M. Gress, H. Heinzow, G. Hilgard, H. Schmidt, A. Herrmann, A. Stallmach, D. Hoffmann, U. Protzer, H. Klinker, P. Schulze, A. Kodal, A. Kremer, J. Siebler, M. Löbermann, T. Götze, J. Weigt, A. Lohse, J. Von Felden, S. Jordan, C.M. Lange, R. Zachoval, J. Mayerle, A. Maieron, D. Moradpour, J.-P. Chave, C. Moreno, M. Muche, H.-J. Epple, M. Müller-Schilling, F. Kocheise, B. Müllhaupt, K. Port, K. Deterding, H. Wedemeyer, M. Cornberg, M. Manns, L. Reinhardt, V. Ellenrieder, J. Rissland, D. Semela, U. Spengler, J. Rockstroh, E. Roeb, M. Sprinzl, P. Galle, R. Stauber, W. Stremmel, B. Strey, R. Thimme, T. Boettler, F. Tacke, A. Teufel, R. Vogelmann, M. Ebert, K. Tomasiewicz, C. Trautwein, T. Koenen, T. Weber, P. Wietzke-Braun, R. Günther, E. Zizer, J. Backhus, T. Seufferlein, W. Angeli, S. Beckebaum, C. Doberauer, E. Durmashkina, A. Hackelsberger, A. Erhardt, A. Garrido-Lüneburg, H. Gattringer, D. Genné, M. Gschwantler, F. Gundling, S. Hametner, R. Schöfl, C. Hartmann, T. Heyer, C. Hirschi, A. Jussios, S. Kanzler, N. Kordecki, M. Kraus, U. Kullig, S. Wollschläger, L. Magenta, B. Terziroli Beretta-Piccoli, M. Menges, L. Mohr, K. Muehlenberg, C. Niederau, B. Paulweber, A. Petrides, M. Pinkernell, R. Piso, W. Rambach, M. Reiser, B. Riecken, A. Rieke, J. Roth, M. Schelling, P. Schlee, A. Schneider, D. Scholz, E. Schott, M. Schuchmann, U. Schulten-Baumer, A. Seelhoff, A. Stich, F. Stickel, J. Ungemach, E. Walter, A. Weber, T. Winzer, W. Abels, M. Adler, F. Audebert, C. Baermann, E. Bästlein, R. Barth, K. Barthel, W. Becker, J. Behrends, J. Benninger, F. Berger, D. Berzow, T. Beyer, M. Bierbaum, O. Blaukat, A. Bodtländer, G. Böhm, N. Börner, U. Bohr, B. Bokemeyer, H.R. Bruch, D. Bucholz, O. Burkhard, N. Busch, C. Chirca, R. Delker, J. Diedrich, M. Frank, M. Diehl, A. Dienethal, P. Dietel, N. Dikopoulos, M. Dreck, F. Dreher, L. Drude, K. Ende, U. Ehrle, K. Baumgartl, F. Emke, R. Glosemeyer, G. Felten, D. Hüppe, U. Fischer, D. Frederking, B. Frick, G. Friese, B. Gantke, P. Geyer, H.R. Schwind, M. Glas, T. Glaunsinger, F. Goebel, U. Göbel, B. Görlitz, R. Graf, H. Gruber, G. Härter, M. Herder, T. Heuchel, S. Heuer, K.-H. Höffl, H. Hörster, J.-U. Sonne, W.P. Hofmann, F. Holst, M. Hunstiger, A. Hurst, E. Jägel-Guedes, C. John, M. Jung, B. Kallinowski, B. Kapzan, W. Kerzel, P. Khaykin, M. Klarhof, U. Klüppelberg, null Wolfratshausen, K. Klugewitz, B. Knapp, U. Knevels, T. Kochsiek, A. Körfer, A. Köster, M. Kuhn, A. Langekamp, B. Künzig, R. Link, M. Littman, H. Löhr, T. Lutz, G. Knecht, U. Lutz, D. Mainz, I. Mahle, P. Maurer, C. Mayer, V. Meister, H. Möller, R. Heyne, D. Moritzen, M. Mroß, M. Mundlos, U. Naumann, O. Nehls, K.R. Ningel, A. Oelmann, H. Olejnik, K. Gadow, E. Pascher, J. Petersen, A. Philipp, M. Pichler, F. Polzien, R. Raddant, M. Riedel, S. Rietzler, M. Rössle, W. Rufle, A. Rump, C. Schewe, C. Hoffmann, D. Schleehauf, W. Schmidt, G. Schmidt-Heinevetter, J. Schmidtler-von Fabris, L. Schneider, A. Schober, S. Niehaus-Hahn, J. Schwenzer, B. Seegers, T. Seidel, G. Seitel, C. Sick, K. Simon, D. Stähler, F. Stenschke, H. Steffens, K. Stein, M. Steinmüller, T. Sternfeld, K. Svensson, W. Tacke, G. Teuber, K. Teubner, J. Thieringer, A. Tomesch, U. Trappe, J. Ullrich, G. Urban, S. Usadel, A. Von Lucadou, F. Weinberger, M. Werheid-Dobers, P. Werner, T. Winter, E. Zehnter, and A. Zipf

