HCV Resistance Associated variants: impact on chronic hepatitis C treatment Dr. Stéphane Chevaliez Associate Professor of Medicine at the University of Paris-Est.
History of Resistance in HCV Concern Only Emerged With the Introduction of DAAs 1-5 IFN alfa IFN alfa + RBV pegifn alfa + RBV DAAs + pegifn alfa + RBV or DAAs only IFN/RBV-containing regimens IFN: Multiple antiviral targets preclude specific mutations in the HCV genome conferring resistance to it 2,3 RBV: Molecular mechanism of action unknown, major role in the prevention of relapse Treatment failure is due to host factors, disease characteristics, and viral factors First DAAs Target specific sites on the HCV molecule Selection of viral variants alters drug interactions with the target to confer resistance to the DAA 2 1986 1998 2001 2011 DAA = direct-acting antiviral; IFN = interferon; PegIFN = pegylated interferon; RBV = ribavirin. 1. Sarrazin and Zeuzem. Gastroenterology. 2010;138:447; 2. Pawlotsky. Therap Adv Gastroenterol. 2009;2:205; 3. Chung et al. Hepatology. 2008;47:306; 4. Lau et al. Hepatology. 2002;35:1002.
Drug-Resistant Variants Observed With All DAAs: Common RAVs in Non-SVR Patients in Clinical Trials NS3/4 Protease Inhibitors 1-13 Boceprevir Telaprevir Simeprevir Asunaprevir Vaniprevir Paritaprevir Grazoprevir (MK-5172) NS5B Polymerase Inhibitors 17-24 Sofosbuvir (nucleoside) MK-382 (nucleoside) Beclabuvir (NNI-1, thumb 1) Deleobuvir (NNI-1, thumb 1) VX222 (NNI-2, thumb 2) Setrobuvir (NNI-3, palm 1) Dasabuvir (NNI-1, palm 1) Position V36 T54 V55 Q80 S122 R155 A156 V158 D168 M175 M28 Q30 L31 H58 Y93 S282 M414 L419 R422 M423 A421 P495 P496 V499 G554 D559 NS5A Inhibitors 5-8,14-16 Daclatasvir Ledipasvir Ombitasvir ACH-3102 GSK-805 Elbasvir (MK-8742) DAA = direct-acting antiviral; RAV = resistance-associated variant; SVR = sustained virologic response. 1. Boceprevir Prescribing Information; 2. Telaprevir Prescribing Information; 3. Lenz O, et al. Hepatology 2011 54 SUPPL. 1 (985A); 4. Lenz O, et al. Antiviral Therapy 2012 17 SUPPL. 1 (A28); 5. McPhee F, et al. Hepatology. 2013;58:902-911; 6. Lok AS, et al. N Engl J Med. 2012;366:216-224; 7. Chayama K, et al. Hepatology. 2012;55:742-748; 8. Karino Y, et al. J Hepatol. 2013;58:646-654; 8. Pasquinelli C, et al. Antimicrob Agents Chemother. 2012;56:1838-1844; 9. Barnard RJ, et al. Virology. 2013;443:278-284; 10. Lawitz E, et al. Antiviral Res. 2013;99:214-220; 11. Barnard R, et al. Journal of Hepatology 2013 58 SUPPL. 1 (S487); 12. Rodriguez-Torres M, et al. Journal of Hepatology 2013 58 SUPPL. 1 (S47); 13. Berger KL, et al. Antimicrob Agents Chemother. 2013;57:4928-4936; 14. Lawitz EJ, et al. Journal of Hepatology 2012 57:1 (24-31); 15.Wong K, et al. Hepatology International 2012 6:1 (200-201); 16. Yang G, et al. Journal of Hepatology 2013 58 SUPPL. 1 (S487-S488); 17. Dvory-Sobol H, et al. Journal of Hepatology 2013 58 SUPPL. 1 (S485); 18. Svarovskaia ES, et al. Hepatology 2012 56 SUPPL. 1 (551A); 19. Pockros PJ, et al. Hepatology. 2013;58:514-523; 20. Le Pogam S, et al. Antimicrob Agents Chemother. 2012 Nov;56(11):5494-502; 21. McPhee F, et al. Journal of Hepatology 2012 56 SUPPL. 2 (S473); 22. Larrey D, et al. Antimicrobial Agents and Chemotherapy 2013 57:10 (4727-4735); 23. Cote-Martin A, et al. Hepatology 2012 56 SUPPL. 1 (576A); 24. Lagace L, et al. Hepatology 2010 52 SUPPL. 1 (1205A-1206A).
Fold Change in EC50 Value In Vitro Resistance Profile of Daclatasvir GT-1a 1 GT-1b 1 GT-2a 2 GT-3a 3 GT-4a 4 8000 7105 7735 6000 6000 4000 4000 2752 2000 0 360 1900 1100 610 28 24 141 98 749 320 1215 169 454 Emergent DCV RAVs observed at N-terminus of NS5A Fold change in EC50 value is genotype (subtype)-dependent Resistance barrier is genotype-specific 2 amino acid substitutions are required to substantially increase resistance in GT-1b 1. Fridell RA et al. Antimicrob Agents Chemother 2010; 54:3641 50; 2. Fridell RA et al. J Virol. 2011; 85(14):7312-20 3. Wang C et al, Antimicrob Agents and Chemother. 2013; 57(1):611-13; 4. Wang C et al, Antimicrob Agents Chemother. 2012; 56(3):1588 90.
Replicon EC50 (nm) Resistance Profile of NS5A Inhibitors in Advanced Development 1000 100 10 DCV 1 LDV 0,1 OBV 0,01 0,001 1 nm GT-1a (H77c) GT-1b (con1) GT-2a (JFH-1) GT-1a and GT-1b activity profiles of 1 st generation NS5A inhibitors in advanced clinical development are generally comparable Varied activity against GT-1a-NS5A-M28T and GT-1b-NS5A-Y93H Profiles of NS5A inhibitors differ against GT-2 an GT-3 reference strains Gao M. Curr. Opin. Virol. 2013; 3(5):514-20; DeGoey DA et al. J. Med. Chem. 2014; 57(5):2047-57.
Persistence of NS3/NS5A RAVs Replacement of emergent NS5A resistance-asociated variants (RAV) is infrequent overtime Complete NS5A replacement observed in 5% (3/59) of virological failures monitored 24 weeks post-treatment Partial NS5A replacement observed in 27% (16/59) GT1b patients NS3 RAVs are less fit than NS5A RAVs and complete replacement with wild-type sequences is more frequent Complete replacement observed in 71% (29/41) GT1b patients Partial replacement observed in 15% (6/41) GT1b patients 3-year long-term follow-up study ongoing Data on file - AI444-046 study interim analysis
Persistence of NS3/NS5A RAVs Replacement of NS5A RAVs has been observed in patients Complete replacement of RAVs was observed by population sequencing in 10 of 73 (14%) GT 1a, 3 of 59 (5%) GT 1b, 1 of 4 (25%) GT 3a, and 0 of 2 GT 4 patients monitored during long-term follow-up Complete replacement of NS3 RAVs with wild-type sequence is observed more frequently compared with NS5A RAVs Complete replacement was observed in 10 of 17 (59%) GT 1a and 29 of 41 (71%) GT 1b patients monitored during long-term follow-up Follow-up after post-treatment week 12 DCV + ASV N = 383 Median days (weeks) 435 (62) Days, min-max 85 1284 Reddy KR, et al. AASLD 2014. Poster 1965
Replacement of SMV-Resistant Viruses by Wild-Type Viruses Lenz et al., J Hepatol 2015;62(5):1008-14.
Probability Persistence of NS5A Inhibitor-Resistant Viruses 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 Time after treatment failure (months)? McPhee et al., Hepatology 2013;58:902-911; Wang et al. Antimicrob Agents Chemother 2013;57:2054-65.
