0
Hépatite C: Résistance      aux Traitements       Prof. Jean-Michel Pawlotsky              CNR des Hépatites B, C et delta...
HCV Resistance• IFN--ribavirintreatmentfailure• HCV resistance to DAAs• TreatmentFailurewith the Triple  Combination of P...
IIFN--RibavirineTreatmentFailure
Incidence of Peg-IFN-Ribavirin              Treatment Failures         60                                     58%        ...
Treatment                      Host  Schedule                      Factors                  Treatment                    F...
Treatment                      Host  Schedule                      Factors                  Treatment                    F...
Viral Resistance• Intrinsic properties of viral strains  that counteract the antiviral action of  antiviral drugs
Incidence of Peg-IFN-Ribavirin              Treatment Failures         60                                     58%        ...
HCV Kinetics by Genotype                   EC-sponsored DITTO-Trial               7   HCV RNA (log IU/ml)                 ...
HCV Kinetics by Genotype                   EC-sponsored DITTO-Trial               7   HCV RNA (log IU/ml)                 ...
HCV Kinetics by Genotype                   EC-sponsored DITTO-Trial               7   HCV RNA (log IU/ml)                 ...
HCV Kinetics by Genotype                   EC-sponsored DITTO-Trial               7   HCV RNA (log IU/ml)                 ...
Summary• HCV resistance to IFN- antiviral effect  exists• Its molecular mechanisms are unknown  and probably complex• It ...
Genome-Wide Association           Studies (GWAS)A population with    > 3 billion nucleotides       GWAS chip          Bioi...
SNP and SVR in the IDEAL Trial                                       IL28B(Ge et al, Nature, 2009;461:399-401)
SVR in the IDEAL Trial According to SNP rs12979860 (genotype 1)                                                100%       ...
Geographic Distribution(Thomas et al, Nature, 2009;461:798-801)
rs12979860 Allele Frequency                        Caucasian                  African American                         anc...
Viral Kinetics According to                       to SNP rs12979860                                  0       Mean HCV RNA ...
Effect on HCV Kinetics                                   (African Americans)                                    0         ...
VK on High-Dose Peg-IFN      According to IL28BGenotype                                                                  ...
SVR Predictors                                          Odds Ratio    95% CI     p-value   rs12979860 CC vs non-CC        ...
IL28B vs RVR to Predict SVR                                           Sensitivity (%)   Specificity (%)    PPV (%)      NP...
Improvement in SVR Prediction   by Combining IL28B and IP-10                   N=272                                      ...
Summary• In patients infected with HCV genotype 1,  the rs12979860 genotype:    • Is strongly associated with the SVR    •...
IIHCV resistance to DAAs
HCV Quasispecies                     Major viral populationIntermediate viral   populations                               ...
Mechanisms of resistance
Mechanisms of Resistancesensitiveresistant
Mechanisms of Resistance            Drugsensitiveresistant
Mechanisms of Resistance            Drug                   sensitivesensitiveresistant          resistant
Mechanisms of Resistance            Drug               Stop drug                   sensitivesensitiveresistant          re...
Mechanisms of Resistance            Drug               Stop drug                   sensitivesensitive                     ...
Mechanisms of Resistance            Drug               Stop drug                   sensitive                              ...
Mechanisms of Resistance            Drug               Stop drug                   sensitive                sensitivesensi...
Chronic HCVinfection is curable    by therapy
Mechanisms of Resistancesensitiveresistant
Mechanisms of Resistance            Drugsensitive                   resistantresistant
Mechanisms of Resistance            Drug               Stop drugsensitive                   resistant               resist...
HCV resistance to DAAs
HCV Life Cycle(Popescu & Dubuisson, Biol Cell 2009;102:63-74)
DAAs in Development• NS3/4A protease inhibitors• Inhibitors of HCV replication    • Nucleoside/nucleotide analogue inhibit...
Antiviral Efficacy of NS3/4A           Protease Inhibitors                                                                ...
NS3/4A ProteaseInhibitors(Raney et al., J BiolChem 2010:285:22725-31)
Amino Acid Substitutions     Associated with PI Resistance                                        Arg155                  ...