Subjects
Hepatology, Genotype, Drug Resistance, Viral, Humans, Hepacivirus, Treatment Failure, Viral Nonstructural Proteins, Hepatitis C, Chronic, Antiviral Agents
Abstract

Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT).We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated.A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H.We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals.There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment.

Published
2022

2. Accuracy of Sensititre YeastOne echinocandins epidemiological cut-off values for identification of FKS mutant Candida albicans and Candida glabrata: a ten year national survey of the Fungal Infection Network of Switzerland (FUNGINOS)

Author

A. Kritikos, D. Neofytos, N. Khanna, P.W. Schreiber, K. Boggian, J. Bille, J. Schrenzel, K. Mühlethaler, R. Zbinden, T. Bruderer, D. Goldenberger, G. Pfyffer, A. Conen, C. Van Delden, S. Zimmerli, D. Sanglard, D. Bachmann, O. Marchetti, F. Lamoth, T. Bregenzer, U. Flückiger, C. Orasch, U. Heininger, M. Franciolli, L. Damonti, M. Rothen, C. Zellweger, P. Tarr, F. Fleisch, C. Chuard, V. Erard, S. Emonet, J. Garbino, C. van Delden, D. Genne, P. Bochud, T. Calandra, J. Chave, P. Graber, R. Monotti, O. Regionale, E. Bernasconi, O. Civico, M. Rossi, M. Krause, R. Piso, F. Bally, N. Troillet, G. Eich, J. Gubler, J. Fehr, A. Imhof, C. Ruef, C. Berger, H. Fankhauser, I. Heinzer, R. Frei, R. Hertel, M. Dolina, O. Petrini, O. Dubuis, S. Graf, M. Risch, E. Ritzler, D. Fracheboud, P. Rohner, R. Lienhardt, C. Andreutti-Zaugg, A. Gallusser, K. Herzog, U. Schibli, L. Tissière, D. Schultze, University of Zurich, and Lamoth, F

Subjects
0301 basic medicine, Microbiology (medical), Antifungal Agents, Candida albicans/genetics, Echinocandin, 030106 microbiology, Population, Drug Resistance, Candida glabrata, 610 Medicine & health, Microbial Sensitivity Tests, Candidiasis/microbiology, 2726 Microbiology (medical), Microbiology, 10234 Clinic for Infectious Diseases, 03 medical and health sciences, chemistry.chemical_compound, Echinocandins, Switzerland/epidemiology, Drug Resistance, Fungal, Candida albicans, polycyclic compounds, medicine, Humans, education, ddc:616, education.field_of_study, biology, Echinocandins/administration & dosage/pharmacology, Micafungin, Candidiasis, General Medicine, 2725 Infectious Diseases, bacterial infections and mycoses, biology.organism_classification, Fungal, Infectious Diseases, chemistry, 10036 Medical Clinic, Population Surveillance, Mutation, Antifungal Agents/pharmacology, Anidulafungin, Caspofungin, Switzerland, medicine.drug
Abstract

Objectives Echinocandins represent the first-line treatment of candidaemia. Acquired echinocandin resistance is mainly observed among Candida albicans and Candida glabrata and is associated with FKS hotspot mutations. The commercial Sensititre YeastOne™ (SYO) kit is widely used for antifungal susceptibility testing, but interpretive clinical breakpoints are not well defined. We determined echinocandins epidemiological cut-off values (ECV) for C. albicans/glabrata tested by SYO and assessed their ability to identify FKS mutants in a national survey of candidaemia. Methods Bloodstream isolates of C. albicans and C. glabrata were collected in 25 Swiss hospitals from 2004 to 2013 and tested by SYO. FKS hotspot sequencing was performed for isolates with an MIC≥ECV for any echinocandin. Results In all, 1277 C. albicans and 347 C. glabrata were included. ECV 97.5% of caspofungin, anidulafungin and micafungin were 0.12, 0.06 and 0.03 μg/mL for C. albicans, and 0.25, 0.12 and 0.03 μg/mL for C. glabrata, respectively. FKS hotspot sequencing was performed for 70 isolates. No mutation was found in the 52 ‘limit wild-type' isolates (MIC=ECV for at least one echinocandin). Among the 18 ‘non-wild-type' isolates (MIC>ECV for at least one echinocandin), FKS mutations were recovered in the only two isolates with MIC>ECV for all three echinocandins, but not in those exhibiting a ‘non-wild-type' phenotype for only one or two echinocandins. Conclusion This 10-year nationwide survey showed that the rate of echinocandin resistance among C. albicans and C. glabrata remains low in Switzerland despite increased echinocandin use. SYO-ECV could discriminate FKS mutants from wild-type isolates tested by SYO in this population.

