Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin.
The pretherapeutic presence of protease inhibitor (PI) resistance-associated variants (RAVs) has not been shown to be predictive of triple-therapy outcomes in treatment-naive patients. However, they may influence the outcome in patients with less effective pegylated interferon (pegIFN)-ribavirin (RBV) backbones. Using hepatitis C virus (HCV) population sequence analysis, we retrospectively investigated the prevalence of baseline nonstructural 3 (NS3) RAVs in a multicenter cohort of poor IFN-RBV responders (i.e., prior null responders or patients with a viral load decrease of <1 log IU/ml during the pegIFN-RBV lead-in phase). The impact of the presence of these RAVs on the outcome of triple therapy was studied. Among 282 patients, the prevalances (95% confidence intervals) of baseline RAVs ranged from 5.7% (3.3% to 9.0%) to 22.0% (17.3% to 27.3%), depending to the algorithm used. Among mutations conferring a >3-fold shift in 50% inhibitory concentration (IC50) for telaprevir or boceprevir, T54S was the most frequently detected mutation (3.9%), followed by A156T, R155K (0.7%), V36M, and V55A (0.35%). Mutations were more frequently found in patients infected with genotype 1a (7.5 to 23.6%) than 1b (3.3 to 19.8%) (P = 0.03). No other sociodemographic or viroclinical characteristic was significantly associated with a higher prevalence of RAVs. No obvious effect of baseline RAVs on viral load was observed. In this cohort of poor responders to IFN-RBV, no link was found with a sustained virological response to triple therapy, regardless of the algorithm used for the detection of mutations. Based on a cross-study comparison, baseline RAVs are not more frequent in poor IFN-RBV responders than in treatment-naive patients and, even in these difficult-to-treat patients, this study demonstrates no impact on treatment outcome, arguing against resistance analysis prior to treatment.
Centre Hospitalier Universitaire Grenoble, Pôle Biologie, Laboratoire de Virologie, Département des Agents Infectieux, Grenoble, France Université Grenoble Alpes, Unit of Virus Host Cell Interactions UMI 3265 UJF-EMBL-CNRS, Grenoble, France slarrat@chu-grenoble.fr.
Sylvie
S
Larrat
Université Européenne de Bretagne, UFR Médecine et des Sciences de la Santé, LUBEM, Brest, France Laboratoire de Virologie, Centre Hospitalier Régional Universitaire, Brest, France.
Sophie
S
Vallet
Centre Hospitalier Universitaire Grenoble, Pôle Recherche, Cellule d'Évaluation Médico-Économique Innovation, Grenoble, France.
Sandra
S
David-Tchouda
Centre Hospitalier Universitaire Grenoble, Pôle Biologie, Laboratoire de Virologie, Département des Agents Infectieux, Grenoble, France Université Grenoble Alpes, TIMC-IMAG/CNRS/UMR 5525, Grenoble, France.
Alban
A
Caporossi
Centre Hospitalier Universitaire Grenoble, Pôle Recherche, Cellule d'Évaluation Médico-Économique Innovation, Grenoble, France.
Jennifer
J
Margier
Laboratoire de Virologie, Centre de Biologie Nord, Hôpital de la Croix Rousse, Lyon, France.
Christophe
C
Ramière
Laboratoire de Virologie, Centre de Biologie Nord, Hôpital de la Croix Rousse, Lyon, France.
Caroline
C
Scholtes
Laboratoire de Virologie, Hôpital Paul Brousse, Villejuif, France INSERM U785, Université Paris-Sud, Faculté de Médecine Le Kremlin-Bicêtre, Paris, France.
Stéphanie
S
Haïm-Boukobza
Laboratoire de Virologie, Hôpital Paul Brousse, Villejuif, France INSERM U785, Université Paris-Sud, Faculté de Médecine Le Kremlin-Bicêtre, Paris, France.
Anne-Marie
AM
Roque-Afonso
Laboratoire de Virologie, Centre Hospitalier Universitaire Hôtel Dieu, Nantes, France.
Bernard
B
Besse
Laboratoire de Virologie, Centre Hospitalier Universitaire Hôtel Dieu, Nantes, France.
Elisabeth
E
André-Garnier
Laboratoire Alphabio, Hôpital Ambroise Paré, Marseille, France.
Sofiane
S
Mohamed
Laboratoire Alphabio, Hôpital Ambroise Paré, Marseille, France.
Philippe
P
Halfon
Laboratoire de Virologie-Bactériologie, Centre Hospitalier Universitaire Angers, Angers, France.
Adeline
A
Pivert
Laboratoire de Virologie-Bactériologie, Centre Hospitalier Universitaire Angers, Angers, France.
