- Email: [email protected]
P1227 FALDAPREVIR EFFICACY IN HCV GENOTYPE-1-INFECTED PATIENTS IN FOUR PHASE 3 TRIALS: ANALYSIS BY NS3 BASELINE POLYMORPHISMS, GENOTYPE-1 SUBTYPE AND GENOTYPE-1A CLADES
POSTERS Methods: Twenty patients were randomized to receive 100 or 200 mg VX-135 QD with RBV for 12 weeks. HCV RNA levels were measured using COBAS® TaqMan® (v.2.0, Roche). The NS5B region was sequenced before, during, and after treatment to monitor for S282T and other potential resistant variants observed in >1 patient. Results: Sequence data were available for all patients at baseline, 2 patients at Week 1 of treatment, and 13 patients who relapsed (1 additional pending). The S282T variant was not observed by population sequencing in any patient (with available data) at any time point. No additional potential resistant variants were identified in patients who relapsed. More sensitive sequencing analyses are underway. Conclusions: These results demonstrate that in these 13 patients who relapsed after 12 weeks of treatment with VX-135 and RBV, no VX-135 resistant variants were detected by population sequencing.
P1227 FALDAPREVIR EFFICACY IN HCV GENOTYPE-1-INFECTED PATIENTS IN FOUR PHASE 3 TRIALS: ANALYSIS BY NS3 BASELINE POLYMORPHISMS, GENOTYPE-1 SUBTYPE AND GENOTYPE-1A CLADES K. Berger1 , C. Sarrazin2 , I.M. Jacobson3 , D.M. Jensen4 , P. Ferenci5 , D. Dieterich6 , J.O. Stern1 , A.-M. Quinson1 , J. Scherer1 , G. Kukolj7 . 1 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, United States; 2 J.W. Goethe University Hospital, Frankfurt, Germany; 3 New York Presbyterian Weill Cornell Medical College, New York, NY, 4 University of Chicago Medicine, Chicago, IL, United States; 5 Medical University of Vienna, Vienna, Austria; 6 Mount Sinai School of Medicine, New York, NY, United States; 7 Boehringer Ingelheim Canada Ltd/Lt´ee., Burlington, ON, Canada E-mail: [email protected]
P1226 NS3 Q80K DID NOT IMPACT EFFICACY OR TREATMENT-EMERGENT RESISTANCE PATTERNS IN HCV GENOTYPE 1-INFECTED PATIENTS RECEIVING FALDAPREVIR + PEGINTERFERON/RIBAVIRIN IN THREE PHASE III TRIALS
Background and Aims: STARTVerso trials evaluated faldaprevir plus pegylated interferon a-2a/ribavirin (PR) for treatment of HCV genotype (GT)-1 infection in treatment-naïve (STARTVerso1 and 2), treatment-experienced (STARTVerso3) and HIV/HCV coinfected (STARTVerso4) patients. The impact of NS3 baseline polymorphisms, GT-1 subtype and GT-1a clade on response to faldaprevir plus PR was evaluated. Methods: NS3/4A population-based sequencing at baseline was performed in 99% of patients (n = 2259). Sequences were classified GT-1a or -1b phylogenetically, including GT-1a clades 1 and 2 (n = 1162). Results: Amino acid polymorphisms in >1% of sequences were detected at 44 GT-1a and 45 GT-1b NS3 residues. No single NS3 polymorphism was associated with reduced SVR12 in faldaprevirtreated patients. GT-1a clade 1 was more prevalent among North American isolates (68%; 370/546) versus European (38%; 232/605). The least conserved NS3 residues were Q80 and N174. Q80K was observed in 58% (354/610) of clade 1 compared to 1.5% (8/551) of clade 2. No significant difference in SVR12 or early predictors of response was observed between GT-1a clades for patients who received faldaprevir plus PR or placebo. Faldaprevir plus PR demonstrated similar efficacy and advantage over PR in patients infected with GT-1a Q80wt or Q80K. R155K was the predominant treatment-emergent variant in both GT-1a clade 1 and 2. Conclusions: GT-1a clade 1 was predominant in North American isolates and had a higher prevalence of Q80K. Neither GT-1a clade nor common baseline NS3 polymorphisms were associated with reduced SVR in patients treated with faldaprevir plus PR, including GT-1a Q80K which reduces susceptibility to some other NS3 protease inhibitors.