Published
2018

3. Efficacy of Retreatment After Failed Direct-acting Antiviral Therapy in Patients With HCV Genotype 1–3 Infections

Author

Julia Dietz, Ulrich Spengler, Beat Müllhaupt, Julian Schulze zur Wiesch, Felix Piecha, Stefan Mauss, Barbara Seegers, Holger Hinrichsen, Christoph Antoni, Perdita Wietzke-Braun, Kai-Henrik Peiffer, Annemarie Berger, Katrin Matschenz, Peter Buggisch, Johanna Backhus, Eugen Zizer, Tobias Boettler, Christoph Neumann-Haefelin, David Semela, Rudolf Stauber, Thomas Berg, Christoph Berg, Stefan Zeuzem, Johannes Vermehren, Christoph Sarrazin, J. Balavoine, E. Giostra, M. Berning, J. Hampe, A. De Gottardi, A. Rauch, N. Semmo, T. Discher, J. Trauth, J. Fischer, M. Gress, R. Günther, H. Heinzow, J. Schmidt, A. Herrmann, A. Stallmach, G. Hilgard, K. Deterding, C.M. Lange, S. Ciesek, H. Wedemeyer, D. Hoffmann, H. Klinker, P. Schulze, F. Kocheise, M. Müller-Schilling, A. Kodal, A. Kremer, M. Ganslmayer, J. Siebler, F. Lammert, J. Rissland, M. Löbermann, T. Götze, A. Canbay, A. Lohse, J. von Felden, S. Jordan, A. Maieron, D. Moradpour, J.-P. Chave, C. Moreno, T. Müller, M. Muche, H.-J. Epple, K. Port, T. von Hahn, M. Cornberg, M. Manns, L. Reinhardt, V. Ellenrieder, J. Rockstroh, J. Schattenberg, M. Sprinzl, P. Galle, E. Roeb, M. Steckstor, W. Schmiegel, N.H. Brockmeyer, T. Seufferlein, W. Stremmel, B. Strey, R. Thimme, A. Teufel, R. Vogelmann, M. Ebert, K. Tomasiewicz, C. Trautwein, F. Tacke, T. Koenen, T. Weber, R. Zachoval, J. Mayerle, B. Raziorrouh, W. Angeli, S. Beckebaum, C. Doberauer, E. Durmashkina, A. Hackelsberger, A. Erhardt, A. Garrido-Lüneburg, H. Gattringer, D. Genné, M. Gschwantler, F. Gundling, S. Hametner, R. Schöfl, C. Hartmann, T. Heyer, C. Hirschi, A. Jussios, S. Kanzler, N. Kordecki, M. Kraus, U. Kullig, S. Wollschläger, L. Magenta, B. Terziroli Beretta-Piccoli, M. Menges, L. Mohr, K. Muehlenberg, C. Niederau, B. Paulweber, A. Petrides, M. Pinkernell, R. Piso, W. Rambach, M. Reiser, B. Riecken, A. Rieke, J. Roth, M. Schelling, P. Schlee, A. Schneider, D. Scholz, E. Schott, M. Schuchmann, U. Schulten-Baumer, A. Seelhoff, A. Stich, F. Stickel, J. Ungemach, E. Walter, A. Weber, T. Winzer, W. Abels, M. Adler, F. Audebert, C. Baermann, E. Bästlein, R. Barth, K. Barthel, W. Becker, J. Behrends, J. Benninger, F. Berger, D. Berzow, T. Beyer, M. Bierbaum, O. Blaukat, A. Bodtländer, G. Böhm, N. Börner, U. Bohr, B. Bokemeyer, H.R. Bruch, D. Bucholz, O. Burkhard, N. Busch, C. Chirca, R. Delker, J. Diedrich, M. Frank, M. Diehl, A. Dienethal, P. Dietel, N. Dikopoulos, M. Dreck, F. Dreher, L. Drude, K. Ende, U. Ehrle, K. Baumgartl, F. Emke, R. Glosemeyer, G. Felten, D. Hüppe, U. Fischer, D. Frederking, B. Frick, G. Friese, B. Gantke, P. Geyer, H.R. Schwind, M. Glas, T. Glaunsinger, F. Goebel, U. Göbel, B. Görlitz, R. Graf, H. Gruber, G. Härter, M. Herder, T. Heuchel, S. Heuer, K.-H. Höffl, H. Hörster, J.-U. Sonne, W.P. Hofmann, F. Holst, M. Hunstiger, A. Hurst, E. Jägel-Guedes, C. John, M. Jung, B. Kallinowski, B. Kapzan, W. Kerzel, P. Khaykin, M. Klarhof, U. Klüppelberg, K. Klugewitz, B. Knapp, U. Knevels, T. Kochsiek, A. Körfer, A. Köster, M. Kuhn, A. Langekamp, B. Künzig, R. Link, M. Littman, H. Löhr, T. Lutz, G. Knecht, U. Lutz, D. Mainz, I. Mahle, P. Maurer, C. Mayer, V. Meister, H. Möller, R. Heyne, D. Moritzen, M. Mroß, M. Mundlos, U. Naumann, O. Nehls, K.&R. Ningel, A. Oelmann, H. Olejnik, K. Gadow, E. Pascher, J. Petersen, A. Philipp, M. Pichler, F. Polzien, R. Raddant, M. Riedel, S. Rietzler, M. Rössle, W. Rufle, A. Rump, C. Schewe, C. Hoffmann, D. Schleehauf, K.J. Schmidt, W. Schmidt, G. Schmidt-Heinevetter, J. Schmidtler-von Fabris, E. Schnaitmann, L. Schneider, A. Schober, S. Niehaus-Hahn, J. Schwenzer, T. Seidel, G. Seitel, C. Sick, K.G. Simon, D. Stähler, F. Stenschke, H. Steffens, K. Stein, M. Steinmüller, T. Sternfeld, K. Svensson, W. Tacke, G. Teuber, K. Teubner, J. Thieringer, A. Tomesch, U. Trappe, J. Ullrich, G. Urban, S. Usadel, A. von Lucadou, F. Weinberger, M. Werheid-Dobers, P. Werner, T. Winter, E. Zehnter, and A. Zipf

