title: Hepatitis C virus NS3 protease genotyping and drug concentration determination during triple therapy with telaprevir or boceprevir for chronic infection with genotype 1 viruses, southeastern France.
abstract: Telaprevir and boceprevir, the two first hepatitis C virus (HCV) NS3 protease inhibitors (PIs), considerably increase rates of sustained virologic response in association with pegylated interferon and ribavirin in chronic HCV genotype 1 infections. The 30 first patients treated by telaprevir or boceprevir including anti-HCV therapies since 2011 in Marseille University hospitals, France, were monitored. HCV loads and plasmatic concentrations of telaprevir and boceprevir were determined on sequential blood samples. HCV NS3 protease gene population sequencing was performed at baseline of treatment and in case of treatment failure. Fifteen patients (including 7 co-infected with HIV) received telaprevir and the other 15 patients (including 4 co-infected with HIV) received boceprevir. At baseline, HCV NS3 protease from six patients harbored amino acid substitutions associated with PI-resistance. Treatment failure occurred at week 12 for 7 patients. Amino acid substitutions associated with PI-resistance were observed in six of these cases. HCV NS3 R155K and T54A/S mutants, all of genotype 1a, were found from four patients. Median (interquartile range) plasma concentrations were 3,092 ng/ml (2,320-3,525) for telaprevir and 486 ng/ml (265-619) for boceprevir. For HIV-HCV co-infected patients, median concentrations were 3,162 ng/ml (2,270-4,232) for telaprevir and 374 ng/ml (229-519) for boceprevir. Plasma drug concentration monitoring revealed undetectable concentrations for two patients at week 4, and probable non-adherence to therapy for another patient. These findings indicate that routine HCV NS3 protease sequencing and plasma PI concentration monitoring might be helpful to characterize cases of therapy failure, at a cost dramatically low compared to that of anti-HCV therapy.
authors: Fondation Institut Hospitalo-Universitaire (IHU) Méditerranée Infection, Assistance Publique - Hôpitaux de Marseille, Centre Hospitalo-Universitaire Timone, Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Fédération de Bactériologie-Hygiène-Virologie, Marseille, France; Aix-Marseille Univ., Facultés de Médecine et de Pharmacie, URMITE UM63 CNRS 7278 IRD 198 INSERM U1095, Marseille, France.
authors: Sarah
authors: S
authors: Aherfi
authors: Caroline
authors: C
authors: Solas
authors: Anne
authors: A
authors: Motte
authors: Jacques
authors: J
authors: Moreau
authors: Patrick
authors: P
authors: Borentain
authors: Saadia
authors: S
authors: Mokhtari
authors: Danielle
authors: D
authors: Botta-Fridlund
authors: Catherine
authors: C
authors: Dhiver
authors: Isabelle
authors: I
authors: Portal
authors: Jean-Marie
authors: JM
authors: Ruiz
authors: Isabelle
authors: I
authors: Ravaux
authors: Sylvie
authors: S
authors: Bregigeon
authors: Isabelle
authors: I
authors: Poizot-Martin
authors: Andreas
authors: A
authors: Stein
authors: René
authors: R
authors: Gérolami
authors: Philippe
authors: P
authors: Brouqui
authors: Catherine
authors: C
authors: Tamalet
authors: Philippe
authors: P
authors: Colson
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005602:France; D005838:Genotype; D016174:Hepacivirus / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006785:Hospitals, University; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010949:Plasma / Q000737:chemistry; D011392:Proline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D017211:Treatment Failure; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D055815:Young Adult; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D011392:Proline; 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
keywords: boceprevir; drug concentration; hepatitis C virus; protease inhibitor; resistance mutation; telaprevir