Ana Belén Pérez1, Natalia Chueca2, Miguel García-Deltoro3, Ana María Martínez-Sapiña4, María Magdalena Lara-Pérez5, Silvia García-Bujalance6, Teresa Aldámiz-Echevarría7, Francisco Jesús Vera-Méndez8, Juan Antonio Pineda9, Marta Casado10, Juan Manuel Pascasio11, Javier Salmerón12, Juan Carlos Alados-Arboledas13, Antonio Poyato14, Francisco Téllez15, Antonio Rivero-Juárez16, Dolores Merino17, María Jesús Vivancos-Gallego18, José Miguel Rosales-Zábal19, Federico García20. 1. Clinical Microbiology Unit, University Hospital Reina Sofía. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain. 2. Clinical Microbiology Unit, University Hospital San Cecilio, Instituto de Investigacion Biosanitaria Ibs.Granada, Granada, Spain. 3. Infectious Diseases Service, Hospital General de Valencia, Valencia, Spain. 4. Clinical Microbiology Unit, Hospital Miguel Servet, Zaragoza, Spain. 5. Clinical Microbiology Unit, Hospital Nuestra Señora de la Candelaria, Tenerife, Spain. 6. Clinical Microbiology Unit, University Hospital La Paz, Madrid, Spain. 7. Infectious Diseases Unit, Hospital Gregorio Marañón, Madrid, Spain. 8. Infectious Diseases Unit, University Hospital Santa Lucía, Cartagena, Spain. 9. Infectious Diseases Unit, University Hospital Nuestra Señora de Valme, Sevilla, Spain. 10. Hepatology Unit, Complejo Hospitalario Torrecárdenas, Almería, Spain. 11. Hepatology Unit, University Hospital Virgen del Rocío, IBIS Instituto de Biomedicina de Sevilla, CIBERehd, Seville, Spain. 12. Hepatology Unit, University Hospital San Cecilio Granada, Instituto de Investigación Biosanitaria Ibs.Granada, CIBERehd, Granada, Spain. 13. Clinical Microbiology Unit, University Hospital Jerez, Cádiz, Spain. 14. Hepatology Unit, University Hospital Reina Sofía, Córdoba, Spain. 15. Infectious Diseases Unit, Hospital Puerto Real, Puerto Real, Cádiz, Spain. 16. Infectious Diseases Unit, University Hospital Reina Sofía, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Córdoba, Spain. 17. Infectious Diseases Unit, University Hospital Juan Ramón Jiménez, Huelva, Spain. 18. Infectious Diseases Unit, University Hospital Ramón y Cajal, Madrid, Spain. 19. Hepatology Unit, Hospital Costa del Sol, Marbella, Málaga, Spain. 20. Clinical Microbiology Unit, University Hospital San Cecilio, Instituto de Investigacion Biosanitaria Ibs.Granada, Granada, Spain. Electronic address: fegarcia@ugr.es.
Abstract
BACKGROUND & AIMS: Most hepatitis C virus (HCV)-infected patients failing NS5A inhibitors develop resistance-associated substitutions (RASs). Here we report the use of resistance-guided retreatment of patients who failed prior NS5A inhibitor-containing regimens in the GEHEP-004 cohort. This is the largest direct-acting antiviral (DAA)-resistance cohort study conducted in Spain. We aim to provide indications on how to use resistance information in settings where sofosbuvir/velpatasvir/voxilaprevir may not be available. METHODS: GEHEP-004 is a prospective multicenter cohort enrolling HCV-infected patients treated with interferon (IFN)-free DAA regimens. Prior to retreatment, population-based sequencing of HCV NS3, NS5A and NS5B genes was performed. After receiving a comprehensive resistance interpretation report, the retreatment regimen was chosen and the sustained virological response (SVR) at 12 weeks after treatment completion (SVR12) was recorded. RESULTS: A total of 342 patients experiencing virological failure after treatment with sofosbuvir/ledipasvir±ribavirin (54%), sofosbuvir/daclatasvir±ribavirin (23%), or paritaprevir-ritonavir/ombitasvir±dasabuvir±ribavirin (20%) were studied. After a resistance report, 186 patients were retreated. An SVR12 was achieved for 88.1% of the patients who failed after sofosbuvir/ledipasvir±ribavirin, 83.3% of the patients who failed after sofosbuvir/daclatasvir±ribavirin, 93.7% of the patients who failed after paritaprevir-ritonavir+ombitasvir±dasabuvir±ribavirin. CONCLUSIONS: In our study, we show how resistance-guided retreatment in conjunction with an interpreted report allows patients to achieve SVR rates close to 90%. We hypothesize that SVR rates may even be improved if resistance data are discussed between experienced virologists and treating clinicians. We believe that our data may be relevant for countries where the access to new DAA combination regimens is limited. LAY SUMMARY: Hepatitis C infection can be cured with currently available antiviral agents. Only a small proportion of patients experience treatment failure, however, in absolute numbers, a high number of patients may require retreatment. Highly effective combinations of antivirals are also available for retreatment. However, these antivirals might not be available in resource-limited settings. Herein, we show how, by analyzing the cause of resistance, retreatment efficacy with old drugs can get very close to the efficacy of new drug combinations.
