1. Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy.
- Author
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Dietz J, Di Maio VC, de Salazar A, Merino D, Vermehren J, Paolucci S, Kremer AE, Lara M, Pardo MR, Zoller H, Degasperi E, Peiffer KH, Sighinolfi L, Téllez F, Graf C, Ghisetti V, Schreiber J, Fernández-Fuertes E, Boglione L, Muñoz-Medina L, Stauber R, Gennari W, Figueruela B, Santos J, Lampertico P, Zeuzem S, Ceccherini-Silberstein F, García F, and Sarrazin C
- Subjects
- Drug Combinations, Europe epidemiology, Female, Humans, Liver Cirrhosis diagnosis, Liver Cirrhosis epidemiology, Male, Middle Aged, Sustained Virologic Response, Treatment Failure, Treatment Outcome, Antiviral Agents administration & dosage, Antiviral Agents adverse effects, Antiviral Agents classification, Antiviral Agents pharmacokinetics, Carbamates administration & dosage, Carbamates adverse effects, Drug Resistance, Multiple, Viral drug effects, Drug Resistance, Multiple, Viral genetics, Drug Therapy, Combination methods, Hepacivirus drug effects, Hepacivirus genetics, Hepacivirus isolation & purification, Hepatitis C, Chronic diagnosis, Hepatitis C, Chronic drug therapy, Hepatitis C, Chronic epidemiology, Hepatitis C, Chronic virology, Heterocyclic Compounds, 4 or More Rings administration & dosage, Heterocyclic Compounds, 4 or More Rings adverse effects, Macrocyclic Compounds administration & dosage, Macrocyclic Compounds adverse effects, Retreatment methods, Retreatment statistics & numerical data, Sofosbuvir administration & dosage, Sofosbuvir adverse effects, Sulfonamides administration & dosage, Sulfonamides adverse effects
- 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%)., Competing Interests: Conflict of interest Julia Dietz: Research support from Gilead. Dolores Merino: Speaking and/or consulting fees from Gilead, ViiV Health Care, Merck/MSD, Janssen. Johannes Vermehren: Speaking and/or consulting fees from Abbott, AbbVie, Gilead, Bristol-Myers Squibb, Medtronic, Merck/MSD, and Roche. Andreas E. Kremer: Speaking and/or consulting fees: AbbVie, Beiersdorf, Bristol-Myers Squibb, CymaBay, Eisai, Falk, Gilead, GSK, Intercept, Lilly, MSD, and Zambon. Heinz Zoller: Speaking and/or consulting fees: Abbott, AbbVie, Bristol-Myers Squibb, Gilead, Merck/MSD, Pharmacosmos, Roche, Vifor. Grant support from Abbvie, Gilead, Pharmacosmos, and Vifor. Elisabetta Degasperi: Speaking and/or consulting fees: AbbVie, Gilead, MSD. Laura Sighinolfi: Speaking and/or consulting fees: Merck/MSD, ViiV Healthcare. Elisa Fernández-Fuertes: Speaking and/or consulting fees: Abbvie, Gilead, Merck/MSD, Janssen, ViiV. Leopoldo Muñoz-Medina: Speaking and/or consulting fees: AbbVie, Gilead, Janssen, ViiV. Rudolf Stauber: Speaking and/or consulting fees: AbbVie, Bayer, BMS, Eisai, Ipsen Gilead, Roche. Pietro Lampertico: Speaking and/or consulting fees: AbbVie, Alnylam, Arrowhead, BMS, Eiger, Gilead, GSK, Janssen, MSD, MYR, Roche, Spring Bank. Stefan Zeuzem: Speaking and/or consulting fees: Abbvie, BMS, Gilead, Janssen, Merck/MSD. Francesca Ceccherini-Silberstein: Speaking and/or consulting fees: Abbvie, Gilead, Janssen, Merck/MSD, ViiV Healthcare. Federico García: Speaking and/or consulting fees: Abbvie, Gilead, Hologic, Merck/MSD, Roche, Qiagen. Christoph Sarrazin: Speaking and/or consulting fees: Abbvie, Gilead, Merck/MSD, Research support: Abbvie, Gilead. All other authors report no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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