Proportion of patients with RAV at baseline (%) Prevalence of NS5A Preexisting RAVs in GT-1b Data from HALLMAK Nippon (026) and HALLMAK DUAL (028) trials 20 18 Japan (N=374) Korea or Taiwan (N=125) 18 16 Non-Asian countries (N = 489) 15 14 12 10 11 10 12 12 10 13 12 8 6 4 2 0 7 27 374 5 6 1 125 7/48 43 374 12 125 6 6 30 489 45 374 15 125 30 489 L28M R30Q L28M or R30Q (no L31 or Y93H) 4 16 374 2 3 125 5 24 489 56 374 13 125 L31F/I/M/V Y93H L31 or Y93H 7 35 489 69 374 16 125 57 489 Baseline RAVs in NS5A were generally more common among Asian patients than non-asians Japanese patients had a higher prevalence of L31 and/or Y93 RAVs than patients from other Asian or non- Asian countries McPhee et al. 2015 APASL Conference Poster.
SVR 12 (%) DUAL SVRs by Baseline RAV Status GT-1b patients with baseline sequence data and excluding non-virologic failures (N = 979) 100 90 80 70 60 50 40 30 20 10 74 29 39 87 87 87 86 813 940 79 66 84 776 895 With RAP RAV 77 89 765 890 Without RAP RAV 0 L28M R30Q L28M or R30Q L31F/I/M/V Y93H L31 or Y93H (no L31 or Y93H) Among all GT-1b patients, only baseline L31 or Y93 RAVs were associated with reduced SVR 12 following DCV+ASV No influence of L28M or R30Q substitutions in the absence of L31 or Y93H 42 18 43 88 824 936 37 38 103 92 804 876 39 55 141 94 787 838 McPhee et al. 2015 APASL Conference Poster
SVR 12 (%) DUAL SVRs by Baseline RAV Status Non-Asian countries (N = 485) With RAV Without RAV 100 90 80 70 60 50 40 30 20 10 0 39 22 57 93 400 428 54 7 13 All patients Treatment-naïve Prior non-responders 97 128 132 29 6 21 92 91 134 145 39 9 23 138 151 IFN ineligible/intolerant McPhee et al. 2015 APASL Conference Poster.
DCV+ASV: RESISTANCE ASSOCIATED POLYMORPHISM (RAP) Baseline NS5A polymorphisms L31 and/or Y93 were present in ~18% of Japanese and ~12% of non-asian patients Baseline NS5A polymorphisms at amino acid positions 31 and 93 affect virologic response to DUAL Baseline resistance testing to select those without key NS5A polymorphisms increases chance of achieving SVR Across all patient groups of prior treatment experience, age and cirrhosis, very high SVR 12 rates were observed in patients without baseline L31 and Y93H polymorphisms
DACLATASVIR+ASUNAPREVIR: RE-TREATMENT OPTIONS
Re-Treatment of GT-1b Patients who do not Achieve SVR with DCV/ASV When GT-1b patients fail DCV/ASV, NS5A-L31M-Y93H and NS3-D168V are most frequently detected together NS5A and NS3 RAPs can persist NS5A resistance variants persist > 1 year post-treatment Although NS3 resistance variants frequently replaced by 1 year posttreatment, persistence has been observed HCV replicon harboring NS5A-L31M-Y93H and NS3-D168V used to study potential retreatment options
In-Vitro Analysis: Retreatment Options for Patients not Achieving SVR with DCV/ASV Friborg J, et al. Infect Dis Ther 2014
In-Vitro Analysis: Retreatment Options for Patients not Achieving SVR with DCV/ASV BMS-791325 = NS5B Thumb 1 inhibitor; alfa = interferon-alfa Friborg J, et al. Infect Dis Ther 2014
In-Vitro Analysis: Retreatment Options for Patients not Achieving SVR with DCV/ASV No elimination of HCV replicons harboring NS5A-L31M-Y93H and NS3- D168V after treatment with DCV/ASV DCV-Trio eliminates DCV/ASV-resistant replicons at 30x EC50 when compared with DCV/ASV Best potential treatment options against DCV/ASV-resistant replicons include: DCV/SOF and SOF/LDV DCV-Trio + SOF and SOF/IFNα/RBV SOF/next-gen NS3 PI and SOF/next-gen NS5A offer future options Retreatment clinical studies required to confirm in vitro findings Friborg J, et al. Infect Dis Ther 2014