Hélène
H
LeGuillou-Guillemette
Laboratoire de Virologie, Centre Hospitalier Universitaire, Institut Fédératif de Biologie, INSERM U563, Centre Hospitalier Universitaire Toulouse Purpan, Toulouse, France.
Florence
F
Abravanel
Laboratoire de Virologie, Centre Hospitalier Universitaire, Institut Fédératif de Biologie, INSERM U563, Centre Hospitalier Universitaire Toulouse Purpan, Toulouse, France.
Matthieu
M
Guivarch
Laboratoire de Virologie, Centre Hospitalier Universitaire Beaujon (HUPNVS), Clichy-la-Garenne, France.
Vincent
V
Mackiewicz
Laboratoire de Virologie, Centre Hospitalier Universitaire Beaujon (HUPNVS), Clichy-la-Garenne, France.
Olivier
O
Lada
Laboratoire de Virologie, Centre Hospitalier Universitaire Charles Nicolle, Rouen, France.
Thomas
http://orcid.org/0000-0001-6173-2908
T
Mourez
Laboratoire de Virologie, Centre Hospitalier Universitaire Charles Nicolle, Rouen, France.
Jean-Christophe
http://orcid.org/0000-0001-6417-4083
JC
Plantier
Laboratoire de Virologie, Centre Hospitalier Universitaire Avicennes, Bobigny, France.
Yazid
Y
Baazia
Laboratoire de Virologie, Centre Hospitalier Universitaire Dupuytren, Limoges, France.
Sophie
S
Alain
Laboratoire de Virologie, Centre Hospitalier Universitaire Dupuytren, Limoges, France.
Sebastien
S
Hantz
Laboratoire de Virologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France.
Vincent
V
Thibault
Service de Bactériologie-Virologie & INSERM U966, Centre Hospitalier Universitaire, Université François Rabelais, Tours, France.
Catherine
C
Gaudy-Graffin
Service de Bactériologie-Virologie & INSERM U966, Centre Hospitalier Universitaire, Université François Rabelais, Tours, France.
Dorine
D
Bouvet
Laboratoire de Virologie, Centre Hospitalier Universitaire, Clermont-Ferrand, France.
Audrey
A
Mirand
Laboratoire de Virologie, Centre Hospitalier Universitaire, Clermont-Ferrand, France.
Cécile
C
Henquell
Laboratoire de Virologie, Centre Hospitalier Universitaire Saint-Antoine, Paris, France.
Joel
J
Gozlan
Laboratoire de Virologie, Centre Hospitalier Universitaire, Rennes, France.
Gisèle
G
Lagathu
Laboratoire de Virologie, Centre Hospitalier Universitaire, Rennes, France.
Charlotte
C
Pronier
Laboratoire de Virologie, Centre Hospitalier Universitaire, Nancy, France.
Aurélie
A
Velay
Laboratoire de Virologie, Centre Hospitalier Universitaire, Nancy, France.
Evelyne
E
Schvoerer
Laboratoire de Virologie, Centre Hospitalier Universitaire Pellegrin Tripode, Bordeaux, France.
Pascale
P
Trimoulet
Laboratoire de Virologie, Centre Hospitalier Universitaire Pellegrin Tripode, Bordeaux, France.
Hervé
H
Fleury
Centre National de Référence des Hépatites Virales B, C et D, Laboratoire de Virologie et INSERM U955, Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
Magali
M
Bouvier-Alias
Laboratoire de Virologie, Centre Hospitalier Universitaire, Amiens, France.
Etienne
E
Brochot
Laboratoire de Virologie, Centre Hospitalier Universitaire, Amiens, France.
Gilles
G
Duverlie
Laboratoire de Virologie, Centre Hospitalier Universitaire St. Louis, Paris, France.
Sarah
S
Maylin
Centre Hospitalier Universitaire Grenoble, Pôle Recherche, Cellule d'Évaluation Médico-Économique Innovation, Grenoble, France.
Stéphanie
S
Gouriou
Centre National de Référence des Hépatites Virales B, C et D, Laboratoire de Virologie et INSERM U955, Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
Jean-Michel
JM
Pawlotsky
Centre Hospitalier Universitaire Grenoble, Pôle Biologie, Laboratoire de Virologie, Département des Agents Infectieux, Grenoble, France Université Grenoble Alpes, Unit of Virus Host Cell Interactions UMI 3265 UJF-EMBL-CNRS, Grenoble, France.
Patrice
P
Morand
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D020128:Inhibitory Concentration 50; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012189:Retrospective Studies; D012254:Ribavirin / Q000627:therapeutic use; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide