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<ul><ul><li>Hépatite C: Résistance aux Traitements </li></ul></ul><ul><li>Prof. Jean-Michel Pawlotsky </li></ul><ul><li>CN...
HCV Resistance <ul><li>HCV resistance to IFN-   therapy </li></ul><ul><li>HCV resistance to ribavirin ? </li></ul><ul><li...
I HCV resistance to  IFN-  Therapy
Incidence of Peg-IFN  -Ribavirin Treatment Failures 2% 0 15 30 45 60 54% 48% 58% 24% 16% 18% Genotype 1  Genotypes 2/3 PE...
Treatment Failure
Treatment Schedule Treatment Failure
Host Factors Treatment Schedule Treatment Failure
Disease Characteristics Host Factors Treatment Schedule Treatment Failure
Viral Factors Disease Characteristics Host Factors Treatment Schedule Treatment Failure
Viral Factors Disease Characteristics Host Factors Treatment Schedule Treatment Failure
Viral Resistance <ul><li>Intrinsic properties of viral strains that counteract the antiviral action of antiviral drugs </l...
Incidence of Peg-IFN  -Ribavirin Treatment Failures 2% 0 15 30 45 60 54% 48% 58% 24% 16% 18% Genotype 1  Genotypes 2/3 PE...
HCV Kinetics by Genotype EC-sponsored DITTO-Trial (Pawlotsky et al., manuscript in preparation)  0 1 2 3 4 5 6 7 HCV RNA (...
HCV Kinetics by Genotype EC-sponsored DITTO-Trial 0 1 2 3 4 5 6 7 HCV RNA (log IU/ml) 0 4 7 8 15 22 29 1 -7 -28 Genotype 4...
HCV Kinetics by Genotype EC-sponsored DITTO-Trial 0 1 2 3 4 5 6 7 HCV RNA (log IU/ml) 0 4 7 8 15 22 29 1 -7 -28 Genotype 4...
HCV Kinetics by Genotype EC-sponsored DITTO-Trial 0 1 2 3 4 5 6 7 HCV RNA (log IU/ml) 0 4 7 8 15 22 29 1 -7 -28 Genotype 4...
Viral Factors Antiviral  resistance Delayed clearance Longer half-life of infected cells
Summary <ul><li>HCV resistance to IFN-   antiviral effect exists </li></ul><ul><li>Its molecular mechanisms are unknown a...
SNP and SVR in the IDEAL Trial (Ge et al, Nature, 2009;461:399-401) IL28B
rs12979860 Allele and SVR (Ge et al, Nature, 2009;461:399-401)
rs12979860 Allele Frequency 12% 39% 49% 37% 16% 47% C/C C/T T/T Caucasian ancestry n=871 African American ancestry n=191 (...
Geographic Distribution (Thomas et al, Nature, 2009;461:798-801)
Effect on HCV Kinetics (Caucasians) (Thompson et al, AASLD 2009)  Δ   HCV RNA (Log 10  IU/mL) C T T T - 3 . 0 - 2 . 0 - 1 ...
Effect on HCV Kinetics (African Americans) Δ   HCV RNA (Log 10  IU/mL) C T T T - 3 . 0 - 2 . 0 - 1 . 0 0 W e e k s - 4 . 0...
-5 -4 -3 -2 -1 0 0 4 8 12 16 20 24 Weeks of therapy HCV RNA reduction (Log 10  IU/mL) TT CT NS P=0.045 P=0.021 P=0.004 P=0...
SVR Predictors (Thompson et al, AASLD 2009)  <0.0001 2.2 1.3 1.7 Fasting blood sugar < 5.6 mmol/L <0.0001 4.1 2.3 3.1 HCV ...
Summary <ul><li>In patients infected with HCV genotype 1, the rs12979860 genotype: </li></ul><ul><ul><ul><li>Is strongly a...
II HCV Resistance to  Ribavirin ?
<ul><li>Direct inhibition of HCV RNA-dependent RNA polymerase ?  </li></ul><ul><li>Depletion of intracellular GTP pools  v...
Ribavirin’s Antiviral Effect (Pawlotsky et al., Gastroenterology 2004;126:703-14)  -1.0 -0.5 0.0 0.5 0 2 4 6 8 10 12 14 16...
Ribavirin’s Antiviral Effect (Pawlotsky et al., Gastroenterology 2004;126:703-14)  -1.5 -1.0 -0.5 0.0 +0.5 0 2 4 6 8 10 12...
Summary <ul><li>Ribavirin mechanisms of action in chronic hepatitis C remain unknown </li></ul><ul><li>Ribavirin direct an...
III HCV Resistance to Direct Acting Antivirals
HCV Resistance <ul><li>Definition </li></ul><ul><ul><li>Selection of viral variants bearing amino acid substitutions that ...
