- Email: [email protected]
sofosbuvir ± ribavirin according to baseline resistance analysis
ORAL PRESENTATIONS Bologna; 6Infectious Diseases, Second University of Naples, Naples; 7 Division of Infectious Disease, Hospital Sacco of Milan; 8Clinical Microbiology,Virology and Bioemergencies, ASST Fatebenefratelli Sacco, Milan; 9Department of Internal Medicine, University Hospital of Messina, Messina; 10Infectious Diseases, “Amedeo di Savoia” Hospital, Turin; 11Hepatology Unit, San Camillo Forlanini Hospital, Rome; 12 Gastroenterology, “P. Giaccone” University Hospital, Palermo; 13 Department of Clinical Medicine and Surgery, University “Federico II” of Naples, Naples; 14Infectious Diseases, Sant’Andrea Hospital – “La Sapienza” University, Rome; 15Division of Hepatology, IRCCS San Martino, IST Genova; 16Infectious Disease, IRCCS AOU San Martino – IST; 17 Hygiene Unit, IRCCS AOU San Martino-IST, Genoa; 18Department of Gastroenterology, Scientific Institute for Digestive Disease “Saverio de Bellis” Hospital, Castellana Grotte, Bari; 19Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena; 20Internal Medicine, Humanitas University, Rozzano, Milan; 21 Liver Transplant Unit, Catholic University of Rome, Rome; 22Infectious Disease Clinic, Hospital of Chieti, Chieti; 23Department of Public Health and Infectious Diseases; 24Gastroenterology, Sapienza University of Rome, Rome; 25Infectious Diseases and Viral Hepatitis Unit, Second University, Naples; 26Unit of Gastroenterology, University of Turin, Turin; 27 Department of Medical and Surgical Sciences, University of Bologna, Bologna; 28Division of Infectious and Tropical Diseases, Fondazione IRCCS Policlinico San Matteo; 29Institute of Infectious Diseases, University of Pavia, Pavia; 30Hepatology Unit, Pescara General Hospital, Pescara; 31Infectious Disease, Hospital “G. Mazzini”, Teramo; 32 Department of Infectious Diseases, Hospital Niguarda Ca’Granda, Milan; 33Hospital Cotugno, Naples; 34General Medicin Unit, SST Santi Paolo e Carlo, Milan; 35Infectious Disease Unit, Avezzano General Hospital, Avezzano; 36Infectious Diseases, University Hospital of Rome Tor Vergata, Rome; 37Infectious Disease Unit, Pescara General Hospital, Pescara, Italy E-mail: [email protected] Background and Aims: Aim of this study was to characterize the presence of resistance associated substitutions (RAS) in a large cohort of HCV patients who failed an Interferon (IFN)-free Direct-ActingAntivirals (DAA) containing regimen. Methods: Among 325 patients failing a DAA-IFN free regimen, 261 (GT1a-1b-2c-3a/h-4a/d/n/r = 57-91-12-64-37; 79.4% cirrhotic; 70.6% treatment-experienced, 16 with DAA), with available resistance test at failure in NS3/NS5A/NS5B (by Sanger sequencing) were analyzed. Results: The majority of patients experienced a virological relapse (84.5%), and 59.0% failed a recommended regimen according to 2015 guidelines: simeprevir + sofosbuvir(SOF) ± ribavirin(RBV) (N = 58), daclatasvir/ledipasvir + SOF ± RBV (N = 23/39), 3D/2D ( paritaprevir/ ombitasvir ± dasabuvir [DSV]) ± RBV (N = 23), SOF + RBV (GT2, N = 11). Interestingly, 4.2% of failures had a misclassified genotype: in particular, 7 previously classified as GT1, were GT3a failing 3D ± RBV. Overall, 59.0% of patients showed at least one RAS related to the DAA-failure; RASs prevalence was higher in breakthrough/nonresponders than in relapsers (92.3% vs 50.9%, p < 0.001) and in patients with unfavourable IL28 CT/TT vs patients with IL28 CC (57.7% vs 12.5%, p = 0.024). RASs prevalence varied according to the DAAclass used (92.4% NS5A-RASs [N = 105], 72.3% NS3-RASs [N = 101], 34.5% DSV-RASs [N = 29)], 20.6% SOF-RASs [N = 218]) and according to HCV-GT. In NS5A-failing patients, Y93H was the most frequent major NS5A-RAS (61.9%), though with different prevalence among genotypes (15.4% GT1a; 90.0% GT1b; 82.6% GT3a; 40.0% GT4). Furthermore, 40.0% of patients presented >2 NS5A-RASs, with complex patterns more frequently in GT1b failures (67.5%, e.g. Y93H + L31M/I).Failures to SOF regimens showed frequent presence of L159F ± C316N (14.7%), particularly in GT1b (37.3%), followed by S282T in 3.6% (higher in GT4). Notably, 42.9% of patients treated with ≥2 DAA classes showed multiclass-resistance, including 100% NS3-NS5A-failures, and 65.5% in 3D-failures. Overall, 6.1% of patients showed RASs in all 3 targets and 13.0% of patients showed
