Julia Dietz1, Velia Chiara Di Maio2, Adolfo de Salazar3, Dolores Merino4, Johannes Vermehren1, Stefania Paolucci5, Andreas E Kremer6, Magdalena Lara7, Maria Rodriguez Pardo8, Heinz Zoller9, Elisabetta Degasperi10, Kai-Henrik Peiffer1, Laura Sighinolfi11, Francisco Téllez12, Christiana Graf1, Valeria Ghisetti13, Jonas Schreiber14, Elisa Fernández-Fuertes15, Lucio Boglione16, Leopoldo Muñoz-Medina17, Rudolf Stauber18, William Gennari19, Blanca Figueruela20, Jesús Santos21, Pietro Lampertico10, Stefan Zeuzem1, Francesca Ceccherini-Silberstein2, Federico García3, Christoph Sarrazin22. 1. Department of Internal Medicine 1, University Hospital, Goethe University, Frankfurt, Germany; German Center for Infection Research (DZIF), External Partner Site, Frankfurt, Germany. 2. Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy. 3. Department of Clinical Microbiology, Hospital Universitario San Cecilio, Instituto de Investigación Ibs, Granada, Spain. 4. Infectious Diseases Unit, Hospital Juan Ramón Jiménez, Spain. 5. Molecular Virology Unit, Microbiology and Virology Department, IRCCS Policlinic Foundation San Matteo, Pavia, Italy. 6. Department of Medicine I, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. 7. Hospital Nuestra Sra de Candelaria, Tenerife, Spain. 8. Hospital Universitario Puerta del Mar, Cádiz, Spain. 9. Department of Medicine I, Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Innsbruck, Austria. 10. Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico - Division of Gastroenterology and Hepatology - CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy. 11. University Hospital of Ferrara, Ferrara, Italy. 12. Infectious Diseases Unit, University Hospital of Puerto Real, Cádiz, Spain. 13. Laboratory of Microbiology and Virology, Amedeo di Savoia Hospital, ASL Città di Torino, Turin, Italy. 14. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 15. Infectious Diseases Unit, Hospital de Poniente, El Ejido, Almería, Spain. 16. Department of Translational Medicine (DiMET), University of Piemonte Orientale, Novara, Italy. 17. Department of Infectious Disease, Hospital Universitario San Cecilio, Granada, Spain. 18. Department of Internal Medicine, Medical University of Graz, Graz, Austria. 19. Microbiology Unit, University Hospital of Modena, Modena, Italy. 20. Hospital Universitario Virgen de Valme, Sevilla, Spain. 21. Infectious Diseases Unit, Hospital Universitario Virgen de la Victoria, Instituto de Investigación, IBIMA, Málaga, Spain. 22. Department of Internal Medicine 1, University Hospital, Goethe University, Frankfurt, Germany; German Center for Infection Research (DZIF), External Partner Site, Frankfurt, Germany; Medizinische Klinik 2, St. Josefs-Hospital, Wiesbaden, Germany. Electronic address: sarrazin@em.uni-frankfurt.de.
Abstract
BACKGROUND & AIMS: There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. METHODS: Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. RESULTS: Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12. CONCLUSIONS: VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients. LAY SUMMARY: The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%).
BACKGROUND & AIMS: There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. METHODS: Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. RESULTS: Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12. CONCLUSIONS: VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients. LAY SUMMARY: The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%).
Authors: Hassaan Zahid; Khawar Aslam; Elin Hoffmann Dahl; Waqas Abbassi; Suleiman Adan; Rafael Van den Bergh; Marta A Balinska; Nasir Hassan Luck Journal: Oxf Med Case Reports Date: 2022-05-23
Authors: María B Pisano; Cecilia G Giadans; Diego M Flichman; Viviana E Ré; María V Preciado; Pamela Valva Journal: World J Gastroenterol Date: 2021-07-14 Impact factor: 5.742
Authors: Stephanie Popping; Valeria Cento; Carole Seguin-Devaux; Charles A B Boucher; Adolfo de Salazar; Eva Heger; Orna Mor; Murat Sayan; Dominique Salmon-Ceron; Nina Weis; Henrik B Krarup; Robert J de Knegt; Oana Săndulescu; Vladimir Chulanov; David A M C van de Vijver; Federico García; Francesca Ceccherini-Silberstein Journal: Viruses Date: 2021-12-22 Impact factor: 5.048