Mechanisms of Resistance sensitive resistant
Mechanisms of Resistance sensitive resistant Drug
Mechanisms of Resistance sensitive resistant Drug resistant sensitive
Mechanisms of Resistance sensitive resistant Drug Stop drug resistant sensitive
Mechanisms of Resistance sensitive resistant sensitive resistant Drug Stop drug resistant sensitive
Mechanisms of Resistance sensitive resistant sensitive resistant + fit Drug Stop drug resistant sensitive
Mechanisms of Resistance sensitive resistant Drug Stop drug resistant sensitive resistant + very fit sensitive
Chronic HCV infection is curable by therapy
Mechanisms of Resistance sensitive resistant
Mechanisms of Resistance sensitive resistant Drug resistant
Mechanisms of Resistance sensitive resistant Drug Stop drug resistant resistant
HCV Life Cycle (Popescu & Dubuisson, Biol Cell 2009;102:63-74)
DAAs in Development <ul><li>NS3/4A protease inhibitors </li></ul><ul><li>Inhibitors of HCV replication </li></ul><ul><ul><...
NS3/4A Protease Active Site
Antiviral Efficacy of NS3/4A PIs -2.8 3 days 200 mg bid Ib GS-9256 -3.9 4.5 days 600 mg bid Ib ACH-1625 -3.3 3 days 300 mg...
Asp168 Ala156 Arg155 Thr54 Val36 (Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: 205-219)  Amino Acid Substitutions Associa...
Resistance and Fitness (Kieffer T, et al. Hepatology 2007;46:631-9) In vivo fitness Resistance
Telaprevir Resistance (Reesink HW, et al. Gastroenterology 2006;131:997-1002) -5 -4 -3 -2 -1 0 1 0 1 2 3 4 5 6 7 8 9 10 11...
Telaprevir Resistance (PROVE2) 0 1 2 3 4 5 6 7 0 10 20 30 40 50 60 70 80 90 HCV RNA (Log 10  IU/mL) Weeks WT A B C D E F A...
Telaprevir Resistance (PROVE2) HCV RNA (Log 10  IU/mL) Weeks WT A B C D E R155K/E + T42S WT A B WT C D E TVR-Peg-IFN SOC 0...
Antiviral Efficacy of NUCs II II Phase -0.7 3 days 100 mg qd IDX184 -2.7 14 days 1500 mg bid R7128 Median/mean log HCV RNA...
HCV Resistance to 2’-C-Methyl Nucleoside Inhibitors 2’C-Me-ATP in the catalytic site (Migliaccio et al., J Biol Chem 2003;...
Antiviral Efficacy of NNIs -1.5 2 days 600 mg bid II ABT-333 -3.2 3 days 750 mg bid Ib VX-222 -1.7 10 days 400 mg tid II V...
RdRp Resistance Mutations (courtesy of Isabel Najera, Roche) A B C D pol Fingers Thumb Palm
Filibuvir (Pfizer) Resistance in IFN Null-Responders (Mori et al., EASL 2010)  Thumb 2 domain M423 Filibuvir
Antiviral Efficacy of  NS5A Inhibitors -3.2 1 day 10 mg qd II BMS790052 Ib Phase -2.1 (only 1b) 5 days 233 mg q8h AZD7295 ...
BMS-790052 Resistance  in vitro (Gao et al., Nature 2010;465:96-100)  1a replicon 11,000±4,000 20,000±6,000 2,100±610 7,30...
Antiviral Efficacy of Cyclophylin Inhibitors -2.2 15 days 900 mg qd Ib SCY-465 II II Phase None 14 days 600 mg bid NIM 811...
Alisporivir Resistance  in vitro 3’UTR NS3 NS4 A B NS5A A NS5B 5’UTR neo HCV IRES EMCV IRES Domain I Domain II Domain III ...
IV Triple Combination Treatment Failure
Prevention of DAA Resistance DAA
Prevention of DAA Resistance DAA Ribavirin Pegylated  IFN-  +
Treatment Failures on Triple Combination with a DAA <ul><li>Treatment-Na ïve:  20-30% </li></ul><ul><li>Treatment-experien...
Expected Higher Failure Rates in Difficult-to-Treat Patients <ul><li>Advanced liver disease </li></ul><ul><li>Liver transp...
Treatment Failures on Triple Combination with a DAA <ul><li>Insufficient response to Peg-IFN   and ribavirin </li></ul><u...
Treatment Failures in SPRINT-1 Failures according to lead-in, 28wk 71 76 70 27 33 17 0 0 0 20 40 60 80 100 <0.5 Log 10  HC...
Treatment Failures in SPRINT-1 Failures according to lead-in, 48wk 0 20 40 60 80 100 <0.5 Log 10  HCV RNA level at week 4 ...
SVR According to Lead-in  (SPRINT-2, non-black) 29% 39% 82% % of patients  with SVR 0 10 20 30 40 50 60 70 80 90 100 BOC/R...
SVR According to Lead-in  (RESPOND-2, non-black) 33% 34% 79% % of patients  with SVR 0 10 20 30 40 50 60 70 80 90 100 BOC/...
Telaprevir Rollover Study 107 0 20 40 60 80 100 37% 55% 75% 97% 59% Patients With Undetectable HCV RNA (%)  TOTAL N=117 Pr...
REALIZE Trial-Telaprevir Arms 0 20 40 60 80 100 31% 57% 86% 65% Patients With Undetectable HCV RNA (%)  TOTAL Prior null-r...
Treatment Failures on Triple Combination with a DAA <ul><li>Insufficient response to Peg-IFN   and ribavirin </li></ul><u...
Incidence of HCV resistance (Hézode et al., N Engl J Med 2009;360:1839-50)  T12P12 T12PR12 T12PR24 Arm 2 16 - 4 22 Relapse...
DAA Resistance -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10  IU/mL)
DAA Resistance -5 -4 -3 -2 -1 0 1 Wild-type, sensitive HCV Study Time Median HCV RNA Change from Baseline (Log 10  IU/mL)
DAA Resistance -5 -4 -3 -2 -1 0 1 Wild-type, sensitive HCV Resistant HCV Study Time Median HCV RNA Change from Baseline (L...
Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10  IU/mL)
Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10  IU/mL) Potent IFN  -ribav...
Triple Combo Failure -5 -4 -3 -2 -1 0 1 Wild-type, sensitive HCV Study Time Median HCV RNA Change from Baseline (Log 10  I...
Triple Combo Failure -5 -4 -3 -2 -1 0 1 Wild-type, sensitive HCV Resistant HCV Study Time Median HCV RNA Change from Basel...
Triple Combo Failure -5 -4 -3 -2 -1 0 1 Wild-type, sensitive HCV Resistant HCV Study Time Median HCV RNA Change from Basel...
Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10  IU/mL) Moderate IFN  -rib...
Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10  IU/mL) Moderate IFN  -rib...
Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10  IU/mL) Moderate IFN  -rib...
Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10  IU/mL) Moderate IFN  -rib...
Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10  IU/mL) Modest or null IFN ...
Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10  IU/mL) Modest or null IFN ...
Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10  IU/mL) Modest or null IFN ...
Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10  IU/mL) Modest or null IFN ...
V Prevention of Treatment Failures
Prevention of Treatment Failure <ul><li>Prediction of treatment failure (assessment of IFN-ribavirin responsiveness) </li>...
SPRINT-2 Trial Boceprevir, Na ïve, Genotype 1 Weeks on therapy 36 0 24 12 48 60 72 *RVR = undetectable HCV RNA at week 4 o...
REALIZE Trial Telaprevir, Nonresponders , Genotype 1 Weeks on therapy 36 0 24 12 48 60 72 *eRVR = undetectable HCV RNA at ...
Prevention of Treatment Failure <ul><li>High-dose pegylated IFN   and/or ribavirin in combination with protease inhibitor...
55% 26% 34% 39% 21% 11% 6% 53% 55% 0% 10% 20% 30% 40% 50% 60% 70% W4 W12 W24 < 1 log 10  HCV-RNA decrease 1 to 2 log 10  H...
GS-9256 (PI) + Tegobuvir (NNI) 0 7 1 4 2 1 2 8 0 1 2 3 4 5 6 7 8 HCV RNA IU/mL (Log) Days (Zeuzem et al., AASLD 2010)  GS-...
GS-9256 (PI) + Tegobuvir (NNI) 0 7 1 4 2 1 2 8 0 1 2 3 4 5 6 7 8 Days (Zeuzem et al., AASLD 2010)  HCV RNA IU/mL (Log) GS-...
BMS-650032 (PI) + BMS-790052 (NS5A) (Lok et al., AASLD 2010)  0 1 2 3 4 6 8 10 12 1 2 3 4 5 6 7 0 1 2 3 4 6 8 10 12 1 2 3 ...
Danoprevir + RG7128 Combo INFORM-1 Trial (Gane et al., Lancet 2010; published online)  Days Days Days Danoprevir, 900 mg b...
Conclusions
Conclusions <ul><li>The administration of DAAs is always associated with the selection of resistant HCV variants </li></ul...
<ul><li>Treatment failure is characterized by the growth of DAA-resistant HCV variants, as a result of virtual monotherapy...
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Hépatite C_Résistance aux traitements.ppt

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Hépatite C_Résistance aux traitements.ppt

  1. 1. <ul><ul><li>Hépatite C: Résistance aux Traitements </li></ul></ul><ul><li>Prof. Jean-Michel Pawlotsky </li></ul><ul><li>CNR des Hépatites B, C et delta </li></ul><ul><li>Laboratoire de Virologie & INSERM U635 </li></ul><ul><li>H ôpital Henri Mondor </li></ul><ul><li>Université Paris XII </li></ul><ul><li>Créteil </li></ul>
  2. 2. HCV Resistance <ul><li>HCV resistance to IFN-  therapy </li></ul><ul><li>HCV resistance to ribavirin ? </li></ul><ul><li>HCV resistance to specific antiviral molecules </li></ul>
  3. 3. I HCV resistance to IFN-  Therapy
  4. 4. Incidence of Peg-IFN  -Ribavirin Treatment Failures 2% 0 15 30 45 60 54% 48% 58% 24% 16% 18% Genotype 1 Genotypes 2/3 PEG-IFN- α 2a+ribavirin (Fried et al) PEG-IFN- α 2a+ribavirin (Hadziyannis et al) PEG-IFN- α 2b+ribavirin (Manns et al) (Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004)
  5. 5. Treatment Failure
  6. 6. Treatment Schedule Treatment Failure
  7. 7. Host Factors Treatment Schedule Treatment Failure
  8. 8. Disease Characteristics Host Factors Treatment Schedule Treatment Failure
  9. 9. Viral Factors Disease Characteristics Host Factors Treatment Schedule Treatment Failure
  10. 10. Viral Factors Disease Characteristics Host Factors Treatment Schedule Treatment Failure
  11. 11. Viral Resistance <ul><li>Intrinsic properties of viral strains that counteract the antiviral action of antiviral drugs </li></ul>
  12. 12. Incidence of Peg-IFN  -Ribavirin Treatment Failures 2% 0 15 30 45 60 54% 48% 58% 24% 16% 18% Genotype 1 Genotypes 2/3 PEG-IFN- α 2a+ribavirin (Fried et al) PEG-IFN- α 2a+ribavirin (Hadziyannis et al) PEG-IFN- α 2b+ribavirin (Manns et al) (Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004)
  13. 13. HCV Kinetics by Genotype EC-sponsored DITTO-Trial (Pawlotsky et al., manuscript in preparation) 0 1 2 3 4 5 6 7 HCV RNA (log IU/ml) 0 4 7 8 15 22 29 1 -7 -28 Genotype 4 Genotype 1 Genotype 3 * = significant difference, 4 and 1 vs 3 * * * * * * * Quantitative assay cutoff Qualitative assay cutoff
  14. 14. HCV Kinetics by Genotype EC-sponsored DITTO-Trial 0 1 2 3 4 5 6 7 HCV RNA (log IU/ml) 0 4 7 8 15 22 29 1 -7 -28 Genotype 4 Genotype 1 Genotype 3 * = significant difference, 4 and 1 vs 3 * * * * * * * Quantitative assay cutoff Qualitative assay cutoff (Pawlotsky et al., manuscript in preparation)
  15. 15. HCV Kinetics by Genotype EC-sponsored DITTO-Trial 0 1 2 3 4 5 6 7 HCV RNA (log IU/ml) 0 4 7 8 15 22 29 1 -7 -28 Genotype 4 Genotype 1 Genotype 3 * = significant difference, 4 and 1 vs 3 * * * * * * * Quantitative assay cutoff Qualitative assay cutoff (Pawlotsky et al., manuscript in preparation)
  16. 16. HCV Kinetics by Genotype EC-sponsored DITTO-Trial 0 1 2 3 4 5 6 7 HCV RNA (log IU/ml) 0 4 7 8 15 22 29 1 -7 -28 Genotype 4 Genotype 1 Genotype 3 * = significant difference, 4 and 1 vs 3 * * * * * * * Quantitative assay cutoff Qualitative assay cutoff (Pawlotsky et al., manuscript in preparation)
  17. 17. Viral Factors Antiviral resistance Delayed clearance Longer half-life of infected cells
  18. 18. Summary <ul><li>HCV resistance to IFN-  antiviral effect exists </li></ul><ul><li>Its molecular mechanisms are unknown and probably complex </li></ul><ul><li>It accounts for only a small part of IFN-  -based treatment failures </li></ul>
  19. 19. SNP and SVR in the IDEAL Trial (Ge et al, Nature, 2009;461:399-401) IL28B
  20. 20. rs12979860 Allele and SVR (Ge et al, Nature, 2009;461:399-401)
  21. 21. rs12979860 Allele Frequency 12% 39% 49% 37% 16% 47% C/C C/T T/T Caucasian ancestry n=871 African American ancestry n=191 (Ge et al, Nature, 2009;461:399-401)
  22. 22. Geographic Distribution (Thomas et al, Nature, 2009;461:798-801)
  23. 23. Effect on HCV Kinetics (Caucasians) (Thompson et al, AASLD 2009) Δ HCV RNA (Log 10 IU/mL) C T T T - 3 . 0 - 2 . 0 - 1 . 0 0 W e e k s - 4 . 0 - 5 . 0 2 4 1 2 0 - 6 . 0 C C
  24. 24. Effect on HCV Kinetics (African Americans) Δ HCV RNA (Log 10 IU/mL) C T T T - 3 . 0 - 2 . 0 - 1 . 0 0 W e e k s - 4 . 0 - 5 . 0 2 4 1 2 0 - 6 . 0 C C (Thompson et al, AASLD 2009)
  25. 25. -5 -4 -3 -2 -1 0 0 4 8 12 16 20 24 Weeks of therapy HCV RNA reduction (Log 10 IU/mL) TT CT NS P=0.045 P=0.021 P=0.004 P=0.0005 VK on High-Dose Peg IFN  According to IL28B Genotype (Chevaliez et al, AASLD 2010)
  26. 26. SVR Predictors (Thompson et al, AASLD 2009) <0.0001 2.2 1.3 1.7 Fasting blood sugar < 5.6 mmol/L <0.0001 4.1 2.3 3.1 HCV RNA ≤ 600,000 IU/mL <0.0001 4.0 2.0 2.8 Caucasian vs African American 0.004 3.6 1.3 2.1 Hispanic vs African American <0.0001 6.7 4.1 5.2 rs12979860 CC vs non-CC <0.0001 4.0 1.8 2.7 METAVIR score ≤F2 p-value 95% CI Odds Ratio
  27. 27. Summary <ul><li>In patients infected with HCV genotype 1, the rs12979860 genotype: </li></ul><ul><ul><ul><li>Is strongly associated with the SVR </li></ul></ul></ul><ul><ul><ul><li>Explains 60% of the ethnic influence on SVR </li></ul></ul></ul><ul><ul><ul><li>Influences HCV kinetics on therapy </li></ul></ul></ul><ul><ul><ul><li>Is probably a marker of patient cell “resistance“ to the effect of IFN-  through mechanisms that remain to be elucidated </li></ul></ul></ul>
  28. 28. II HCV Resistance to Ribavirin ?
  29. 29. <ul><li>Direct inhibition of HCV RNA-dependent RNA polymerase ? </li></ul><ul><li>Depletion of intracellular GTP pools via IMPDH inhibition ? </li></ul><ul><li>RNA mutagenesis leading to &quot;error catastrophe&quot; ? </li></ul><ul><li>Enhancement of IFN-induced responses in the liver ? </li></ul>Ribavirin’s Antiviral Mechanisms
  30. 30. Ribavirin’s Antiviral Effect (Pawlotsky et al., Gastroenterology 2004;126:703-14) -1.0 -0.5 0.0 0.5 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Mean HCV RNA decrease (log IU/ml) Time (days) Controls Ribavirin monotherapy
  31. 31. Ribavirin’s Antiviral Effect (Pawlotsky et al., Gastroenterology 2004;126:703-14) -1.5 -1.0 -0.5 0.0 +0.5 0 2 4 6 8 10 12 14 Days HCV RNA changes (log IU/ml) -1.5 -1.0 -0.5 0.0 +0.5 0 2 4 6 8 10 12 14 Days HCV RNA changes (log IU/ml) -1.5 -1.0 -0.5 0.0 +0.5 0 2 4 6 8 10 12 14 Days HCV RNA changes (log IU/ml) -1.5 -1.0 -0.5 0.0 +0.5 0 2 4 6 8 10 12 14 Days HCV RNA changes (log IU/ml)
  32. 32. Summary <ul><li>Ribavirin mechanisms of action in chronic hepatitis C remain unknown </li></ul><ul><li>Ribavirin direct antiviral effect is modest and transient </li></ul><ul><li>Long-term ribavirin administration does not select for specific resistance substitutions </li></ul>
  33. 33. III HCV Resistance to Direct Acting Antivirals
  34. 34. HCV Resistance <ul><li>Definition </li></ul><ul><ul><li>Selection of viral variants bearing amino acid substitutions that alter the drug target and thereby confer reduced susceptibility to the drug </li></ul></ul><ul><li>Resistant variants are pre-existing at baseline as minor viral populations </li></ul><ul><ul><li>All single mutants </li></ul></ul><ul><ul><li>~10% of double mutants </li></ul></ul>(Pawlotsky JM, Ther Adv Gastroenterol 2009;2:205-219; Perelson AS, unpublished data)
  35. 35. Mechanisms of Resistance sensitive resistant
  36. 36. Mechanisms of Resistance sensitive resistant Drug
  37. 37. Mechanisms of Resistance sensitive resistant Drug resistant sensitive
  38. 38. Mechanisms of Resistance sensitive resistant Drug Stop drug resistant sensitive
  39. 39. Mechanisms of Resistance sensitive resistant sensitive resistant Drug Stop drug resistant sensitive
  40. 40. Mechanisms of Resistance sensitive resistant sensitive resistant + fit Drug Stop drug resistant sensitive
  41. 41. Mechanisms of Resistance sensitive resistant Drug Stop drug resistant sensitive resistant + very fit sensitive
  42. 42. Chronic HCV infection is curable by therapy
  43. 43. Mechanisms of Resistance sensitive resistant
  44. 44. Mechanisms of Resistance sensitive resistant Drug resistant
  45. 45. Mechanisms of Resistance sensitive resistant Drug Stop drug resistant resistant
  46. 46. HCV Life Cycle (Popescu & Dubuisson, Biol Cell 2009;102:63-74)
  47. 47. DAAs in Development <ul><li>NS3/4A protease inhibitors </li></ul><ul><li>Inhibitors of HCV replication </li></ul><ul><ul><ul><li>Nucleoside/nucleotide analogue inhibitors of RdRp </li></ul></ul></ul><ul><ul><ul><li>Non-nucleoside inhibitors of RdRp (NNIs) </li></ul></ul></ul><ul><ul><ul><li>NS5A inhibitors </li></ul></ul></ul><ul><ul><ul><li>Cyclophylin inhibitors </li></ul></ul></ul>
  48. 48. NS3/4A Protease Active Site
  49. 49. Antiviral Efficacy of NS3/4A PIs -2.8 3 days 200 mg bid Ib GS-9256 -3.9 4.5 days 600 mg bid Ib ACH-1625 -3.3 3 days 300 mg bid Ib BMS-650032 II II II II II III III Phase -4.2 7 days 400 mg bid Narlaprevir -4.7 8 days -4.0 14 days 240 mg qd BI201335 700 mg bid Vaniprevir (MK-7009) -3.8 14 days 200 mg q8h Danoprevir (RG7227) -4.1 7 days 200 mg qd TMC435 -1.6 7 days 400 mg tid Boceprevir -4.4 14 days 750 mg q8h Telaprevir Median/mean log HCV RNA reduction Duration Dose Drug
  50. 50. Asp168 Ala156 Arg155 Thr54 Val36 (Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: 205-219) Amino Acid Substitutions Associated with PI Resistance
  51. 51. Resistance and Fitness (Kieffer T, et al. Hepatology 2007;46:631-9) In vivo fitness Resistance
  52. 52. Telaprevir Resistance (Reesink HW, et al. Gastroenterology 2006;131:997-1002) -5 -4 -3 -2 -1 0 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Study Time (Days) Median HCV RNA Change from Baseline (Log 10 IU/mL) Placebo VX-950 450 mg q8h VX-950 1250 mg q12h
  53. 53. Telaprevir Resistance (PROVE2) 0 1 2 3 4 5 6 7 0 10 20 30 40 50 60 70 80 90 HCV RNA (Log 10 IU/mL) Weeks WT A B C D E F A B C D E R155K/N V36L/M WT A40T V36L/M + A40T R155K/N + A40T V36L/M + R155K/N V36L/M + R155K/N + A40T TVR-Peg-IFN (Chevaliez S, et al., EASL 2009)
  54. 54. Telaprevir Resistance (PROVE2) HCV RNA (Log 10 IU/mL) Weeks WT A B C D E R155K/E + T42S WT A B WT C D E TVR-Peg-IFN SOC 0 1 2 3 4 5 6 7 0 8 16 24 32 40 48 56 64 72 (Chevaliez S, et al., EASL 2009)
  55. 55. Antiviral Efficacy of NUCs II II Phase -0.7 3 days 100 mg qd IDX184 -2.7 14 days 1500 mg bid R7128 Median/mean log HCV RNA reduction Duration Dose Drug
  56. 56. HCV Resistance to 2’-C-Methyl Nucleoside Inhibitors 2’C-Me-ATP in the catalytic site (Migliaccio et al., J Biol Chem 2003;278:49164-70)
  57. 57. Antiviral Efficacy of NNIs -1.5 2 days 600 mg bid II ABT-333 -3.2 3 days 750 mg bid Ib VX-222 -1.7 10 days 400 mg tid II VCH-759 Ib II II II II Phase -1.3 (1a), -3.8 (1b) 7 days 800 mg bid MK-3281 -3.1 3 days 800 mg q8h BI207127 -2.9 3 days 800 mg bid ANA598 -2.1 8 days 300 mg bid Filibuvir -1.4 8 days 40 mg bid GS-9190 Median/mean log HCV RNA reduction Duration Dose Drug
  58. 58. RdRp Resistance Mutations (courtesy of Isabel Najera, Roche) A B C D pol Fingers Thumb Palm
  59. 59. Filibuvir (Pfizer) Resistance in IFN Null-Responders (Mori et al., EASL 2010) Thumb 2 domain M423 Filibuvir
  60. 60. Antiviral Efficacy of NS5A Inhibitors -3.2 1 day 10 mg qd II BMS790052 Ib Phase -2.1 (only 1b) 5 days 233 mg q8h AZD7295 Median/mean log HCV RNA reduction Duration Dose Drug
  61. 61. BMS-790052 Resistance in vitro (Gao et al., Nature 2010;465:96-100) 1a replicon 11,000±4,000 20,000±6,000 2,100±610 7,300±1,100 8,700±1,900 4,100±360 5.9±3.7 49±13 61±15 2.6±0.3 EC50 4,000 6,000 610 1,100 1,900 360 1 19 24 1 Fold-change 117±29 L31V 11±7 Y93C 55±15 L31M 41±16 Q30R 75±31 Q30H 31±23 M28T 100 wt 20±7 Y93H 144±47 L31V 100 wt 1b replicon Replication level (% wt) Sustitution Subtype
  62. 62. Antiviral Efficacy of Cyclophylin Inhibitors -2.2 15 days 900 mg qd Ib SCY-465 II II Phase None 14 days 600 mg bid NIM 811 -3.6 14 days 1200 mg bid Alisporivir (DEBIO-025) Median/mean log HCV RNA reduction Duration Dose Drug
  63. 63. Alisporivir Resistance in vitro 3’UTR NS3 NS4 A B NS5A A NS5B 5’UTR neo HCV IRES EMCV IRES Domain I Domain II Domain III 36 213 250 342 356 447 R262Q R318W A241P D320E (Coelmont et al., EASL 2009) 3.67 R318W + D320E 1.72 A241P + R262Q + R318W 1.37 R262Q + R318W A241P + R262Q + R318W + D320E A241P + R318W A241P + R262Q 1.58 3.89 1.02 Fold-change vs wt
  64. 64. IV Triple Combination Treatment Failure
  65. 65. Prevention of DAA Resistance DAA
  66. 66. Prevention of DAA Resistance DAA Ribavirin Pegylated IFN-  +
  67. 67. Treatment Failures on Triple Combination with a DAA <ul><li>Treatment-Na ïve: 20-30% </li></ul><ul><li>Treatment-experienced: 40-50% </li></ul>
  68. 68. Expected Higher Failure Rates in Difficult-to-Treat Patients <ul><li>Advanced liver disease </li></ul><ul><li>Liver transplant </li></ul><ul><li>HIV coinfected </li></ul><ul><li>Hemodialysis </li></ul><ul><li>Immunosuppressed patients </li></ul><ul><li>African Americans </li></ul><ul><li>etc… </li></ul>
  69. 69. Treatment Failures on Triple Combination with a DAA <ul><li>Insufficient response to Peg-IFN  and ribavirin </li></ul><ul><li>Growth of uncontrolled DAA-resistant HCV variants </li></ul>