also extra-target-RASs, probably due to natural resistance. Finally, 11 patients, all cirrhotic, experienced at least 2 subsequent virologic failures to IFN-free DAA regimens. Conclusions: In this real life setting, RASs prevalence at failure was remarkably high in all genes tested (with a partial exception for NS5B). This multiclass-resistance advocates for HCV resistance testing at failure in all 3 genes for the best second-line therapeutic tailoring. PS-155 High sustained virologic response rates in hepatitis C virus genotype 3 patients with and without cirrhosis treated with daclatasvir/sofosbuvir or velpatasvir/sofosbuvir ± ribavirin according to baseline resistance analysis J. Vermehren, J. Dietz, K.-H. Peiffer, N. Weiler, V. Mücke, G. Dultz, C. Welsch, S. Zeuzem, T.M. Welzel, C. Sarrazin. Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany E-mail: [email protected] Background and Aims: Hepatitis C virus (HCV) genotype (GT) 3 is currently the most difficult-to-treat genotype. Suboptimal sustained virologic response (SVR) rates have been observed in patients who received sofosbuvir (SOF) + ribavirin (RBV). Treatment with daclatasvir (DCV) or velpatasvir (VEL) in combination with SOF ± RBV has been shown to be superior to SOF/RBV alone. However, resistanceassociated substitutions (RASs) in the NS5A gene were associated with lower SVR rates with either treatment regimen. Here we investigated the efficacy of individually tailored treatment based on resistance analysis. Methods: Patients with HCV GT3 infection were treated with DCV/ SOF ± RBV for 12–24 weeks or VEL/SOF ± RBV for 12 weeks according to baseline (BL) RASs (A30K, Y93H), prior treatment failure and presence of cirrhosis. Population sequencing of the NS5A coding region was performed for all patients. In DCV-treated patients, in whom NS5A RASs were detected, RBV was added and treatment was extended to 24 weeks if they also had cirrhosis. RBV was also added and treatment extended in patients with prior treatment failure and cirrhosis regardless of BL RASs. In VEL-treated patients, RBV was added if BL RASs or cirrhosis were present. Results: In total, 130 patients with HCV GT3 of whom 63% were male, 42% had cirrhosis, and 45% had failed previous therapy were treated with DCV/SOF ± RBV (n = 97) or VEL/SOF ± RBV (n = 33). The A30K RAS was detected in 15% and 4% of DCV- and VEL-treated patients. Y93H was detected in 10% and 15%, respectively. Treatment was extended in 41% of DCV patients. RBV was added in 46% and 40% of patients treated with DCV and VEL, respectively. In DCV patients, SVR was achieved in 95% (n = 70/74; excluding patients lost to follow-up, who died or discontinued treatment early due to non-treatment related reasons). The SVR rate was 88% in patients with cirrhosis and prior treatment failure (n = 22/25). There were only 4 virologic relapsers, all of who had no RASs at baseline but Y93H was the dominant variant after treatment failure. Three of 4 failure patients had been treated with DCV/SOF + RBV for 24 weeks because of prior treatment failure and cirrhosis. In contrast, all patients with baseline RASs achieved SVR. Full SVR data for all DCV- and VEL-treated patients will be presented. Conclusions: In this real-world cohort of HCV GT3-infected patients, tailored treatment with consideration of baseline resistance analysis, presence of cirrhosis and/or prior treatment failure achieved high rates of virologic response. PS-156 MAGELLAN-1, Part 2: glecaprevir and pibrentasvir for 12 or 16 weeks in patients with chronic hepatitis C virus genotype 1 or 4 and prior direct-acting antiviral treatment failure F. Poordad1, S. Pol2, A. Asatryan3, M. Buti4, D. Shaw5, C. Hézode6, J. Lalezari7, F. Felizarta8, R.W. Reindollar9, S.C. Gordon10, S. Pianko11, M.W. Fried12, D.E. Bernstein13, J. Gallant14, C.-W. Lin3, Y. Lei3, T.I. Ng3, T. Pilot-Matias3, J. Kort3, F. Mensa3. 1The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States;