Subjects
medicine.medical_specialty, Elbasvir, Daclatasvir, Genotype, Sustained Virologic Response, Sofosbuvir, Combination therapy, Voxilaprevir, Hepacivirus, Viral Nonstructural Proteins, Chronic liver disease, Antiviral Agents, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Drug Resistance, Viral, medicine, Humans, Hepatology, business.industry, Ribavirin, Liver Neoplasms, Gastroenterology, Hepatitis C, Chronic, medicine.disease, Hepatitis C, chemistry, Grazoprevir, 030220 oncology & carcinogenesis, Retreatment, Drug Therapy, Combination, 030211 gastroenterology & hepatology, business, medicine.drug
Abstract

Hepatitis C virus infection is causing chronic liver disease, cirrhosis, and hepatocellular carcinoma. By combining direct-acting antivirals (DAAs), high sustained virologic response rates (SVRs) can be achieved. Resistance-associated substitutions (RASs) are commonly observed after DAA failure, and especially nonstructural protein 5A (NS5A) RASs may impact retreatment options.1-3 Data on retreatment of DAA failure patients using first-generation DAAs are limited.4-7 Recently, a second-generation protease- and NS5A-inhibitor plus sofosbuvir (voxilaprevir/velpatasvir/sofosbuvir [VOX/VEL/SOF]) was approved for retreatment after DAA failure.8 However, this and other second-generation regimens are not available in many resource-limited countries or are not reimbursed by regular insurance, and recommendations regarding the selection of retreatment regimens using first-generation DAAs are very important. This study aimed to analyze patients who were re-treated with first-generation DAAs after failure of a DAA combination therapy.