  70. 70. Treatment Failures in SPRINT-1 Failures according to lead-in, 28wk 71 76 70 27 33 17 0 0 0 20 40 60 80 100 <0.5 Log 10 HCV RNA level at week 4 (Lead-in phase) 0.5 – <1.0 1.0 – <1.5 1.5 – <2.0 2.0 – <3.0 3.0 – <4.0 ≥ 4.0 Undetectable N=7 N=21 N=10 N=11 N=21 N=12 N=11 N=3 Treatment failures (%) (Kwo et al., AASLD 2009)
  71. 71. Treatment Failures in SPRINT-1 Failures according to lead-in, 48wk 0 20 40 60 80 100 <0.5 Log 10 HCV RNA level at week 4 (Lead-in phase) 0.5 – <1.0 1.0 – <1.5 1.5 – <2.0 2.0 – <3.0 3.0 – <4.0 ≥ 4.0 Undetectable N=9 N=13 N=17 N=10 N=14 N=17 N=12 N=9 (Kwo et al., AASLD 2009) 56 38 35 20 21 18 8 0 Treatment failures (%)
  72. 72. SVR According to Lead-in (SPRINT-2, non-black) 29% 39% 82% % of patients with SVR 0 10 20 30 40 50 60 70 80 90 100 BOC/RGT BOC/PR48 (Poordad et al., AASLD 2010) 82% <1 log HCV RNA decrease ≥ 1 log HCV RNA decrease
  73. 73. SVR According to Lead-in (RESPOND-2, non-black) 33% 34% 79% % of patients with SVR 0 10 20 30 40 50 60 70 80 90 100 BOC/RGT BOC/PR48 (Bacon et al., AASLD 2010) 73% <1 log HCV RNA decrease ≥ 1 log HCV RNA decrease
  74. 74. Telaprevir Rollover Study 107 0 20 40 60 80 100 37% 55% 75% 97% 59% Patients With Undetectable HCV RNA (%) TOTAL N=117 Prior null-response N=51 Prior partial response N=29 Prior breakthrough N=8 Prior relapse N=29 (Berg et al., EASL 2010)
  75. 75. REALIZE Trial-Telaprevir Arms 0 20 40 60 80 100 31% 57% 86% 65% Patients With Undetectable HCV RNA (%) TOTAL Prior null-response Prior partial response Prior relapse (Vertex press release, Sept 7, 2010)
  76. 76. Treatment Failures on Triple Combination with a DAA <ul><li>Insufficient response to Peg-IFN  and ribavirin </li></ul><ul><li>Growth of uncontrolled DAA-resistant HCV variants </li></ul>
  77. 77. Incidence of HCV resistance (Hézode et al., N Engl J Med 2009;360:1839-50) T12P12 T12PR12 T12PR24 Arm 2 16 - 4 22 Relapse 8 9 - 2 19 Breakthrough 2 13 1 3 19 Relapse - - 1 - 1 Breakthrough 3 4 1 - 8 Relapse 4 - - - 4 Breakthrough High-level resistance Low-level resistance Wild-type VL <LOD N Event
  78. 78. DAA Resistance -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL)
  79. 79. DAA Resistance -5 -4 -3 -2 -1 0 1 Wild-type, sensitive HCV Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL)
  80. 80. DAA Resistance -5 -4 -3 -2 -1 0 1 Wild-type, sensitive HCV Resistant HCV Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL)
  81. 81. Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL)
  82. 82. Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL) Potent IFN  -ribavirin effect
  83. 83. Triple Combo Failure -5 -4 -3 -2 -1 0 1 Wild-type, sensitive HCV Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL) Potent IFN  -ribavirin effect
  84. 84. Triple Combo Failure -5 -4 -3 -2 -1 0 1 Wild-type, sensitive HCV Resistant HCV Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL) Potent IFN  -ribavirin effect
  85. 85. Triple Combo Failure -5 -4 -3 -2 -1 0 1 Wild-type, sensitive HCV Resistant HCV Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL) CURED Potent IFN  -ribavirin effect
  86. 86. Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL) Moderate IFN  -ribavirin effect
  87. 87. Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL) Moderate IFN  -ribavirin effect Wild-type, sensitive HCV
  88. 88. Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL) Moderate IFN  -ribavirin effect Wild-type, sensitive HCV Resistant HCV
  89. 89. Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL) Moderate IFN  -ribavirin effect Wild-type, sensitive HCV Resistant HCV CURED or RELAPSE with RESISTANT VIRUS
  90. 90. Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL) Modest or null IFN  -ribavirin effect
  91. 91. Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL) Modest or null IFN  -ribavirin effect Wild-type, sensitive HCV
  92. 92. Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL) Modest or null IFN  -ribavirin effect Wild-type, sensitive HCV Resistant HCV
