Development and persistence of DAA resistance associated mutations in patients failing HCV treatment.
BACKGROUND
Direct-acting antiviral agents (DAAs) combined with pegylated-interferon (PegIFN) and ribavirin (RBV) are still a standard treatment in patients with genotype 1HCV infection. However, virologic response could be impaired by baseline or early selection of resistant HCV strains.


OBJECTIVE
The aim of this study was to determine the onset and persistence of resistance-associated mutations (RAMs) in the NS3 and NS5B genes of DAA-naïve patients failing treatment.


METHODS
Direct sequencing of HCV NS3 was performed in 49 DAA-naïve patients with HCV genotype 1 infection.


RESULTS
Eight out of 23 patients (34.7%) failed PegIFN/RBV/telaprevir during the 12-weeks of therapy. Treatment failure was associated with the development of RAMs at amino-acids 36,54,80 and 155 of the HCV protease in 6/8 patients (75%). Among patients treated with PegIFN/RBV/boceprevir treatment, 4/18 (22.2%) failed therapy. Of these, 2 (50%) carried virus strains which developed a RAM at amino-acids 54 and 155. Among HCV strains with RAMs, 7 belonged to genotype 1a and 1 to 1b. Finally, in 6/10 (60%) patients, drug-resistant variants could still be detected for up to 3-7 months after stopping therapy.


CONCLUSIONS
A higher rate (p=0.49) of treatment failure was observed in patients receiving telaprevir- compared to the boceprevir-based combination. In addition, compared with genotype 1b, genotype 1a was associated with higher rates (p=0.01) of treatment failure due to virus resistant strains. Resistance testing at baseline and during DAA treatment should be taken into consideration when treating patients with new HCV combination therapies.
Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy.
Stefania
S
Paolucci
Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy.
Loretta
L
Fiorina
Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy.
Bianca
B
Mariani
Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy.
Viviana
V
Landini
Institute of Infectious Diseases, University of Pavia, 27100, Pavia, Italy.
Roberto
R
Gulminetti
Institute of Infectious Diseases, University of Pavia, 27100, Pavia, Italy.
Stefano
S
Novati
Institute of Infectious Diseases, University of Pavia, 27100, Pavia, Italy.
Renato
R
Maserati
Division of Infectious and Tropical Diseases, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy.
Giorgio
G
Barbarini
Division of Infectious and Tropical Diseases, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy.
Raffaele
R
Bruno
Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy; Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100, Pavia, Italy. Electronic address: f.baldanti@smatteo.pv.it.
Fausto
F
Baldanti
D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D020125:Mutation, Missense; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D009842:Oligopeptides; D011392:Proline; 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; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
Drug resistance; HCV genotype 1; Hepatitis C virus; Protease inhibitors; Sequencing