title: Telaprevir or boceprevir based therapy for chronic hepatitis C infection: development of resistance-associated variants in treatment failure.
abstract: The use of triple-therapy, pegylated-interferon, ribavirin and either of the first generation hepatitis C virus (HCV) protease inhibitors telaprevir or boceprevir, is the new standard of care for treating genotype 1 chronic HCV. Clinical trials have shown response rates of around 70-80%, but there is limited data from the use of this combination outside this setting. Through an expanded access programme, we treated 59 patients, treatment naïve and experienced, with triple therapy. Baseline factors predicting treatment response or failure during triple therapy phase were identified in 58 patients. Thirty seven (63.8%) of 58 patients had undetectable HCV RNA 12weeks after the end of treatment. Genotype 1a (p=0.053), null-response to previous treatment (p=0.034), the rate of viral load decline after 12weeks of previous interferon-based treatment (p=0.033) were all associated with triple-therapy failure. The most common cause of on-treatment failure for telaprevir-based regimens was the development of resistance-associated variants (RAVs) at amino acids 36 and/or 155 of HCV protease (p=0.027) whereas in boceprevir-based regimens mutations at amino acid 54 were significant (p=0.015). SVR12 rates approaching 64% were achieved using triple therapy outside the clinical trial setting, in a patient cohort that included cirrhotics.
authors.affiliation: Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, United Kingdom. Electronic address: malcolm.macartney@nhs.net.
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Macartney
authors.affiliation: Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, United Kingdom.
authors.forename: Dianne
authors.initials: D
authors.lastname: Irish
authors.affiliation: Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, United Kingdom.
authors.forename: Simon H
authors.initials: SH
authors.lastname: Bridge
authors.affiliation: Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Garcia-Diaz
authors.affiliation: Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, United Kingdom.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Booth
authors.affiliation: Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, United Kingdom.
authors.forename: Adele L
authors.initials: AL
authors.lastname: McCormick
authors.affiliation: Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, United Kingdom.
authors.forename: Wendy
authors.initials: W
authors.lastname: Labbett
authors.affiliation: Department of Population Studies, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, United Kingdom.
authors.forename: Colette
authors.initials: C
authors.lastname: Smith
authors.affiliation: Directorate of Hepatology, Nephrology and Transplantation, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, United Kingdom.
authors.forename: Carmen
authors.initials: C
authors.lastname: Velazquez
authors.affiliation: UCL Institute for Liver and Digestive Health, Royal Free Campus, Rowland Hill Street, London NW3 2PF, United Kingdom.
authors.forename: Sudeep
authors.initials: S
authors.lastname: Tanwar
authors.affiliation: UCL Institute for Liver and Digestive Health, Royal Free Campus, Rowland Hill Street, London NW3 2PF, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Trembling
authors.affiliation: Directorate of Hepatology, Nephrology and Transplantation, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Jacobs
authors.affiliation: Directorate of Hepatology, Nephrology and Transplantation, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, United Kingdom.
authors.forename: Geoff
authors.initials: G
authors.lastname: Dusheiko
authors.affiliation: Directorate of Hepatology, Nephrology and Transplantation, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, United Kingdom; UCL Institute for Liver and Digestive Health, Royal Free Campus, Rowland Hill Street, London NW3 2PF, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Rosenberg
authors.affiliation: Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, United Kingdom.
authors.forename: Tanzina
authors.initials: T
authors.lastname: Haque
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009842:Oligopeptides / Q000627:therapeutic use*; D011392:Proline / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D012254:Ribavirin / Q000627:therapeutic use; D017211:Treatment Failure; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000235:genetics; 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; D012367:RNA, Viral; 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: Drug resistance; HCV; Protease inhibitors; Telaprevir