Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy.

Antiviral Agents / administration & dosage Carbamates / administration & dosage Drug Combinations Drug Resistance, Multiple, Viral / drug effects Drug Therapy, Combination / methods Europe / epidemiology Female Hepacivirus / drug effects Hepatitis C, Chronic / diagnosis Heterocyclic Compounds, 4 or More Rings / administration & dosage Humans Liver Cirrhosis / diagnosis Macrocyclic Compounds / administration & dosage Male Middle Aged Retreatment / methods Sofosbuvir / administration & dosage Sulfonamides / administration & dosage Sustained Virologic Response Treatment Failure Treatment Outcome

DAA Direct-acting antivirals HCV Hepatitis C virus Rescue therapy Resistance-associated substitutions Voxilaprevir/velpatasvir/sofosbuvir

Journal

Journal of hepatology

ISSN: 1600-0641

Titre abrégé: J Hepatol

Pays: Netherlands

ID NLM: 8503886

Informations de publication

Date de publication:
04 2021

Historique:

received: 08 06 2020

revised: 09 11 2020

accepted: 10 11 2020

pubmed: 22 11 2020

medline: 29 1 2022

entrez: 21 11 2020

Statut: ppublish

Résumé

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. 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. 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. 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. 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%).

Sections du résumé

BACKGROUND & AIMS

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%).

Identifiants

DOI: 10.1016/j.jhep.2020.11.017 PMID: 33220331

pubmed: 33220331

pii: S0168-8278(20)33770-3

doi: 10.1016/j.jhep.2020.11.017

pii:

doi:

Substances chimiques

Antiviral Agents 0

Carbamates 0

Drug Combinations 0

Heterocyclic Compounds, 4 or More Rings 0

Macrocyclic Compounds 0

Sulfonamides 0

sofosbuvir velpatasvir voxilaprevir drug combination 0

Sofosbuvir WJ6CA3ZU8B

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

801-810

Investigateurs

Alessio Aghemo (A)

Tiziano Allice (T)

Massimo Andreoni (M)

Mario Angelico (M)

Fausto Baldanti (F)

Silvia Barbaliscia (S)

Ada Bertoli (A)

Vanni Borghi (V)

Vincenza Calvaruso (V)

Giuseppe Cariti (G)

Antonio Craxì (A)

Simona Francioso (S)

Carlo Federico Perno (CF)

Pietro Pozzoni (P)

Pier Luigi Toniutto (PL)

Maurizio Zazzi (M)

Ana Belén Pérez (AB)

Cristina Quilez (C)

Juan Carlos Alados (JC)

Joaquin Cabezas (J)

Juan Ignacio Arenas Ruiz-Tapiador (JIA)

Miguel Jimenez (M)

Juan Manuel Pascasio-Acevedo (JM)

Manuel Alberto Macias Rodriguez (MAM)

Jose Miguel Rosales Zabal (JMR)

Miguel García Deltoro (MG)

Ana María Martinez Sapiña (AMM)

Ana Fuentes (A)

Natalia Chueca (N)

Christoph P Berg (CP)

Andreas Herrmann (A)

Andreas Stallmach (A)

Kerstin Port (K)

M Katja Deterding (M)

Heiner Wedermeyer (H)

Markus Cornberg (M)

Michael P Manns (MP)

Christophe Moreno (C)

Julian Schulze Zur Wiesch (JSZ)

Felix Piecha (F)

Ansgar Lohse (A)

Jürgen Siebler (J)

Nikolaus Kordecki (N)

Lorenzo Magenta (L)

Burkhard Jäger (B)

Hjördis Möller (H)

Renate Heyne (R)

Tomas Beyer (T)

Stephan Grunwald (S)

Axels Baumgarten (A)

Eva Jägel-Guedes (E)

Wolfgang Schmidt (W)

Commentaires et corrections

Type : CommentIn

Informations de copyright

Déclaration de conflit d'intérêts

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.