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J Antimicrob Chemother. 2016 Mar;71(3):739-50. doi: 10.1093/jac/dkv403. Epub 2015 Dec 17.

HCV NS3 sequencing as a reliable and clinically useful tool for the assessment of genotype and resistance mutations for clinical samples with different HCV-RNA levels.

Collaborators (129)

Mariani R, Paoloni M, Iapadre N, Grimaldi A, Menzaghi B, Quirino T, Vecchiet J, Bruzzone B, De Maria A, Di Biagio A, Marenco S, Nicolini LA, Picciotto A, Viscoli C, Casinelli K, Monache MD, Lichtner M, Mastroianni C, Aghemo A, Bruno S, Cerrone M, Colombo M, Monforte AD, Danieli E, Donato F, Gubertini G, Landonio S, Magni CF, Mancon A, Micheli V, Monico S, Niero F, Puoti M, Rizzardini G, Russo ML, Alfieri R, Gnocchi M, Orro A, Milanesi L, Baldelli E, Bertolotti M, Borghi V, Mussini C, Romagnoli D, Brancaccio G, Caporaso N, Gaeta GB, Lembo V, Morisco F, Calvaruso V, Craxì A, Di Marco V, Mazzola A, Petta S, D'Amico E, Cacciatore P, Consorte A, Palitti VP, Parruti G, Pieri A, Polilli E, Tontodonati M, Andreoni M, Angelico M, Antenucci F, Antonucci FP, Aragri M, Armenia D, Baiocchi L, Bellocchi M, Bertoli A, Biliotti E, Biolato M, Carioti L, Ceccherini-Silberstein F, Cento V, Cerasari G, Cerva C, Ciotti M, D'Ambrosio C, D'Ettorre G, De Leonardis F, De Sanctis A, Di Maio VC, Di Paolo D, Francioso S, Furlan C, Gallo P, Gasbarrini A, Giannelli V, Gianserra L, Grieco A, Grieco S, Lambiase L, Lattanzi B, Lenci I, Malagnino V, Manuelli M, Merli M, Miglioresi L, Milana M, Nosotti L, Palazzo D, Pasquazzi C, Pellicelli A, Perno CF, Romano M, Santopaolo F, Santoro MM, Sarmati L, Sarrecchia C, Sforza D, Siciliano M, Sorbo MC, Spaziante M, Svicher V, Taliani G, Teti E, Tisone G, Vespasiani-Gentilucci U, Vullo V, Mangia A, Babudieri S, Maida I, Melis M, Mura MS, Falconi L, Di Giammartino D, Tarquini P.

Author information

1
Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy.
2
Hepatology Unit, University Hospital of Rome 'Tor Vergata', Rome, Italy.
3
Infectious Disease Unit, Pescara General Hospital, Pescara, Italy.
4
Unit of Microbiology, Hospital Sacco of Milan, Milan, Italy.
5
Infectious Diseases, Sant'Andrea Hospital-'La Sapienza' University, Rome, Italy.
6
Infectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
7
Infectious Diseases Unit, Department of Social Health (DISSAL) of the University of Genoa, IRCCS S. Martino-IST, Genova, Italy.
8
Infectious Disease, University Hospital of Rome 'Tor Vergata', Rome, Italy.
9
Division of Infectious Disease, Hospital Sacco of Milan, Milan, Italy.
10
Department of Internal Medicine, Gastroenterology Unit, University of Genova, Genova, Italy.
11
Hepatology Unit, National Institute of Health, Migration and Poverty, Rome, Italy.
12
Gastroenterology Unit, Department of Clinical Medicine, 'La Sapienza' University, Rome, Italy.
13
Gastroenterology, Catholic University of Rome, Rome, Italy.
14
Department of Biomedical, Metabolic and Neural Sciences, NOCSAE Baggiovara, Modena, Italy.
15
Hepatology Unit, San Camillo Forlanini Hospital, Rome, Italy.
16
Infectious Disease Clinic, Chieti, Italy.
17
Department of Clinical Medicine, Policlinico Umberto I, 'Sapienza' University of Rome, Rome, Italy.
18
Department of Infectious Diseases, University of Rome 'Sapienza' (Polo Pontino), Latina, Italy.
19
Campus Biomedico, Rome, Italy.
20
S. Pertini Hospital, Rome, Italy.
21
Università 'Federico II', Naples, Italy.
22
Department of Public Health and Infectious Diseases, University of Rome 'Sapienza', Rome, Italy.
23
Department of Internal Medicine, Humanitas University, Rozzano, Milan, Italy.
24
Hospital Niguarda Ca'Granda, Milan, Italy.
25
Liver Transplant Centre, Tor Vergata University, Rome, Italy.
26
Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy Molecular Virology Unit, University Hospital of Rome 'Tor Vergata', Rome, Italy.
27
Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy ceccherini@med.uniroma2.it.

Abstract

OBJECTIVES:

This study aims to evaluate the reliability and clinical utility of NS3 sequencing in hepatitis C virus (HCV) 1-infected patients who were candidates to start a PI-containing regimen.

METHODS:

NS3 protease sequencing was performed by in-house-developed HCV-1 subtype-specific protocols. Phylogenetic analysis was used to test sequencing reliability and concordance with previous genotype/subtype assignment by commercial genotyping assays.

RESULTS:

Five hundred and sixty-seven HCV plasma samples with quantifiable HCV-RNA from 326 HCV-infected patients were collected between 2011 and 2014. Overall, the success rate of NS3 sequencing was 88.9%. The success rate between the two subtype protocols (HCV-1a/HCV-1b) was similarly high for samples with HCV-RNA >3 log IU/mL (>92% success rate), while it was slightly lower for HCV-1a samples with HCV-RNA ≤3 log IU/mL compared with HCV-1b samples. Phylogenetic analysis confirmed the genotype/subtype given by commercial genotyping assays in 92.9% (303/326) of cases analysed. In the remaining 23 cases (7.1%), 1 was HCV-1g (previously defined as subtype 1a), 1 was HCV-4d (previously defined as genotype 1b) and 1 was HCV-1b (previously defined as genotype 2a/2c). In the other cases, NS3 sequencing precisely resolved the either previous undetermined/discordant subtype 1 or double genotype/subtype assignment by commercial genotyping assays. Resistance-associated variants (RAVs) to PI were detected in 31.0% of samples. This prevalence changed according to PI experience (17.1% in PI-naive patients versus 79.2% in boceprevir/telaprevir/simeprevir-failing patients). Among 96 patients with available virological outcome following boceprevir/telaprevir treatment, a trend of association between baseline NS3 RAVs and virological failure was observed (particularly for HCV-1a-infected patients: 3/21 failing patients versus 0/22 achieving sustained virological response; P = 0.11).

CONCLUSIONS:

HCV-NS3 sequencing provides reliable results and at the same time gives two clinically relevant pieces of information: a correct subtype/genotype assignment and the detection of variants that may interfere with the efficacy of PI.

PMID:
26679249
DOI:
10.1093/jac/dkv403
[Indexed for MEDLINE]

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