Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Bourlière M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med 2017;376: DOI: /NEJMoa

2 Table of contents POLARIS-1 Study Investigators... 3 POLARIS-4 Study Investigators... 4 POLARIS-1 Inclusion Criteria... 5 POLARIS-1 Exclusion Criteria... 6 POLARIS-4 Inclusion Criteria... 7 POLARIS-4 Exclusion Criteria... 8 Table S1. POLARIS-1: Reasons for screen failure... 9 Table S2. POLARIS-4: Reasons for screen failure Figure S1. Patient disposition: POLARIS Figure S2. Patient disposition: POLARIS Table S3. HCV RNA and change from baseline by visit through end of treatment in POLARIS Table S4. HCV RNA and change from baseline by visit through end of treatment in POLARIS Table S5. Characteristics of patients in the SOF-VEL-VOX group who relapsed in POLARIS Table S6. Characteristics of patients who relapsed in POLARIS Table S7. SVR12 rates in POLARIS-1 by baseline resistance (15% cutoff) Table S8. SVR12 rates in POLARIS-4 by baseline resistance (15% cutoff) Table S9. Serious adverse events in POLARIS Table S10. Serious adverse events in POLARIS Table S11. Grade 3 and 4 adverse events in POLARIS Table S12. Grade 3 and 4 adverse events in POLARIS Table S13. Grade 3 and 4 laboratory abnormalities in POLARIS Table S14. Grade 3 and 4 laboratory abnormalities in POLARIS

3 POLARIS-1 Study Investigators Australia Simone Strasser, Stuart Roberts, Gregory Dore, Stephen Pianko, Barbara Leggett, Alexander Thompson Canada Stephen Shafran, Brian Conway, Bernard Willems, Alnoor Ramji, Jordan Feld, Sergio Borgia, Stephen Congly France Marc Bourlière, Stanislas Pol, Didier Samuel, Victor de Ledinghen, Danielle Botta-Fridlund, Ghassan Riachi, Christophe Hezode, Fabien Zoulim, Jean-Pierre Bronowicki, François Habersetzer, Philippe Mathurin, Dominique Guyader, Jean-Didier Grange, Véronique Loustaud- Ratti, Vlad Ratziu, Lawrence Serfaty, Albert Tran, Dominique Larrey, Laurent Alric, Tarik Asselah, Armando Abergel, Vincent Leroy, Sophie Metivier Germany Michael Manns, Peter Buggisch, Stefan Zeuzem, Thomas Berg, Tobias Goeser, Ulrich Spengler New Zealand Edward Gane, Catherine A.M. Stedman Puerto Rico Grissel Ortiz-Lasanta United Kingdom Stephen Ryder, Graham Foster, Ashley Brown, Kosh Agarwal, Andrew Ustianowski, Richard Aspinall United States of America Adrian Di Bisceglie, Mitchell Shiffman, Myron Tong, Peter Ruane, Eugene Schiff, Michael Bennett, Stuart Gordon, Anna Patel, Kris Kowdley, Anna Lok, Sergio Rojter, Michael Charlton, Lisa Nyberg, Raymond Chung, Elizabeth Verna, John Vierling, Marco Lacerda, Coleman Smith, Mandana Khalili, Steven Flamm, Raymond Rubin, William Smith, Gregory Everson, Mark Sulkowski, Tram Tran, Michael Curry, James Levin, Norman Gitlin, K. Rajender Reddy, Kimberly Workowski, Natarajan Ravendhran, Ronald Nahass, Michael Ryan, Eric Lawitz, Ziad Younes, Arun Sanyal, Mindie Nguyen, Giuseppe Morelli, Bradley Freilich, Marcelo Kugelmas, Aasim Sheikh, Thomas Sepe, Mitchell Davis, David Pound, Constance Benson, Federico Hinestrosa, Norbert Brau, Robert Herring, Timothy Morgan, Charles Landis, Zeid Kayali, Mordechai Rabinovitz, James Cooper, Brian Pearlman, Obaid Shaikh,William Harlan III, Ritu Agarwal 3

