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

Aminoisobutyric Acids Antiviral Agents / pharmacology Benzimidazoles Cyclopropanes Drug Resistance, Viral Genotype Germany / epidemiology Hepacivirus / genetics Humans Italy / epidemiology Lactams, Macrocyclic Leucine / analogs & derivatives Prevalence Proline / analogs & derivatives Pyrrolidines Quinoxalines Retreatment Retrospective Studies Spain Sulfonamides Viral Nonstructural Proteins / genetics

Journal

The Journal of antimicrobial chemotherapy

ISSN: 1460-2091

Titre abrégé: J Antimicrob Chemother

Pays: England

ID NLM: 7513617

Informations de publication

Date de publication:
01 11 2020

Historique:

received: 16 02 2020

accepted: 02 06 2020

pubmed: 11 8 2020

medline: 25 6 2021

entrez: 11 8 2020

Statut: ppublish

Résumé

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

Identifiants

DOI: 10.1093/jac/dkaa304 PMID: 32772078

pubmed: 32772078

pii: 5886939

doi: 10.1093/jac/dkaa304

doi:

Substances chimiques

Aminoisobutyric Acids 0

Antiviral Agents 0

Benzimidazoles 0

Cyclopropanes 0

Lactams, Macrocyclic 0

Pyrrolidines 0

Quinoxalines 0

Sulfonamides 0

Viral Nonstructural Proteins 0

pibrentasvir 2WU922TK3L

Proline 9DLQ4CIU6V

Leucine GMW67QNF9C

glecaprevir K6BUU8J72P

Types de publication

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

Langues

eng

Sous-ensembles de citation

Pagination

3349-3358

Investigateurs

T Götze (T)

A Canbay (A)

K Port (K)

M Cornberg (M)

M Manns (M)

L Reinhardt (L)

V Ellenrieder (V)

E Zizer (E)

N Dikopoulos (N)

J Backhus (J)

T Seufferlein (T)

S Beckebaum (S)

S Hametner (S)

R Schöfl (R)

C Niederau (C)

P Schlee (P)

M Dreck (M)

B Görlitz (B)

H Hinrichsen (H)

B Seegers (B)

M Jung (M)

R Link (R)

S Mauss (S)

V Meister (V)

E Schnaitmann (E)

C Sick (C)

K G Simon (KG)

K J Schmidt (KJ)

Massimo Andreoni (M)

Antonio Craxì (A)

P Giaccone (P)

Carlo Federico Perno (CF)

Maurizio Zazzi (M)

Ada Bertoli (A)

Mario Angelico (M)

Chiara Masetti (C)

Valerio Giannelli (V)

San Camillo (S)

Paola Begini (P)

Adriano De Santis (A)

Gloria Taliani (G)

Miriam Lichtner (M)

Barbara Rossetti (B)

Cinzia Caudai (C)

Raffaele Cozzolongo (R)

S De Bellis (S)

Mario Starace (M)

Carmine Minichini (C)

Gianfranco Gaeta (G)

Maria Antonietta Pisaturo (MA)

Vincenzo Messina (V)

Chiara Dentone (C)

Bianca Bruzzone (B)

Simona Landonio (S)

Carlo Magni (C)

Marco Merli (M)

Elisabetta De Gasperi (E)

Granda Ospedale Maggiore Policlinico (GOM)

Hamid Hasson (H)

Enzo Boeri (E)

Ilaria Beretta (I)

Chiara Molteni (C)

A Manzoni Elena Maffezzini (AME)

Nicoletta Dorigoni (N)

Lorenza Guella (L)

Informations de copyright

© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.