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Abstract Details
Resistance-associated Substitutions in Patients With Chronic Hepatitis C Virus Genotype 4 Infection
J Viral Hepat. 2020 May 12. doi: 10.1111/jvh.13322. Online ahead of print.
Julia Dietz12, Olga V Kalinina34, Johannes Vermehren12, Kai-Henrik Peiffer12, Katrin Matschenz5, Peter Buggisch5, Claus Niederau6, Jörn M Schattenberg7, Beat Müllhaupt8, Sabine Yerly9, Marc Ringelhan10, Roland M Schmid10, Christoph Antoni11, Tobias Müller12, Julian Schulze Zur Wiesch1314, Felix Piecha13, Darius Moradpour15, Katja Deterding161718, Heiner Wedemeyer161718, Christophe Moreno19, Thomas Berg20, Christoph P Berg21, Stefan Zeuzem12, Christoph Welsch12, Christoph Sarrazin1222, European HCV Resistance Study Group
Author information
1Department of Internal 1, University Hospital, Goethe University, Frankfurt, Germany.
2German Center for Infection Research (DZIF), External Partner Site, Frankfurt, Germany.
3Helmholtz Centre for Infection Research (HZI), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrücken, Germany.
7Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
8Swiss Hepato-Pancreato-Biliary Center and Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.
9Laboratory of Virology, University Hospital Geneva, University of Geneva, Geneva, Switzerland.
10Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
11Department of Medicine II, Heidelberg University Hospital at Mannheim, Mannheim, Germany.
12Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany.
13Department of Internal Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
14German Center for Infection Research (DZIF), Partner Site, Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.
15Division of Gastroenterology and Hepatology, University Hospital Lausanne, Lausanne, Switzerland.
16Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany.
17Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.
18German Center for Infection Research (DZIF), Partner Site, Hannover-Braunschweig, Hannover, Germany.
19Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
20Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.
21Department of Internal Medicine I, University of Tübingen, Tübingen, Germany.
22St. Josefs-Hospital, Medizinische Klinik II, Wiesbaden, Germany.
Abstract
Data on the prevalence of resistance-associated substitutions (RASs) and their implications for treatment with direct-acting antivirals (DAAs) are sparse in European patients with HCV genotype 4. This study investigated RASs before and after DAA failure in different genotype 4 subtypes and evaluated retreatment efficacies. Samples of 195 genotype 4-infected patients were collected in the European Resistance Database and investigated for NS3, NS5A and NS5B RASs. Retreatment efficacies in DAA failure patients were analysed retrospectively. After NS5A inhibitor (NS5Ai) failure, subtype 4r was frequent (30%) compared to DAA-naïve patients (5%) and the number of NS5A RASs was significantly higher in subtype 4r compared to 4a or 4d (median three RASs vs no or one RAS, respectively, P < .0001). RASsL28V, L30R and M31L pre-existed in subtype 4r and were maintained after NS5Ai failure. Typical subtype 4r RASs were located in subdomain 1a of NS5A, close to membrane interaction and protein-protein interaction sites that are responsible for multimerization and hence viral replication. Retreatment of 37 DAA failure patients was highly effective with 100% SVR in prior SOF/RBV, PI/SOF and PI/NS5Ai failures. Secondary virologic failures were rare (n = 2; subtype 4d and 4r) and only observed in prior NS5Ai/SOF failures (SVR 90%). In conclusion, subtype 4r harboured considerably more RASs compared to other subtypes. A resistance-tailored retreatment using first- and second-generation DAAs was highly effective with SVR rates ≥90% across all subtypes and first-line treatment regimens.