4 POLARIS-4 Study Investigators Australia Simone Strasser, Stuart Roberts, Gregory Dore, Stephen Pianko, Barbara Leggett Canada Stephen Shafran, Brian Conway, Curtis Cooper, Alnoor Ramji, Jordan Feld, Sergio Borgia, Stephen Congly France Marc Bourliere, Stanislas Pol, Didier Samuel, Victor de Ledinghen, Danielle Botta-Fridlund, Fabien Zoulim, Jean-Pierre Bronowicki, Philippe Mathurin, Jean-Didier Grange, Véronique Loustaud Ratti, Lawrence Serfaty, Albert Tran, Dominique Larrey, Laurent Alric, Tarik Asselah, Armando Abergel, Vincent Leroy, Sophie Metivier Germany Michael Manns, Peter Buggisch, Stefan Zeuzem, Thomas Berg, Tobias Goeser, Ulrich Spengler New Zealand Edward Gane Puerto Rico Grisell Ortiz-Lasanta United Kingdom Graham Foster, Ashley Brown, Kosh Agarwal, Jane Collier, Daniel Forton United States of America Adrian Di Bisceglie, Mitchell Shiffman, Myron Tong, Peter Ruane, Eugene Schiff, Michael Bennett, Sonal Kumar, Stuart Gordon, Ilan Weisberg, Kris Kowdley, Anna Lok, Sergio Rojter, Michael Charlton, Lisa Nyberg, Raymond Chung, John Vierling, Marco Lacerda, Coleman Smith, Mandana Khalili, Steven Flamm, Raymond Rubin, Gregory Everson, Mark Sulkowski, Tram Tran, Michael Curry, James Levin, Norman Gitlin, K. Rajender Reddy, Kimberly Workowski, Natarajan Ravendhran, Ronald Nahass, Michael Ryan, Eric Lawitz, Ziad Younes, Arun Sanyal, Mindie Nguyen, Giuseppe Morelli, Bradley Freilich, Marcelo Kugelmas, Bal Raj Bhandari, Aasim Sheikh, Thomas Sepe, Mitchell Davis, Constance Benson, Federico Hinestrosa, Robert Herring, Timothy Morgan, John Poulos, Charles Landis, Zeid Kayali, Mordechai Rabinovitz, Shyamasundaran Kottilil, Meena Bansal, James Cooper, Brian Pearlman, Obaid Shaikh, William Harlan III, Elizabeth Verna 4

5 POLARIS-1 Inclusion Criteria 5

6 POLARIS-1 Exclusion Criteria 6

7 POLARIS-4 Inclusion Criteria 7

8 POLARIS-4 Exclusion Criteria 8

9 Table S1. Reasons for screen failure: POLARIS-1 9

10 Table S2. Reasons for screen failure: POLARIS-4 10

11 Figure S1. Patient disposition: POLARIS patients were screened 416 were eligible for treatment and were randomized/enrolled 104 were not randomized/enrolled 99 did not meet eligibility criteria 4 withdrew consent 1 lost to follow-up before determining eligibility 152 were assigned to receive placebo 264 were assigned to receive sofosbuvir-velpatasvirvoxilaprevir for 12 weeks 3 d/c treatment due to adverse events 1 never received treatment 2 discontinued treatment 1 due to adverse events 1 was lost to follow-up 149 completed treatment 261 completed treatment 152 assessed for efficacy and safety 263 assessed for efficacy and safety 11

12 Figure S2. Patient disposition: POLARIS screened 333 were eligible for treatment and were randomized/enrolled 64 were not randomized/enrolled 60 did not meet eligibility criteria 2 withdrew consent 2 were lost to follow-up 182 were assigned to receive sofosbuvir-velpatasvirvoxilaprevir for 8 weeks 151 were assigned to receive sofosbuvir-velpatasvir for 12 weeks 182 began treatment 151 began treatment 2 discontinued treatment: LTFU 182 completed treatment 149 completed treatment 182 assessed for efficacy and safety 151 assessed for efficacy and safety 12

13 Table S3. HCV RNA (log 10 IU/mL) and change from baseline by visit through end of treatment in POLARIS-1 13

14 Table S4. HCV RNA (log 10 IU/mL) and change from baseline by visit through end of treatment in POLARIS-4 14

15 Table S5. Characteristics of patients in the sofosbuvir-velpatasvir-voxilaprevir group in POLARIS-1 who had virologic failure Age Sex Race BMI Genotype Cirrhosis IL28B Baseline HCV RNA log 10 IU/mL Prior HCV regimen Resistance-associated substitutions NS3 NS5A Baseline Relapse Baseline Relapse 61 M White a Yes CT 6.7 LDV-SOF for 24 weeks in 2015 Q80K Q80K Y93N Y93N 60 M White a Yes CC 7.6 SOF-VEL for 12 weeks in 2013 None None Y93Y/H Y93H 62 F White a Yes CT 6.3 DCV-SOF for 12 weeks in 2015 None None A30K A30K 65 M White a Yes CT 4.9 DCV-SOF for 25 weeks in 2015 None None None None 60 M White a Yes TT 5.3 SOF-VEL for 12 weeks in 2015 None None Y93Y/H Y93H 61 M White d Yes CT 5.7 LDV-SOF for 12 weeks in 2015 None None L30R L30R, Y93H 60* M Black a Yes TT 6.3 LDV-SOF Q80K Q80K Q30T *This patient, the only one to have virologic breakthrough rather than relapse on this study, had low plasma concentrations of GS (the chief sofosbuvir metabolite), velpatasvir, and voxilaprevir at weeks 8 and 12, suggestive of nonadherence. Q30T L31L/M Y93Y/H 15