K. Berger1 , C. Sarrazin2 , P. Ferenci3 , D.M. Jensen4 , I.M. Jacobson5 , J.O. Stern1 , A.-M. Quinson1 , J. Scherer1 , G. Kukolj6 . 1 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, United States; 2 J.W. Goethe University Hospital, Frankfurt, Germany; 3 Medical University of Vienna, Vienna, Austria; 4 University of Chicago Medicine, Chicago, IL, 5 New York Presbyterian Weill Cornell Medical College, New York, NY, United States; 6 Boehringer Ingelheim Canada Ltd/Lt´ee., Burlington, ON, Canada E-mail: [email protected] Background and Aims: Faldaprevir (FDV) is a once-daily HCV NS3/4A protease inhibitor. This analysis characterised baseline and emergent viral variants in the Phase 3 STARTVerso1, 2 and 3 trials of FDV with pegylated interferon a-2a/ribavirin (PR) in treatment-naïve and treatment-experienced patients with chronic HCV genotype (GT)-1 infection. Methods: NS3/4A population-based sequencing was performed at baseline (n = 1962) and in FDV virologic failures (n = 479). Baseline polymorphisms and variants that emerged in virologic failures were analysed. Results: No single NS3 protease polymorphism was associated with reduced SVR12 in FDV-treatment arms; similar SVR12 benefit compared to placebo was observed with wild-type GT-1a Q80 and the common GT-1a K80 (+22% and +19%, respectively, vs placebo in treatment-naive). Among virologic failures, 96% (273/285) of GT-1a and 86% (167/194) of GT-1b encoded treatment-emergent resistance-associated variants (RAVs). The predominant FDV RAVs were R155K in GT-1a (89%; 254/285) and D168 substitutions in GT-1b (80%; 156/194). Among treatment-experienced patients with GT-1a infection, modestly more D168 RAVs (39% vs 7%) and fewer R155 RAVs (77% vs 100%) were observed with higher FDV trough concentrations (upper quartile [n = 26] vs lower quartile [n = 30]). Q80K did not emerge de novo as a predominant variant in virologic failures. NS3 S61L emerged in 6% (12/194) of GT-1b virologic failures, always with D168V. Conclusions: Common baseline NS3 polymorphisms did not reduce SVR12 in treatment-naïve or treatment-experienced patients treated with FDV+PR. FDV treatment-emergent NS3 RAVs (R155 and D168) were detected in the majority of virologic failures and the novel GT-1b NS3 S61L variant emerged at a low frequency with D168V.
P1228 COMPARATIVE RESISTANCE ANALYSIS BETWEEN CIRRHOTIC AND NON-CIRRHOTIC TREATMENT EXPERIENCED PATIENTS WHO FAILED TREATMENT WITH A COMBINATION OF VANIPREVIR (MK-7009) AND PEGYLATED INTERFERON AND RIBAVIRIN (P/R) S. Ludmerer, R. Barnard, J. Brunhoffer, A. Howe, P.M.T. Hwang, R. Liu, A. Zhou, N. Mobashery. Merck & Co., Whitehouse, NJ, United States E-mail: [email protected] Background and Aims: Vaniprevir is an oral HCV-NS3/4A protease inhibitor being developed in Japan for treatment of chronic hepatitis C infection. Study 009 assessed sustained viral response (SVR) to vaniprevir + P/R in cirrhotic and non-cirrhotic priortreatment failures to P/R. This sub-analysis compares resistance to vaniprevir among cirrhotic to non-cirrhotic patients who met the protocol-defined virologic failure criteria. Methods: Samples from patients at baseline and at the time of virologic failure (HCV-RNA >1000 IU/mL) were analyzed by population-based sequencing of NS3/4A.
Journal of Hepatology 2014 vol. 60 | S361–S522
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P1227 FALDAPREVIR EFFICACY IN HCV GENOTYPE-1-INFECTED PATIENTS IN FOUR PHASE 3 TRIALS: ANALYSIS BY NS3 BASELINE POLYMORPHISMS, GENOTYPE-1 SUBTYPE AND GENOTYPE-1A CLADES K. Berger1 , C. Sarrazin2 , I.M. Jacobson3 , D.M. Jensen4 , P. Ferenci5 , D. Dieterich6 , J.O. Stern1 , A.-M. Quinson1 , J. Scherer1 , G. Kukolj7 . 1 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, United States; 2 J.W. Goethe University Hospital, Frankfurt, Germany; 3 New York Presbyterian Weill Cornell Medical College, New York, NY, 4 University of Chicago Medicine, Chicago, IL, United States; 5 Medical University of Vienna, Vienna, Austria; 6 Mount Sinai School of Medicine, New York, NY, United States; 7 Boehringer Ingelheim Canada Ltd/Lt´ee., Burlington, ON, Canada E-mail: [email protected]
P1226 NS3 Q80K DID NOT IMPACT EFFICACY OR TREATMENT-EMERGENT RESISTANCE PATTERNS IN HCV GENOTYPE 1-INFECTED PATIENTS RECEIVING FALDAPREVIR + PEGINTERFERON/RIBAVIRIN IN THREE PHASE III TRIALS
Background and Aims: STARTVerso trials evaluated faldaprevir plus pegylated interferon a-2a/ribavirin (PR) for treatment of HCV genotype (GT)-1 infection in treatment-naïve (STARTVerso1 and 2), treatment-experienced (STARTVerso3) and HIV/HCV coinfected (STARTVerso4) patients. The impact of NS3 baseline polymorphisms, GT-1 subtype and GT-1a clade on response to faldaprevir plus PR was evaluated. Methods: NS3/4A population-based sequencing at baseline was performed in 99% of patients (n = 2259). Sequences were classified GT-1a or -1b phylogenetically, including GT-1a clades 1 and 2 (n = 1162). Results: Amino acid polymorphisms in >1% of sequences were detected at 44 GT-1a and 45 GT-1b NS3 residues. No single NS3 polymorphism was associated with reduced SVR12 in faldaprevirtreated patients. GT-1a clade 1 was more prevalent among North American isolates (68%; 370/546) versus European (38%; 232/605). The least conserved NS3 residues were Q80 and N174. Q80K was observed in 58% (354/610) of clade 1 compared to 1.5% (8/551) of clade 2. No significant difference in SVR12 or early predictors of response was observed between GT-1a clades for patients who received faldaprevir plus PR or placebo. Faldaprevir plus PR demonstrated similar efficacy and advantage over PR in patients infected with GT-1a Q80wt or Q80K. R155K was the predominant treatment-emergent variant in both GT-1a clade 1 and 2. Conclusions: GT-1a clade 1 was predominant in North American isolates and had a higher prevalence of Q80K. Neither GT-1a clade nor common baseline NS3 polymorphisms were associated with reduced SVR in patients treated with faldaprevir plus PR, including GT-1a Q80K which reduces susceptibility to some other NS3 protease inhibitors.