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also extra-target-RASs, probably due to natural resistance. Finally, 11 patients, all cirrhotic, experienced at least 2 subsequent virologic failures to IFN-free DAA regimens. Conclusions: In this real life setting, RASs prevalence at failure was remarkably high in all genes tested (with a partial exception for NS5B). This multiclass-resistance advocates for HCV resistance testing at failure in all 3 genes for the best second-line therapeutic tailoring. PS-155 High sustained virologic response rates in hepatitis C virus genotype 3 patients with and without cirrhosis treated with daclatasvir/sofosbuvir or velpatasvir/sofosbuvir ± ribavirin according to baseline resistance analysis J. Vermehren, J. Dietz, K.-H. Peiffer, N. Weiler, V. Mücke, G. Dultz, C. Welsch, S. Zeuzem, T.M. Welzel, C. Sarrazin. Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany E-mail: [email protected] Background and Aims: Hepatitis C virus (HCV) genotype (GT) 3 is currently the most difficult-to-treat genotype. Suboptimal sustained virologic response (SVR) rates have been observed in patients who received sofosbuvir (SOF) + ribavirin (RBV). Treatment with daclatasvir (DCV) or velpatasvir (VEL) in combination with SOF ± RBV has been shown to be superior to SOF/RBV alone. However, resistanceassociated substitutions (RASs) in the NS5A gene were associated with lower SVR rates with either treatment regimen. Here we investigated the efficacy of individually tailored treatment based on resistance analysis. Methods: Patients with HCV GT3 infection were treated with DCV/ SOF ± RBV for 12–24 weeks or VEL/SOF ± RBV for 12 weeks according to baseline (BL) RASs (A30K, Y93H), prior treatment failure and presence of cirrhosis. Population sequencing of the NS5A coding region was performed for all patients. In DCV-treated patients, in whom NS5A RASs were detected, RBV was added and treatment was extended to 24 weeks if they also had cirrhosis. RBV was also added and treatment extended in patients with prior treatment failure and cirrhosis regardless of BL RASs. In VEL-treated patients, RBV was added if BL RASs or cirrhosis were present. Results: In total, 130 patients with HCV GT3 of whom 63% were male, 42% had cirrhosis, and 45% had failed previous therapy were treated with DCV/SOF ± RBV (n = 97) or VEL/SOF ± RBV (n = 33). The A30K RAS was detected in 15% and 4% of DCV- and VEL-treated patients. Y93H was detected in 10% and 15%, respectively. Treatment was extended in 41% of DCV patients. RBV was added in 46% and 40% of patients treated with DCV and VEL, respectively. In DCV patients, SVR was achieved in 95% (n = 70/74; excluding patients lost to follow-up, who died or discontinued treatment early due to non-treatment related reasons). The SVR rate was 88% in patients with cirrhosis and prior treatment failure (n = 22/25). There were only 4 virologic relapsers, all of who had no RASs at baseline but Y93H was the dominant variant after treatment failure. Three of 4 failure patients had been treated with DCV/SOF + RBV for 24 weeks because of prior treatment failure and cirrhosis. In contrast, all patients with baseline RASs achieved SVR. Full SVR data for all DCV- and VEL-treated patients will be presented. Conclusions: In this real-world cohort of HCV GT3-infected patients, tailored treatment with consideration of baseline resistance analysis, presence of cirrhosis and/or prior treatment failure achieved high rates of virologic response. PS-156 MAGELLAN-1, Part 2: glecaprevir and pibrentasvir for 12 or 16 weeks in patients with chronic hepatitis C virus genotype 1 or 4 and prior direct-acting antiviral treatment failure F. Poordad1, S. Pol2, A. Asatryan3, M. Buti4, D. Shaw5, C. Hézode6, J. Lalezari7, F. Felizarta8, R.W. Reindollar9, S.C. Gordon10, S. Pianko11, M.W. Fried12, D.E. Bernstein13, J. Gallant14, C.-W. Lin3, Y. Lei3, T.I. Ng3, T. Pilot-Matias3, J. Kort3, F. Mensa3. 1The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States;
Journal of Hepatology 2017 vol. 66 | S63–S94
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