Resistance and Fitness                                                In vivo                                             ...
from Baseline (Log10 IU/mL)        Telaprevir Resistance                                      1        Median HCV RNA Chan...
MK-5172 Resistance Profile                         700                         600      Vaniprevir                        ...
Nucleoside/Nucleotide Analogue    Inhibitors of HCV RdRp                                                                Me...
HCV Resistance to 2’-C-Methyl      Nucleoside Inhibitors                                    2’C-Me-ATP in the catalytic si...
Non-NucleosideInhibitors of       HCV RdRp (NNIs)                                                     Median/mean logDrug ...
RdRp Resistance Mutations                                              Fingers                     Thumb                  ...
Filibuvir (Pfizer) Resistance            in IFN Null-Responders                                        Filibuvir          ...
Antiviral Efficacy of             NS5A Inhibitors                                             Median/mean logDrug        P...
BMS-790052 Resistance in vitro                                                                         Replication        ...
Antiviral Efficacy of           Cyclophylin Inhibitors                                                          Median/mea...
Alisporivir Resistance in vitro                     HCV                  EMCV                               neo           ...
IIITreatmentFailurewith the Triple   Combination of Peg-IFN,  Ribavirin and Telaprevir or          Boceprevir
Pre-existence of PI-resistant        HCV variants
MathematicalModeling • “…all possible single and double mutants are   predicted to begenerated multiple times eachday“ • “...
Pre-existingHCV                 ResistantVariants by UDPS                                                           Respon...
Summary• Viruseswithaminoacid substitutions  known to confer resistance to HCV  proteaseinhibitorspre-exist, generally  (b...
Resistance and PI  monotherapy
Telaprevir Resistance                                                  Placebo        VX-950 450 mg q8h            VX-950 ...
DAA Resistance                                       1        from Baseline (Log10 IU/mL)         Median HCV RNA Change   ...
DAA Resistance                                       1        from Baseline (Log10 IU/mL)         Median HCV RNA Change   ...
DAA Resistance                                       1        from Baseline (Log10 IU/mL)         Median HCV RNA Change   ...
Summary• The administration of a proteaseinhibitoralone  selects pre-existingresistant viral variant  populations,  whichg...
Triple Combination TreatmentFailure
TreatmentFailures on Triple           Combinationwith a DAA     • Due to an inadequateresponseto Peg-       IFN and ribav...
SVR According to Lead-in                                         (SPRINT-2, non-black)                                100 ...
SVR According to Lead-in                                         (RESPOND-2, non-black)                                100...
REALIZE                                   Rx-experienced, Gen 1, Telaprevir                                   100         ...
DAA Resistance                                       1        from Baseline (Log10 IU/mL)         Median HCV RNA Change   ...
Median HCV RNA Change                   from Baseline (Log10 IU/mL)             -5                  -4                    ...
Triple Combo Failure                                         Potent IFN-ribavirin effect                               1f...
Triple Combo Failure                                              Potent IFN-ribavirin effect                            ...
Triple Combo Failure                                              Potent IFN-ribavirin effect                            ...
Triple Combo Failure                                              Potent IFN-ribavirin effect                            ...
Triple Combo Failure                                        Moderate IFN-ribavirin effect                               1...
Triple Combo Failure                                             Moderate IFN-ribavirin effect                           ...
Triple Combo Failure                                             Moderate IFN-ribavirin effect                           ...
Triple Combo Failure                                              Moderate IFN-ribavirin effect                          ...
Triple Combo Failure                                       Modest or null IFN-ribavirin effect                           ...
Triple Combo Failure                                           Modest or null IFN-ribavirin effect                       ...
Triple Combo Failure                                           Modest or null IFN-ribavirin effect                       ...
Triple Combo Failure                                            Modest or null IFN-ribavirin effect                      ...
Summary• Treatment failure (i.e. the failure to eradicate  HCV infection) with the triple combination of  Peg-IFN, ribavi...
Treatmentfailure and resistance       in Phase III trials
Boceprevir Resistance in    Patients withTreatmentFailure                                                                 ...
Boceprevir Resistance in    Patients withTreatmentFailure                                                    Frequency and...
Treatment Failure-PROVE2                                                                                                  ...