Published
2021

4. Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals

Author

Julia Dietz, Simone Susser, Johannes Vermehren, Kai-Henrik Peiffer, Georgios Grammatikos, Annemarie Berger, Peter Ferenci, Maria Buti, Beat Müllhaupt, Bela Hunyady, Holger Hinrichsen, Stefan Mauss, Jörg Petersen, Peter Buggisch, Gisela Felten, Dietrich Hüppe, Gaby Knecht, Thomas Lutz, Eckart Schott, Christoph Berg, Ulrich Spengler, Thomas von Hahn, Thomas Berg, Stefan Zeuzem, Christoph Sarrazin, C. Antoni, R. Vogelmann, M. Ebert, J. Backhus, T. Seufferlein, J. Balavoine, E. Giostra, C. Berg, M. Cornberg, H. Wedemeyer, M. Manns, A. De Gottardi, R. Esteban, T. Discher, E. Roeb, M. Gress, R. Günther, P. Wietzke-Braun, A. Herrmann, A. Stallmach, D. Hoffmann, H. Klinker, A. Kodal, F. Lammert, M. Löbermann, J. Schulze zur Wiesch, J. von Felden, F. Piecha, A. Lohse, T. Götze, P. Malfertheiner, J. Mayerle, D. Moradpour, C. Moreno, C. Neumann-Haefelin, R. Thimme, L. Reinhardt, V. Ellenrieder, J. Schattenberg, M. Sprinzl, P. Galle, J. Schmidt, E. Schott, H.-J. Epple, J. Siebler, R. Stauber, M. Steckstor, W. Schmiegel, W. Stremmel, B. Strey, K. Tomasiewicz, C. Trautwein, R. Zachoval, W. Angeli, S. Beckebaum, C. Doberauer, K. Ende, A. Erhardt, A. Garrido-Lüneburg, H. Gattringer, D. Genné, M. Gschwantler, F. Gundling, C. Hartmann, T. Heyer, C. Hirschi, S. Kanzler, N. Kordecki, M. Kraus, U. Kullig, L. Magenta, B. Terziroli Beretta-Piccoli, M. Menges, L. Mohr, K. Muehlenberg, C. Niederau, B. Paulweber, A. Petrides, R. Piso, W. Rambach, M. Reiser, B. Riecken, J. Roth, R. Schöfl, A. Maieron, A. Schneider, M. Schuchmann, U. Schulten-Baumer, A. Seelhoff, D. Semela, A. Stich, C. Vollmer, J. Brückner, J. Ungemach, E. Walter, A. Weber, T. Winzer, W. Abels, M. Adler, F. Audebert, C. Baermann, E. Bästlein, R. Barth, K. Barthel, K. Baumgartl, W. Becker, J. Benninger, T. Beyer, A. Bodtländer, G. Böhm, U. Bohr, A. Moll, U. Naumann, N. Börner, H.R. Bruch, N. Busch, O. Burkhard, C. Chirca, A. Dienethal, P. Dietel, F. Dreher, P. Efken, U. Ehrle, F. Emke, J. Fischer, U. Fischer, D. Frederking, B. Frick, B. Gantke B, P. Geyer, T. Glaunsinger, F. Goebel, U. Göbel, R. Graf, M. Herder, T. Heuchel, S. Heuer, R. Heyne, K.H. Höffl, W.P. Hofmann, F. Holst, H. Hörster, C. John, M.C. Jung, B. Kallinowski, W. Kerzel, P. Khaykin, M. Klarhof, B. Knapp, U. Knevels, A. Körfer, A. Köster, B. Künzig, A. Langenkamp, M. Kuhn, M. Littman, H. Löhr, L. Ludwig, U. Lutz, P. Maurer, C. Mayer, V. Meister, D. Moritzen, M. Mroß, M. Mundlos, O. Nehls, K. Ningel, A. Oelmann, H. Olejnik, E. Pascher, A. Philipp, M. Pichler, F. Polzien, R. Raddant, M. Riedel, S. Rietzler, A. Rump, W. Schmidt, J. Schmidtler-von Fabris, L. Schneider, A. Schober, J. Schwenzer, T. Seidel, G. Seitel, C. Sick, K. Simon, D. Stähler, H. Steffens, K. Svensson, W. Tacke, K. Teubner, J. Thieringer, U. Trappe, J. Ullrich, S. Usadel, A. von Lucadou, M. Werheid-Dobers, E. Zehnter, and A. Zipf

Subjects
0301 basic medicine, Simeprevir, Ledipasvir, Oncology, medicine.medical_specialty, Daclatasvir, Time Factors, Sofosbuvir, Genotype, viruses, Voxilaprevir, Hepacivirus, Viral Nonstructural Proteins, Antiviral Agents, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Drug Resistance, Viral, Medicine, Humans, Protease Inhibitors, Treatment Failure, Retrospective Studies, Hepatology, business.industry, Drug Substitution, Gastroenterology, virus diseases, Glecaprevir, Hepatitis C, Chronic, Virology, digestive system diseases, Ombitasvir, Europe, 030104 developmental biology, Phenotype, chemistry, Paritaprevir, Retreatment, 030211 gastroenterology & hepatology, Drug Therapy, Combination, business, medicine.drug
Abstract

Background & Aims Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. Methods We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naive patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis. Results RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed. Conclusions We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.

Published
2017

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