BACKGROUND & AIMS: Most hepatitis C virus (HCV)-infected patients failing NS5A inhibitors develop resistance-associated substitutions (RASs). Here we report the use of resistance-guided retreatment of patients who failed prior NS5A inhibitor-containing regimens in the GEHEP-004 cohort. This is the largest direct-acting antiviral (DAA)-resistance cohort study conducted in Spain. We aim to provide indications on how to use resistance information in settings where sofosbuvir/velpatasvir/voxilaprevir may not be available. METHODS: GEHEP-004 is a prospective multicenter cohort enrolling HCV-infected patients treated with interferon (IFN)-free DAA regimens. Prior to retreatment, population-based sequencing of HCV NS3, NS5A and NS5B genes was performed. After receiving a comprehensive resistance interpretation report, the retreatment regimen was chosen and the sustained virological response (SVR) at 12 weeks after treatment completion (SVR12) was recorded. RESULTS: A total of 342 patients experiencing virological failure after treatment with sofosbuvir/ledipasvir±ribavirin (54%), sofosbuvir/daclatasvir±ribavirin (23%), or paritaprevir-ritonavir/ombitasvir±dasabuvir±ribavirin (20%) were studied. After a resistance report, 186 patients were retreated. An SVR12 was achieved for 88.1% of the patients who failed after sofosbuvir/ledipasvir±ribavirin, 83.3% of the patients who failed after sofosbuvir/daclatasvir±ribavirin, 93.7% of the patients who failed after paritaprevir-ritonavir+ombitasvir±dasabuvir±ribavirin. CONCLUSIONS: In our study, we show how resistance-guided retreatment in conjunction with an interpreted report allows patients to achieve SVR rates close to 90%. We hypothesize that SVR rates may even be improved if resistance data are discussed between experienced virologists and treating clinicians. We believe that our data may be relevant for countries where the access to new DAA combination regimens is limited. LAY SUMMARY: Hepatitis C infection can be cured with currently available antiviral agents. Only a small proportion of patients experience treatment failure, however, in absolute numbers, a high number of patients may require retreatment. Highly effective combinations of antivirals are also available for retreatment. However, these antivirals might not be available in resource-limited settings. Herein, we show how, by analyzing the cause of resistance, retreatment efficacy with old drugs can get very close to the efficacy of new drug combinations.
Authors: Anita Y M Howe; Chaturaka Rodrigo; Evan B Cunningham; Mark W Douglas; Julia Dietz; Jason Grebely; Stephanie Popping; Javier Alejandro Sfalcin; Milosz Parczewski; Christoph Sarrazin; Adolfo de Salazar; Ana Fuentes; Murat Sayan; Josep Quer; Midori Kjellin; Hege Kileng; Orna Mor; Johan Lennerstrand; Slim Fourati; Velia Chiara Di Maio; Vladimir Chulanov; Jean-Michel Pawlotsky; P Richard Harrigan; Francesca Ceccherini-Silberstein; Federico Garcia Journal: JHEP Rep Date: 2022-02-24