Summary• In Phase III trials, approximatelyhalf of the  patients whofailed to eradicate HCV  wereinfected by dominant vira...
Post-treatmentfailureoutcome
Long-Term Follow-Up After       Treatment Failure (EXTEND)                                                       Median fo...
Probability of Telaprevir-          Resistant Variant Detection                               1.0                         ...
Probability of Telaprevir-          Resistant Variant Detection                                    1.0                    ...
Treatment Failure-PROVE2                                                  100%                                            ...
Post-FailureFollow-up                                                           (Boceprevir)                              ...
Summary• The decrease of telaprevir- or boceprevir-resistant  viral populations starts immediately after  administration o...
Practicalrole of HCV resistancetesting
Viral SequenceAnalysis Tools                  Population (direct) sequencing                     Reverse hybridization Rev...
Practical Recommendations• Prior to therapy:     • All patients shouldbeconsidered as harboringminor viral       populatio...
Practical Recommendations• In case of treatmentfailure:     • Proteaseinhibitor-resistant viral populations have been     ...
IVHCV Resistance inAll-oral,   IFN-freeregimens
GS-9256 (PI) + Tegobuvir (NNI)                                 8                  GS-9256 + tegobuvir                     ...
GS-9256 (PI) + Tegobuvir (NNI)                                 8                  GS-9256 + tegobuvir                     ...
BMS-650032 (PI) + BMS-790052 (NS5A)                          7        HCV RNA (log10)                          6          ...
Danoprevir + RG7128 Combo                                           INFORM-1 Trial                                        ...
Upcoming SlideShare
Loading in...5
×

Pawlotsky du 2012 hepatites-resistance

995

Published on

Published in: Health & Medicine, Technology
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
995
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
88
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Transcript of "Pawlotsky du 2012 hepatites-resistance"

  1. 1. Hépatite C: Résistance aux Traitements Prof. Jean-Michel Pawlotsky CNR des Hépatites B, C et delta Laboratoire de Virologie & INSERM U635 Hôpital Henri Mondor Université Paris XII Créteil
  2. 2. HCV Resistance• IFN--ribavirintreatmentfailure• HCV resistance to DAAs• TreatmentFailurewith the Triple Combination of Peg-IFN, Ribavirin and Telaprevir or Boceprevir• HCV Resistance in All-oral, IFN-freeregimens
  3. 3. IIFN--RibavirineTreatmentFailure
  4. 4. Incidence of Peg-IFN-Ribavirin Treatment Failures 60 58% 54% PEG-IFN-α2a+ribavirin (Fried et al) PEG-IFN-α2a+ribavirin (Hadziyannis et al) 48% PEG-IFN-α2b+ribavirin (Manns et al) 45 30 24% 16% 18% 15 2% 0 Genotype 1 Genotypes 2/3(Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004)
  5. 5. Treatment Host Schedule Factors Treatment Failure Disease Viral FactorsCharacteristics
  6. 6. Treatment Host Schedule Factors Treatment Failure Disease Viral FactorsCharacteristics
