Prevalence of Single and Multiple Natural NS3, NS5A and NS5B Resistance-Associated Substitutions in Hepatitis C Virus Genotypes 1-4 in Italy

Bertoli, A.; Sorbo, M.; Aragri, M.; Lenci, I.; Teti, E.; Polilli, E.; Di Maio, V.; Gianserra, L.; Biliotti, E.; Masetti, C.; Magni, C.; Babudieri, S.; Nicolini, L.; Milana, M.; Cacciatore, P.; Sarmati, L.; Pellicelli, A.; Paolucci, S.; Craxì, A.; Morisco, F.; Palitti, V.; Siciliano, M.; Coppola, N.; Iapadre, N.; Puoti, M.; Rizzardini, G.; Taliani, G.; Pasquazzi, C.; Andreoni, M.; Parruti, G.; Angelico, M.; Perno, C.; Cento, V.; Ceccherini-Silberstein, F.; Andreone, P.; Baldanti, F.; Barbarini, G.; Boccaccio, V.; Boglione, L.; Bolis, M.; Bonora, S.; Borghi, V.; Brancaccio, G.; Bruno, S.; Bruzzone, B.; Calvaruso, V.; Caporaso, N.; Ciaccio, A.; Ciancio, A.; Colombatto, P.; Cozzolongo, R.; D'Ambrosio, C.; D'Ettorre, G.; De Leonardis, F.; De Luca, A.; Di Biagio, A.; Di Perri, G.; Francioso, S.; Gaeta, G.; Gasbarrini, A.; Ghisetti, V.; Giorgini, A.; Grieco, A.; Gubertini, G.; Gulminetti, R.; Lambiase, L.; Landonio, S.; Lichtner, M.; Maida, I.; Marenco, S.; Marinaro, L.; Maserati, R.; Melis, M.; Menzaghi, B.; Meregalli, E.; Micheli, V.; Niero, F.; Paoloni, M.; Pieri, A.; Rendina, M.; Romagnoli, D.; Rossetti, B.; Ruggiero, T.; Sangiovanni, V.; Starace, M.; Sticchi, L.; Tarquini, P.; Toniutto, P.; Vullo, V.; Zazzi, M.

doi:10.1038/s41598-018-26862-y

Natural resistance-associated substitutions (RASs) are reported with highly variable prevalence across different HCV genotypes (GTs). Frequency of natural RASs in a large Italian real-life cohort of patients infected with the 4 main HCV-GTs was investigated. NS3, NS5A and NS5B sequences were analysed in 1445 HCV-infected DAA-naïve patients. Sanger-sequencing was performed by home-made protocols on 464 GT1a, 585 GT1b, 92 GT2c, 199 GT3a, 16 GT4a and 99 GT4d samples. Overall, 20.7% (301/1455) of patients showed natural RASs, and the prevalence of multiclass-resistance was 7.3% (29/372 patients analysed). NS3-RASs were particularly common in GT1a and GT1b (45.2-10.8%, respectively), mainly due to 80K presence in GT1a (17%). Almost all GTs showed high prevalence of NS5A-RASs (range: 10.2-45.4%), and especially of 93H (5.1%). NS5A-RASs with fold-change >100x were detected in 6.8% GT1a (30H/R-31M-93C/H), 10.3% GT1b (31V-93H), 28.4% GT2c (28C-31M-93H), 8.5% GT3a (30K-93H), 45.5% GT4a (28M-30R-93H) and 3.8% GT4d (28V-30S-93H). Sofosbuvir RAS 282T was never detected, while the 159F and 316N RASs were found in GT1b (13.4-19.1%, respectively). Natural RASs are common in Italian patients infected with HCV-GTs 1-4. High prevalence of clinically-relevant RASs (such as Y93H) supports the appropriateness of HCV resistance-test to properly guide DAA-based therapy.

Prevalence of Single and Multiple Natural NS3, NS5A and NS5B Resistance-Associated Substitutions in Hepatitis C Virus Genotypes 1-4 in Italy / Bertoli, A.; Sorbo, M.; Aragri, M.; Lenci, I.; Teti, E.; Polilli, E.; Di Maio, V.; Gianserra, L.; Biliotti, E.; Masetti, C.; Magni, C.; Babudieri, S.; Nicolini, L.; Milana, M.; Cacciatore, P.; Sarmati, L.; Pellicelli, A.; Paolucci, S.; Craxì, A.; Morisco, F.; Palitti, V.; Siciliano, M.; Coppola, N.; Iapadre, N.; Puoti, M.; Rizzardini, G.; Taliani, G.; Pasquazzi, C.; Andreoni, M.; Parruti, G.; Angelico, M.; Perno, C.; Cento, V.; Ceccherini-Silberstein, F.; Andreone, P.; Baldanti, F.; Barbarini, G.; Boccaccio, V.; Boglione, L.; Bolis, M.; Bonora, S.; Borghi, V.; Brancaccio, G.; Bruno, S.; Bruzzone, B.; Calvaruso, V.; Caporaso, N.; Ciaccio, A.; Ciancio, A.; Colombatto, P.; Cozzolongo, R.; D'Ambrosio, C.; D'Ettorre, G.; De Leonardis, F.; De Luca, A.; Di Biagio, A.; Di Perri, G.; Francioso, S.; Gaeta, G.; Gasbarrini, A.; Ghisetti, V.; Giorgini, A.; Grieco, A.; Gubertini, G.; Gulminetti, R.; Lambiase, L.; Landonio, S.; Lichtner, M.; Maida, I.; Marenco, S.; Marinaro, L.; Maserati, R.; Melis, M.; Menzaghi, B.; Meregalli, E.; Micheli, V.; Niero, F.; Paoloni, M.; Pieri, A.; Rendina, M.; Romagnoli, D.; Rossetti, B.; Ruggiero, T.; Sangiovanni, V.; Starace, M.; Sticchi, L.; Tarquini, P.; Toniutto, P.; Vullo, V.; Zazzi, M.. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 8:1(2018), p. 8988. [10.1038/s41598-018-26862-y]