  93. 93. Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL) Modest or null IFN  -ribavirin effect Wild-type, sensitive HCV Resistant HCV RELAPSE or BREAKTHROUGH with RESISTANT VIRUS
  94. 94. V Prevention of Treatment Failures
  95. 95. Prevention of Treatment Failure <ul><li>Prediction of treatment failure (assessment of IFN-ribavirin responsiveness) </li></ul><ul><li>Prevention of treatment failure in poor IFN responders </li></ul>
  96. 96. SPRINT-2 Trial Boceprevir, Na ïve, Genotype 1 Weeks on therapy 36 0 24 12 48 60 72 *RVR = undetectable HCV RNA at week 4 of boceprevir treatment (i.e. at week 8) Boceprevir 800 mg tid + Peg-IFN  2b + RBV Follow-up Peg-IFN  2b + RBV Peg-IFN  2b + RBV Follow-up 4 Peg-IFN  2b + RBV Follow-up Peg-IFN  2b + RBV Follow-up no RVR Boceprevir 800 mg tid + Peg-IFN  2b + RBV Peg-IFN  2b + RBV RVR 28 N > 1000
  97. 97. REALIZE Trial Telaprevir, Nonresponders , Genotype 1 Weeks on therapy 36 0 24 12 48 60 72 *eRVR = undetectable HCV RNA at week 4 and week 12 Telaprevir 750 mg q8h + Peg-IFN  2a + RBV Follow-up Peg-IFN  2a + RBV Peg-IFN  2a + RBV Peg-IFN  2a + RBV Follow-up 28 4 Peg-IFN  2a + RBV Follow-up Telaprevir 750 mg q8h + Peg-IFN  2a + RBV N = 260 N = 260 N = 130
  98. 98. Prevention of Treatment Failure <ul><li>High-dose pegylated IFN  and/or ribavirin in combination with protease inhibitors </li></ul><ul><li>Quadruple therapy in order to increase the barrier to resistance of DAAs in combination with pegylated IFN  and ribavirin </li></ul><ul><li>IFN-free regimens with multiple DAAs </li></ul>
  99. 99. 55% 26% 34% 39% 21% 11% 6% 53% 55% 0% 10% 20% 30% 40% 50% 60% 70% W4 W12 W24 < 1 log 10 HCV-RNA decrease 1 to 2 log 10 HCV-RNA decrease ≥ 2 log 10 HCV-RNA decrease Undetectable HCV-RNA ( <15 IU/mL) 1% 8% 22% (Hézode et al., AASLD 2010) High-Dose Pegylated IFN-  and Ribavirin in Non-Responders
  100. 100. GS-9256 (PI) + Tegobuvir (NNI) 0 7 1 4 2 1 2 8 0 1 2 3 4 5 6 7 8 HCV RNA IU/mL (Log) Days (Zeuzem et al., AASLD 2010) GS-9256 + tegobuvir ( < 2 5 I U / m L )
  101. 101. GS-9256 (PI) + Tegobuvir (NNI) 0 7 1 4 2 1 2 8 0 1 2 3 4 5 6 7 8 Days (Zeuzem et al., AASLD 2010) HCV RNA IU/mL (Log) GS-9256 + tegobuvir GS-9256 + tegobuvir + ribavirin ( < 2 5 I U / m L )
  102. 102. BMS-650032 (PI) + BMS-790052 (NS5A) (Lok et al., AASLD 2010) 0 1 2 3 4 6 8 10 12 1 2 3 4 5 6 7 0 1 2 3 4 6 8 10 12 1 2 3 4 5 6 7 Weeks HCV RNA (log 10 ) HCV RNA (log 10 ) No Peg/ribavirin +Peg/ribavirin Weeks
  103. 103. Danoprevir + RG7128 Combo INFORM-1 Trial (Gane et al., Lancet 2010; published online) Days Days Days Danoprevir, 900 mg bid + RG7128 Danoprevir, 900 mg bid + pegIFN  and ribavirin Increasing doses of danoprevir and RG7128
  104. 104. Conclusions
  105. 105. Conclusions <ul><li>The administration of DAAs is always associated with the selection of resistant HCV variants </li></ul><ul><li>In combination regimens, the antiviral effect of pegylated IFN  and ribavirin prevents the growth of DAA-resistant variants and leads to viral eradication </li></ul><ul><li>Treatment failure with the triple combination of pegylated IFN  , ribavirin and a DAA is due to an insufficient antiviral response to IFN  and ribavirin </li></ul>
  106. 106. <ul><li>Treatment failure is characterized by the growth of DAA-resistant HCV variants, as a result of virtual monotherapy with the DAA </li></ul><ul><li>Prevention of treatment failure in patients with an insufficient response to pegylated IFN and ribavirin is based on: </li></ul><ul><ul><ul><li>An accurate assessment of IFN responsiveness (lead-in phase, baseline parameters) </li></ul></ul></ul><ul><ul><ul><li>Alternative options for true IFN null responders that must be assessed in prospective clinical trials </li></ul></ul></ul>Conclusions

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