  7. 7. Viral Resistance• Intrinsic properties of viral strains that counteract the antiviral action of antiviral drugs
  8. 8. Incidence of Peg-IFN-Ribavirin Treatment Failures 60 58% 54% PEG-IFN-α2a+ribavirin (Fried et al) PEG-IFN-α2a+ribavirin (Hadziyannis et al) 48% PEG-IFN-α2b+ribavirin (Manns et al) 45 30 24% 16% 18% 15 2% 0 Genotype 1 Genotypes 2/3(Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004)
  9. 9. HCV Kinetics by Genotype EC-sponsored DITTO-Trial 7 HCV RNA (log IU/ml) *= significant difference, 4 and 6 5 4 * 3 Quantitative assay cutoff * Genotype 4 Genotype 1 * 2 Qualitative assay * cutoff * * Genotype 3 1 * 0 -28 -7 01 4 7 8 15 22 29(Pawlotsky et al., manuscript in preparation)
  10. 10. HCV Kinetics by Genotype EC-sponsored DITTO-Trial 7 HCV RNA (log IU/ml) *= significant difference, 4 and 6 5 4 * 3 Quantitative assay cutoff * Genotype 4 Genotype 1 * 2 Qualitative assay * cutoff * * Genotype 3 1 * 0 -28 -7 01 4 7 8 15 22 29(Pawlotsky et al., manuscript in preparation)
  11. 11. HCV Kinetics by Genotype EC-sponsored DITTO-Trial 7 HCV RNA (log IU/ml) *= significant difference, 4 and 6 5 4 * 3 Quantitative assay cutoff * Genotype 4 Genotype 1 * 2 Qualitative assay * cutoff * * Genotype 3 1 * 0 -28 -7 01 4 7 8 15 22 29(Pawlotsky et al., manuscript in preparation)
  12. 12. HCV Kinetics by Genotype EC-sponsored DITTO-Trial 7 HCV RNA (log IU/ml) *= significant difference, 4 and 6 5 4 * 3 Quantitative assay cutoff * Genotype 4 Genotype 1 * 2 Qualitative assay * cutoff * * Genotype 3 1 * 0 -28 -7 01 4 7 8 15 22 29(Pawlotsky et al., manuscript in preparation)
  13. 13. Summary• HCV resistance to IFN- antiviral effect exists• Its molecular mechanisms are unknown and probably complex• It accounts for only a small part of IFN- -based treatment failures
  14. 14. Genome-Wide Association Studies (GWAS)A population with > 3 billion nucleotides GWAS chip Bioinformatics to SNP association distinct clinical > 10 million SNPs > 500,000 ‘tag’ SNPs process data and phenotypes > 90% coverage of associate common genetic genotype with variation phenotype
  15. 15. SNP and SVR in the IDEAL Trial IL28B(Ge et al, Nature, 2009;461:399-401)
  16. 16. SVR in the IDEAL Trial According to SNP rs12979860 (genotype 1) 100% Sustained virological response (%) 80% 60% 40% 20% 0% TT CT CC N=186 N=559 N=392(Ge et al., Nature 2009;461:399-401)
  17. 17. Geographic Distribution(Thomas et al, Nature, 2009;461:798-801)
  18. 18. rs12979860 Allele Frequency Caucasian African American ancestry ancestry n=871 n=191 12% 16% 39% 37% 49% 47% C/C C/T T/T(Ge et al, Nature, 2009;461:399-401)
  19. 19. Viral Kinetics According to to SNP rs12979860 0 Mean HCV RNA Decrease -1.0 (Log10 IU/mL) -2.0 -3.0 TT -4.0 CT p< 0.001 -5.0 CC -6.0 0 2 4 12 Weeks(Thompson et al., Gastroenterology 2010:139;120-9)
  20. 20. Effect on HCV Kinetics (African Americans) 0 ΔHCV RNA (Log10 IU/mL) -1.0 TT -2.0 CT -3.0 -4.0 -5.0 CC -6.0 0 2 4 12 Weeks(Thompson et al., Gastroenterology 2010:139;120-9)