16 Table S6. Characteristics of patients with virologic failure in POLARIS-4 Age Sex Race BMI Genotype Cirrhosis Sofosbuvir-Velpatasvir-Voxilaprevir for 12 weeks IL28B HCV RNA Prior HCV regimen Resistance-associated substitutions NS3 NS5A BL VF BL VF 62 M AI a Yes CT 6.8 SIM-SOF for 12 weeks in 2014 None None None None Sofosbuvir-Velpatasvir for 12 weeks 59 M White a No CT 5.7 SIM-SOF for 12 weeks in 2014 R155K I170V R155K None Y93H 64 M White a Yes CT 6.1 SIM-SOF for 12 weeks in 2015 Q80K Q80K L31M 60 F Black a Yes TT 6.7 SOF-RBV for 24 weeks in 2015 Q80K Q80K K24K/R None 59 M White a Yes TT 6.3 SIM-SOF for 12 weeks in 2016 Q80K Assay failure None Y93H 63 M Black a No TT 7.0 SOF-PEG-RBV for 12 weeks in 2014 None None None None 63 F Black b No CT 6.5 SOF-RBV for 12 weeks in 2014 Y56F Y56F None None 56 M White a Yes CT 6.8 SOF-RBV for 24 weeks in 2015 None None None Y93H 58 M White a Yes CC 6.9 SOF-RBV for 18 weeks in 2014 None None None Y93H 49 M White a No CC 7.2 SOF-RBV for 16 weeks in 2014 None None None Y93H 56 M White a Yes CC 6.4 SOF-RBV for 24 weeks in 2014 None None None Y93H 60 M White a Yes CT 6.8 SOF-RBV for 28 weeks in 2013 None Assay failure None Y93H 63 M White a Yes CT 6.8 PEG-MER-DNV-RBV for 24 weeks in 2012 L31M H58H/D Y93Y/C None None None Y93H 54 F Asian a Yes CC 6.7 SOF-RBV for 24 weeks in 2014 None None None Y93H 63 M White a Yes CT 6.1 SOF-PEG-RBV for 12 weeks in 2014 None None A30K 58* M Black a/2d/ 2j No CT 5.4 SOF-RBV for 12 weeks in 2016 None None VF=virologic failure; AI = American Indian; MER=mericitabine; DNV=danoprevir. *This patient, the only one to have virologic breakthrough rather than relapse, was also the only patient with an NS5B RAS at any timepoint the S282T variant at time of virologic failure, but not baseline. T24S L31M A30K Y93H T24S L31M Y93H 16

17 Table S7. SVR12 rates in POLARIS-1 by baseline resistance (15% cutoff) Sofosbuvir-velpatasvir-voxilaprevir for 12 weeks (N=260) No NS3 or NS5A RASs 42/43 (97.7%) Any NS3 or NS5A RAS 199/205 (97.1%) NS3 Only 9/9 (100%) NS5A Only 120/124 (96.8%) NS3 and NS5A 70/72 (97.2%) RASs not determined for both NS3 and NS5A 12/12 (100%) RAS=resistance-associated substitution Patients who did not have observed virologic failure (ie, those who were lost to follow-up or withdrew consent) are excluded from this analysis. 17

18 Table S8. SVR12 rates in POLARIS-4 by baseline resistance (15% cutoff) SOF/VEL/VOX 12 Weeks (N = 179) SOF/VEL 12 Weeks (N = 151) No NS3 or NS5A RASs 85/86 (98.8%) 67/75 (89.3%) Any NS3 or NS5A RAS 83/83 (100.0%) 63/70 (90.0%) NS3 Only 39/39 (100.0%) 29/32 (90.6%) NS5A Only 40/40 (100.0%) 32/34 (94.1%) NS3 and NS5A 4/4 (100.0%) 2/4 (50.0%) RASs not determined for both NS3 and NS5A 10/10 (100.0%) 6/6 (100.0%) RAS=resistance-associated substitution Patients who did not have observed virologic failure (ie, those who were lost to follow-up or withdrew consent) are excluded from this analysis. 18

19 Table S9. Serious adverse events in POLARIS-1 19

20 Table S10. Serious adverse events in POLARIS-4 20

21 Table S11. Grade 3 and 4 adverse events in POLARIS-1 21

22 Table S12. Grade 3 and 4 adverse events in POLARIS-4 22

23 Table S13. Grade 3 and 4 laboratory abnormalities in POLARIS-1 23

24 Table S13. Grade 3 and 4 laboratory abnormalities in POLARIS-1 (continued) 24

25 Table S14. Grade 3 and 4 laboratory abnormalities in POLARIS-4 25

26 Table S14. Grade 3 and 4 laboratory abnormalities in POLARIS-4 (continued) 26