K. Berger1 , C. Sarrazin2 , P. Ferenci3 , D.M. Jensen4 , I.M. Jacobson5 , J.O. Stern1 , A.-M. Quinson1 , J. Scherer1 , G. Kukolj6 . 1 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, United States; 2 J.W. Goethe University Hospital, Frankfurt, Germany; 3 Medical University of Vienna, Vienna, Austria; 4 University of Chicago Medicine, Chicago, IL, 5 New York Presbyterian Weill Cornell Medical College, New York, NY, United States; 6 Boehringer Ingelheim Canada Ltd/Lt´ee., Burlington, ON, Canada E-mail: [email protected] Background and Aims: Faldaprevir (FDV) is a once-daily HCV NS3/4A protease inhibitor. This analysis characterised baseline and emergent viral variants in the Phase 3 STARTVerso1, 2 and 3 trials of FDV with pegylated interferon a-2a/ribavirin (PR) in treatment-naïve and treatment-experienced patients with chronic HCV genotype (GT)-1 infection. Methods: NS3/4A population-based sequencing was performed at baseline (n = 1962) and in FDV virologic failures (n = 479). Baseline polymorphisms and variants that emerged in virologic failures were analysed. Results: No single NS3 protease polymorphism was associated with reduced SVR12 in FDV-treatment arms; similar SVR12 benefit compared to placebo was observed with wild-type GT-1a Q80 and the common GT-1a K80 (+22% and +19%, respectively, vs placebo in treatment-naive). Among virologic failures, 96% (273/285) of GT-1a and 86% (167/194) of GT-1b encoded treatment-emergent resistance-associated variants (RAVs). The predominant FDV RAVs were R155K in GT-1a (89%; 254/285) and D168 substitutions in GT-1b (80%; 156/194). Among treatment-experienced patients with GT-1a infection, modestly more D168 RAVs (39% vs 7%) and fewer R155 RAVs (77% vs 100%) were observed with higher FDV trough concentrations (upper quartile [n = 26] vs lower quartile [n = 30]). Q80K did not emerge de novo as a predominant variant in virologic failures. NS3 S61L emerged in 6% (12/194) of GT-1b virologic failures, always with D168V. Conclusions: Common baseline NS3 polymorphisms did not reduce SVR12 in treatment-naïve or treatment-experienced patients treated with FDV+PR. FDV treatment-emergent NS3 RAVs (R155 and D168) were detected in the majority of virologic failures and the novel GT-1b NS3 S61L variant emerged at a low frequency with D168V.
P1228 COMPARATIVE RESISTANCE ANALYSIS BETWEEN CIRRHOTIC AND NON-CIRRHOTIC TREATMENT EXPERIENCED PATIENTS WHO FAILED TREATMENT WITH A COMBINATION OF VANIPREVIR (MK-7009) AND PEGYLATED INTERFERON AND RIBAVIRIN (P/R) S. Ludmerer, R. Barnard, J. Brunhoffer, A. Howe, P.M.T. Hwang, R. Liu, A. Zhou, N. Mobashery. Merck & Co., Whitehouse, NJ, United States E-mail: [email protected] Background and Aims: Vaniprevir is an oral HCV-NS3/4A protease inhibitor being developed in Japan for treatment of chronic hepatitis C infection. Study 009 assessed sustained viral response (SVR) to vaniprevir + P/R in cirrhotic and non-cirrhotic priortreatment failures to P/R. This sub-analysis compares resistance to vaniprevir among cirrhotic to non-cirrhotic patients who met the protocol-defined virologic failure criteria. Methods: Samples from patients at baseline and at the time of virologic failure (HCV-RNA >1000 IU/mL) were analyzed by population-based sequencing of NS3/4A.
Journal of Hepatology 2014 vol. 60 | S361–S522
S497