  21. 21. VK on High-Dose Peg-IFN According to IL28BGenotype Weeks of therapy 0 4 8 12 16 20 24 0 HCV RNA reduction (Log10 IU/mL) -1 NS P=0.045 -2 P=0.021 TT -3 -4 CT P=0.004 -5 -6 P=0.0005(Chevaliez S, et al., Gastroenterology 2011;141:119-127)
  22. 22. SVR Predictors Odds Ratio 95% CI p-value rs12979860 CC vs non-CC 5.2 4.1 6.7 <0.0001 HCV RNA ≤ 600,000 IU/mL 3.1 2.3 4.1 <0.0001 Caucasian vs African American 2.8 2.0 4.0 <0.0001 Hispanic vs African American 2.1 1.3 3.6 0.004 METAVIR score ≤F2 2.7 1.8 4.0 <0.0001 Fasting blood sugar < 5.6 mmol/L 1.7 1.3 2.2 <0.0001(Thompson et al, Gastroenterology 2010)
  23. 23. IL28B vs RVR to Predict SVR Sensitivity (%) Specificity (%) PPV (%) NPV (%) CC vs non CC 56 (52-60) 79 (76-82) 69 (65-74) 68 (65-71) Caucasian RVR vs non RVR 25 (21-29) 96 (94-97) 84 (77-89) 59 (56-62)(Thompson et al., Gastroenterology 2010;139:1181-9)
  24. 24. Improvement in SVR Prediction by Combining IL28B and IP-10 N=272 89% 79% 100% 64% 50% 48% 24% CC 20% 0% CT < 600 pg/ml > 600 pg/ml TT serum IP-10(Darling et al.,Hepatology 2010;53:14-22)
  25. 25. Summary• In patients infected with HCV genotype 1, the rs12979860 genotype: • Is strongly associated with the SVR • Explains 60% of the ethnic influence on SVR • Influences HCV kinetics on therapy • Is probably a marker of patient cell “resistance“ to the effect of IFN- through mechanisms that remain to be elucidated
  26. 26. IIHCV resistance to DAAs
  27. 27. HCV Quasispecies Major viral populationIntermediate viral populations Minor viral populations
  28. 28. Mechanisms of resistance
  29. 29. Mechanisms of Resistancesensitiveresistant
  30. 30. Mechanisms of Resistance Drugsensitiveresistant
  31. 31. Mechanisms of Resistance Drug sensitivesensitiveresistant resistant
  32. 32. Mechanisms of Resistance Drug Stop drug sensitivesensitiveresistant resistant
  33. 33. Mechanisms of Resistance Drug Stop drug sensitivesensitive sensitiveresistant resistant resistant
  34. 34. Mechanisms of Resistance Drug Stop drug sensitive sensitivesensitiveresistant resistant resistant + fit
  35. 35. Mechanisms of Resistance Drug Stop drug sensitive sensitivesensitiveresistant resistant resistant + very fit
  36. 36. Chronic HCVinfection is curable by therapy
  37. 37. Mechanisms of Resistancesensitiveresistant
  38. 38. Mechanisms of Resistance Drugsensitive resistantresistant
  39. 39. Mechanisms of Resistance Drug Stop drugsensitive resistant resistantresistant
  40. 40. HCV resistance to DAAs
  41. 41. HCV Life Cycle(Popescu & Dubuisson, Biol Cell 2009;102:63-74)
  42. 42. DAAs in Development• NS3/4A protease inhibitors• Inhibitors of HCV replication • Nucleoside/nucleotide analogue inhibitors of RdRp • Non-nucleoside inhibitors of RdRp (NNIs) • NS5A inhibitors • Cyclophylin inhibitors
  43. 43. Antiviral Efficacy of NS3/4A Protease Inhibitors Median/meanDrug Phase Dose Duration log HCV RNA reductionTelaprevir (Janssen) Approved 750 mg q8h 14 days -4.4Boceprevir (Merck) Approved 400 mg tid 7 days -1.6TMC435 (Janssen) III 200 mg qd 7 days -4.1Danoprevir (RG7227, Roche) II 200 mg q8h 14 days -3.8Vaniprevir (MK-7009, Merck) II 700 mg bid 8 days -4.7BI201335 (BI) II 240 mg qd 14 days -4.0Narlaprevir (Merck) II 400 mg bid 7 days -4.2BMS-650032 (BMS) II 300 mg bid 3 days -3.3ABT-450/r (Abbott) II 200 mg qd 3 days -4.1GS-9451 (Gilead) I 400 mg qd 3 days -3.5MK-5172 (Merck) I 400 mg qd 7 days -5.4
