Yael Gozlan1, Ziv Ben-Ari2,3, Roy Moscona1, Rachel Shirazi1, Aviya Rakovsky1, Arij Kabat1, Ella Veizman2, Tania Berdichevski2, Peretz Weiss2, Oranit Cohen-Ezra2, Yoav Lurie4, Inna Gafanovich4, Marius Braun3,5, Michal Cohen-Naftaly3,5, Amir Shlomai3,5, Oren Shibolet3,6, Ehud Zigmond3,6, Eli Zuckerman7, Michal Carmiel-Haggai8,9, Assy Nimer9,10, Rawi Hazzan11, Yaakov Maor12, Yona Kitay-Cohen13, Yonat Shemer-Avni14, Zipi Kra-Oz15, Licita Schreiber16, Ofer Peleg17, Saleta Sierra18, P Richard Harrigan19, Ella Mendelson1,20, Orna Mor1. 1. Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat-Gan, Israel. 2. Liver Disease Center, Sheba Medical Center, Ramat-Gan, Israel. 3. The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 4. Liver Unit, Shaare Zedek Medical Center, Jerusalem, Israel. 5. Liver Institute, Rabin Medical Center, Petah-Tikva, Israel. 6. Department of Gastroenterology, Tel-Aviv Medical Center, Tel Aviv, Israel. 7. Liver Unit, Carmel Medical Center, Haifa, Israel. 8. Liver Unit, Galilee Medical Center, Naharya, Israel. 9. Faculty of Medicine in the Galilee, Bar-Ilan University, Ramat-Gan, Israel. 10. Internal Medicine Department, Galilee Medical Center, Naharya, Israel. 11. Liver Unit, Haemek Medical Center, Afula, Israel. 12. Division of Gastroenterology, Kaplan Health Sciences Centre, Department of Medicine, Faculty of Medicine, Hebrew University, Rehovot, Israel. 13. Gastroenterology and Hepatology Institute, Meir Medical Center, Kfar Saba, Israel. 14. Virology Laboratory, Soroka Medical Center, Beer Sheva, Israel. 15. Virology Laboratory, Rambam Medical Center, Haifa, Israel. 16. Maccabi Health Services, Mega Laboratory, Rehovot, Israel. 17. Genaphora Ltd, Rehovot, Israel. 18. Institute of Virology, University of Cologne, Cologne, Germany. 19. BC Centre for Excellence in HIV, Vancouver, BC, Canada. 20. School of Public Health, Tel Aviv University, Tel Aviv, Israel.
Abstract
BACKGROUND: Direct-acting antiviral (DAA) treatment regimens and response rates of patients with HCV genotype-1 (GT1) are currently considered subtype-dependent. Identification of clinically relevant resistance-associated substitutions (RASs) in the NS3 and NS5A proteins at baseline and in DAA failures, may also impact clinical decisions. METHODS: In a multicentre cohort study (n=308), NS3 or NS5B sequencing (n=248) was used to discriminate between GT1 subtypes. The correlation between baseline NS3 and NS5A RASs on the 12-week sustained virological response (SVR12) rates of 160 of the patients treated with second-generation DAAs was also assessed. Post-treatment resistance analysis was performed on samples from 58 patients exhibiting DAA virological failure. RESULTS: GT1a, GT1b and GT1d subtypes were identified in 23.0%, 75.4% and 1.2% of tested samples. GT1b was most prevalent (97.7%, 128/131) among patients born in the former Soviet Union. The Q80K NS3 RAS was identified in 17.5% (10/57) of the GT1a carriers, most of whom were Israeli-born. NS3 and NS5A baseline RASs showed a negligible correlation with SVR12 rates. Treatment-emergent RASs were observed among 8.9% (4/45) and 76.9% (10/13) of first- and second-generation DAA failures, respectively, with D168V/E (NS3), Y93H and L31M (NS5A) being the most prevalent mutations. CONCLUSIONS: NS3 sequencing analysis can successfully discriminate between GT1 subtypes and identify NS3 amino acid substitutions. While pre-treatment NS3 and NS5A RASs marginally affect second-generation DAA SVR12 rates, post-treatment resistance analysis should be considered prior to re-therapy.
BACKGROUND: Direct-acting antiviral (DAA) treatment regimens and response rates of patients with HCV genotype-1 (GT1) are currently considered subtype-dependent. Identification of clinically relevant resistance-associated substitutions (RASs) in the NS3 and NS5A proteins at baseline and in DAA failures, may also impact clinical decisions. METHODS: In a multicentre cohort study (n=308), NS3 or NS5B sequencing (n=248) was used to discriminate between GT1 subtypes. The correlation between baseline NS3 and NS5A RASs on the 12-week sustained virological response (SVR12) rates of 160 of the patients treated with second-generation DAAs was also assessed. Post-treatment resistance analysis was performed on samples from 58 patients exhibiting DAA virological failure. RESULTS: GT1a, GT1b and GT1d subtypes were identified in 23.0%, 75.4% and 1.2% of tested samples. GT1b was most prevalent (97.7%, 128/131) among patients born in the former Soviet Union. The Q80K NS3 RAS was identified in 17.5% (10/57) of the GT1a carriers, most of whom were Israeli-born. NS3 and NS5A baseline RASs showed a negligible correlation with SVR12 rates. Treatment-emergent RASs were observed among 8.9% (4/45) and 76.9% (10/13) of first- and second-generation DAA failures, respectively, with D168V/E (NS3), Y93H and L31M (NS5A) being the most prevalent mutations. CONCLUSIONS: NS3 sequencing analysis can successfully discriminate between GT1 subtypes and identify NS3 amino acid substitutions. While pre-treatment NS3 and NS5A RASs marginally affect second-generation DAA SVR12 rates, post-treatment resistance analysis should be considered prior to re-therapy.
Authors: Kate Childs; Elliot Merritt; Aisling Considine; Alberto Sanchez-Fueyo; Kosh Agarwal; Marc Martinez-Llordella; Ivana Carey Journal: Open Forum Infect Dis Date: 2017-04-03 Impact factor: 3.835