Prevalence of resistance-associated substitutions and retreatment of patients failing a glecaprevir/pibrentasvir regimen.

Adolfo de Salazar, Julia Dietz, Velia Chiara di Maio, Johannes Vermehren, Stefania Paolucci, Beat Müllhaupt, Nicola Coppola, Joaquín Cabezas, Rudolf E Stauber, Massimo Puoti, Juan Ignacio Arenas Ruiz Tapiador, Christiana Graf, Marianna Aragri, Miguel Jimenez, Annapaola Callegaro, Juan Manuel Pascasio Acevedo, Manuel Alberto Macias Rodriguez, Jose Miguel Rosales Zabal, Valeria Micheli, Miguel Garcia Del Toro, Francisco Téllez, Federico García, Christoph Sarrazin, Francesca Ceccherini-Silberstein

Journal: The Journal of antimicrobial chemotherapy 2021;75(11):3349-3358

PMID: 32772078

Full Text on Ovid Technologies, Inc. View on PubMed

Abstract

OBJECTIVES

To investigate resistance-associated substitutions (RASs) as well as retreatment efficacies in a large cohort of European patients with failure of glecaprevir/pibrentasvir.

METHODS

Patients were identified from three European Resistance Reference centres in Spain, Italy and Germany. Sequencing of NS3, NS5A and NS5B was conducted and substitutions associated with resistance to direct antiviral agents were analysed. Clinical and virological parameters were documented retrospectively and retreatment efficacies were evaluated.

RESULTS

We evaluated 90 glecaprevir/pibrentasvir failures [3a (n = 36), 1a (n = 23), 2a/2c (n = 20), 1b (n = 10) and 4d (n = 1)]. Ten patients were cirrhotic, two had previous exposure to PEG-interferon and seven were coinfected with HIV; 80 had been treated for 8 weeks. Overall, 31 patients (34.4%) failed glecaprevir/pibrentasvir without any NS3 or NS5A RASs, 62.4% (53/85) showed RASs in NS5A, 15.6% (13/83) in NS3 and 10% (9/90) in both NS5A and NS3. Infection with HCV genotypes 1a and 3a was associated with a higher prevalence of NS5A RASs. Patients harbouring two (n = 34) or more (n = 8) RASs in NS5A were frequent. Retreatment was initiated in 56 patients, almost all (n = 52) with sofosbuvir/velpatasvir/voxilaprevir. The overall sustained virological response rate was 97.8% in patients with end-of-follow-up data available.

CONCLUSIONS

One-third of patients failed glecaprevir/pibrentasvir without resistance. RASs in NS5A were more prevalent than in NS3 and were frequently observed as dual and triple combination patterns, with a high impact on NS5A inhibitor activity, particularly in genotypes 1a and 3a. Retreatment of glecaprevir/pibrentasvir failures with sofosbuvir/velpatasvir/voxilaprevir achieved viral suppression across all genotypes.

Address: Clinical Microbiology Unit, University Hospital San Cecilio, Instituto de Investigacion Ibs.Granada. Granada, Spain.; Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany; German Center for Infection Research (DZIF), External Partner Site, Frankfurt, Germany.; Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.; Molecular Virology Unit, Microbiology and Virology Department, IRCCS Policlinic Foundation San Matteo, Pavia, Italy.; Swiss Hepato-Pancreato-Biliary Center and Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.; Department of Mental Health and Public Medicine, Infectious Diseases Unit, University of Campania "L. Vanvitelli", Naples, Italy.; Department of Hepatology, Marqués de Valdecilla University Hospital, Santander, Spain.; Department of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.; Infectious Diseases, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.; Infectious Diseases Unit, University Hospital Donostia, San Sebastián, Spain.; Hepatology Unit, Hospital Regional de Málaga, Málaga, Spain.; Microbiology and Virology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.; Hepatology Unit, University Hospital Virgen del Rocío, Seville, Spain.; Department of Digestive Diseases, Hospital Universitario Puerta del Mar, Cádiz, Spain.; Gastrointestinal Unit, Hospital Costa del Sol, Marbella, Málaga, Spain.; Clinical Microbiology, Virology and Bioemergencies, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy.; Infectious Diseases Unit, Hospital General de Valencia, Valencia, Spain.; Infectious Diseases Unit, Hospital Puerto Real, Puerto Real, Cádiz, Spain.; Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany; German Center for Infection Research (DZIF), External Partner Site, Frankfurt, Germany.; Medizinische Klinik 2, St. Josefs Hospital, Wiesbaden, Germany.

DOI: 10.1093/jac/dkaa304

Link outs

Subscription / membership required

Full Text Sources:

MeSH Terms: Aminoisobutyric Acids, Antiviral Agents, Benzimidazoles, Cyclopropanes, Drug Resistance, Viral, Genotype, Germany, Hepacivirus, Humans, Italy, Lactams, Macrocyclic, Leucine, Prevalence, Proline, Pyrrolidines, Quinoxalines, Retreatment, Retrospective Studies, Spain, Sulfonamides, Viral Nonstructural Proteins