  44. 44. NS3/4A ProteaseInhibitors(Raney et al., J BiolChem 2010:285:22725-31)
  45. 45. Amino Acid Substitutions Associated with PI Resistance Arg155 Asp168 Ala156 Thr54 Val36(Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: 205-219)
  46. 46. Resistance and Fitness In vivo fitness Resistance(Kieffer T, et al. Hepatology 2007;46:631-9)
  47. 47. from Baseline (Log10 IU/mL) Telaprevir Resistance 1 Median HCV RNA Change 0 -1 -2 -3 -4 -5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Study Time (Days) Placebo VX-950 450 mg q8h VX-950 1250 mg q12h(Reesink HW, et al. Gastroenterology 2006;131:997-1002)
  48. 48. MK-5172 Resistance Profile 700 600 Vaniprevir 500 MK-5172 EC50 [nM] 400 300 200 100 0(Merck, unpublished data)
  49. 49. Nucleoside/Nucleotide Analogue Inhibitors of HCV RdRp Median/mean logDrug Phase Dose Duration HCV RNA levelreductionMericitabine (RG7128, Roche) II 1500 mg bid 14 days -2.7IDX184 (Idenix) II 100 mg qd 3 days -0.7PSI-7977 (Pharmasset) II 400 mg qd 3 days -1.9PSI-938 (Pharmasset) II 300 mg qd 7 days -3.9INX-189 (Inhibitex) Ib 100 mg qd 7 days -2.5PSI-879 (Pharmasset) I - - -
  50. 50. 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)
  51. 51. Non-NucleosideInhibitors of HCV RdRp (NNIs) Median/mean logDrug Phase Dose Duration HCV RNA reductionTegobuvir (Gilead) II 40 mg bid 8 days -1.4Filibuvir (Pfizer) II 300 mg bid 8 days -2.1ANA598 (Anadys) II 800 mg bid 3 days -2.9BI207127 (BI) II 800 mg q8h 3 days -3.1ABT-333 (Abbott) II 600 mg bid 2 days -1.5VX-222 (Vertex) Ib 750 mg bid 3 days -3.7
  52. 52. RdRp Resistance Mutations Fingers Thumb pol A C B Palm D(courtesy of Isabel Najera, Roche)
  53. 53. Filibuvir (Pfizer) Resistance in IFN Null-Responders Filibuvir M423 Thumb 2 domain(Mori et al., EASL 2010)
  54. 54. Antiviral Efficacy of NS5A Inhibitors Median/mean logDrug Phase Dose Duration HCV RNA reductionBMS790052 II 10 mg qd 1 day -3.2AZD7295 Ib 233 mg q8h 6 days -2.1 (only 1b)PPI-461 Ib 100 mg qd 3 days -3.7GS-5885 Ib 30 mg qd 3 days -3.3
  55. 55. BMS-790052 Resistance in vitro Replication Subtype Sustitution EC50 Fold-change level (% wt) wt 2.6±0.3 1 100 1b replicon L31V 61±15 24 144±47 Y93H 49±13 19 20±7 wt 5.9±3.7 1 100 M28T 4,100±360 360 31±23 Q30H 8,700±1,900 1,900 75±31 Q30R 7,300±1,100 1,100 41±16 1a replicon L31M 2,100±610 610 55±15 L31V 20,000±6,000 6,000 117±29 Y93C 11,000±4,000 4,000 11±7(Gao et al., Nature 2010;465:96-100)
  56. 56. Antiviral Efficacy of Cyclophylin Inhibitors Median/meanlDrug Phase Dose Duration og HCV RNA reductionAlisporivir(DEBIO-025) II 1200 mg bid 14 days -3.6SCY-465 Ib 900 mg qd 15 days -2.2
  57. 57. Alisporivir Resistance in vitro HCV EMCV neo NS3 NS4 NS5A NS5B 5’UTR 3’UTR IRES IRES A A B 36 213 250 342 356 447 Domain I Domain II Domain III A241P R262Q R318W D320E A241P + A241P + A241P + A241P + R262Q + R318W + R262Q + R262Q + R262Q R318W R318W D320E R318W R318W + D320E Fold- change 1.02 1.58 1.37 3.67 1.72 3.89 vs wt(Coelmont et al., EASL 2009)
  58. 58. IIITreatmentFailurewith the Triple Combination of Peg-IFN, Ribavirin and Telaprevir or Boceprevir
  59. 59. Pre-existence of PI-resistant HCV variants
  60. 60. MathematicalModeling • “…all possible single and double mutants are predicted to begenerated multiple times eachday“ • “…all viable single and double mutants that confer drugresistancepreexist and maycompetewith the wild-type virus duringtherapy“ • “[triple mutants] canbeselected by sequential mutations when single or double mutants replicate“(Rong et al., Sci Transl Med 2010;2:30ra32)
  61. 61. Pre-existingHCV ResistantVariants by UDPS Response genotype subtype Patient pegIFN V36 T54 Q80 R155 A156 D168 I170 IL28B HCV RBV TVR V55A A/M A/S R/K K/T/Q S/T/V A/V/T/H A/T Pt-1 CT 1a NR - 90.0% - - 0.1% 0.4% 0.1% 0.5% Pt-2 CT 1a NR - - - - 0.1% 1.1% - 0.2% Pt-3 CT 1b RR - - - - 0.5% 0.5% - 0.2% Pt-4 TT 1b RR - 29.4% - - - 1.3% - 0.1% Pt-5 CT 1a RR - - - - 0.1% 2.9% 0.1% - Pt-6 CT 1b RR 4.2% - - - 0.1% 0.1% 0.1% 0.1% Pt-7 CT 1a SVR - 11.1% - 0.7% - 0.3% - 0.3% Pt-8 CT 1a SVR - - - - 0.1% 0.5% 0.1% - Pt-9 CC 1a SVR - - - - 0.6% 1.8% - - Pt-10 CC 1a SVR - - - - 0.6% - - 0.1% Pt-11 TT 1a RR - - 100.0% 0.1% 6.0% 3.2% 0.1% 0.3% Pt-12 CT 1b SVR - - - - - 0.3% - 0.1% Pt-13 CT 1b SVR - - - - 0.2% 0.2% - 0.8% Pt-14 TT 1b NR - - - - 0.1% 0.2% - 0.1% Pt-15 CT 1b SVR - - - - 0.4% 0.2% 0.1% 0.1% Pt-16 CT 1a SVR - - 1.3% 0.5% 7.8% 0.2% 0.1% 0.1% Pt-17 CT 1a SVR - 47.4% - - 0.1% 0.4% 0.1% 0.1% Pt-18 CT 1b SVR - 20.0% - - 0.1% 0.4% 0.1% 0.1% SVR: sustained virological response; RR: response-relapse; NR: non-response *SNP rs12979860(Chevaliez S., et al. EASL 2011)
  62. 62. Summary• Viruseswithaminoacid substitutions known to confer resistance to HCV proteaseinhibitorspre-exist, generally (but not always) as minor viral populations, in 100% of HCV-infected patients
  63. 63. Resistance and PI monotherapy
  64. 64. Telaprevir Resistance Placebo VX-950 450 mg q8h VX-950 1250 mg q12h 1 from Baseline (Log10 IU/mL) Median HCV RNA Change 0 -1 -2 -3 -4 -5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Study Time (Days)(Reesink HW, et al. Gastroenterology 2006;131:997-1002)
  65. 65. DAA Resistance 1 from Baseline (Log10 IU/mL) Median HCV RNA Change 0 -1 -2 -3 -4 -5 Study Time(Pawlotsky JM. Hepatology 2011;53:1742-51)
  66. 66. DAA Resistance 1 from Baseline (Log10 IU/mL) Median HCV RNA Change 0 Wild-type, sensitive HCV -1 -2 -3 -4 -5 Study Time(Pawlotsky JM. Hepatology 2011;53:1742-51)
  67. 67. DAA Resistance 1 from Baseline (Log10 IU/mL) Median HCV RNA Change 0 Wild-type, sensitive HCV -1 -2 Resistant HCV -3 -4 -5 Study Time(Pawlotsky JM. Hepatology 2011;53:1742-51)
  68. 68. Summary• The administration of a proteaseinhibitoralone selects pre-existingresistant viral variant populations, whichgrowexponentiallyuntiltheybecome dominant if treatmentiscontinued
  69. 69. Triple Combination TreatmentFailure
  70. 70. TreatmentFailures on Triple Combinationwith a DAA • Due to an inadequateresponseto Peg- IFN and ribavirin • Results in uncontrolledoutgrowthofresistantHCV variantsselected by the proteaseinhibitor(Pawlotsky JM. Hepatology 2011;53:1742-51)
  71. 71. SVR According to Lead-in (SPRINT-2, non-black) 100 90 82% 82% % of patients with SVR 80 70 60 <1 log HCV RNA 50 decrease 39% 40 ≥1 log HCV RNA 29% decrease 30 20 10 0 BOC/RGT BOC/PR48(Poordad et al., N Engl J Med 2011;364:1185-206)
  72. 72. SVR According to Lead-in (RESPOND-2, non-black) 100 90 79% % of patients with SVR 80 73% 70 60 <1 log HCV RNA 50 decrease 40 33% 34% ≥1 log HCV RNA 30 decrease 20 10 0 BOC/RGT BOC/PR48(Bacon et al., N Engl J Med 2011;364:1207-17)
  73. 73. REALIZE Rx-experienced, Gen 1, Telaprevir 100 94% Patients With Undetectable HCV <1 log decrease 82% ≥1 log decrease 80 RNA (%) 62% 60 59% 56% 54% 40 33% 20 15% 0 Overall Prior Prior partial Prior relapse response null-response(Foster et al., EASL 2011)
  74. 74. DAA Resistance 1 from Baseline (Log10 IU/mL) Median HCV RNA Change 0 Wild-type, sensitive HCV -1 -2 Resistant HCV -3 -4 -5 Study Time(Pawlotsky JM. Hepatology 2011;53:1742-51)
  75. 75. Median HCV RNA Change from Baseline (Log10 IU/mL) -5 -4 -3 -2 -1 0 1Study Time Triple Combo Failure
  76. 76. Triple Combo Failure Potent IFN-ribavirin effect 1from Baseline (Log10 IU/mL) Median HCV RNA Change 0 -1 -2 -3 -4 -5 Study Time
  77. 77. Triple Combo Failure Potent IFN-ribavirin effect 1from Baseline (Log10 IU/mL) Median HCV RNA Change 0 Wild-type, sensitive HCV -1 -2 -3 -4 -5 Study Time
  78. 78. Triple Combo Failure Potent IFN-ribavirin effect 1from Baseline (Log10 IU/mL) Median HCV RNA Change 0 Wild-type, sensitive HCV -1 -2 Resistant HCV -3 -4 -5 Study Time
  79. 79. Triple Combo Failure Potent IFN-ribavirin effect 1from Baseline (Log10 IU/mL) Median HCV RNA Change 0 Wild-type, sensitive HCV -1 -2 -3 -4 CURED Resistant HCV -5 Study Time
  80. 80. Triple Combo Failure Moderate IFN-ribavirin effect 1from Baseline (Log10 IU/mL) Median HCV RNA Change 0 -1 -2 -3 -4 -5 Study Time
  81. 81. Triple Combo Failure Moderate IFN-ribavirin effect 1from Baseline (Log10 IU/mL) Median HCV RNA Change 0 Wild-type, sensitive HCV -1 -2 -3 -4 -5 Study Time
  82. 82. Triple Combo Failure Moderate IFN-ribavirin effect 1from Baseline (Log10 IU/mL) Median HCV RNA Change 0 Wild-type, sensitive HCV -1 -2 Resistant HCV -3 -4 -5 Study Time
  83. 83. Triple Combo Failure Moderate IFN-ribavirin effect 1 from Baseline (Log10 IU/mL) Median HCV RNA Change 0 Wild-type, sensitive HCV CURED -1 -2 or Resistant HCV -3RELAPSE with RESISTANT VIRUS -4 -5 Study Time
  84. 84. Triple Combo Failure Modest or null IFN-ribavirin effect 1from Baseline (Log10 IU/mL) Median HCV RNA Change 0 -1 -2 -3 -4 -5 Study Time
  85. 85. Triple Combo Failure Modest or null IFN-ribavirin effect 1from Baseline (Log10 IU/mL) Median HCV RNA Change 0 Wild-type, sensitive HCV -1 -2 -3 -4 -5 Study Time
  86. 86. Triple Combo Failure Modest or null IFN-ribavirin effect 1from Baseline (Log10 IU/mL) Median HCV RNA Change 0 Wild-type, sensitive HCV -1 -2 Resistant HCV -3 -4 -5 Study Time
  87. 87. Triple Combo Failure Modest or null IFN-ribavirin effect 1 from Baseline (Log10 IU/mL) Median HCV RNA Change 0 Wild-type, sensitive HCV -1RELAPSE or BREAKTHROUGH Resistant HCV -2 with RESISTANT VIRUS -3 -4 -5 Study Time
  88. 88. Summary• Treatment failure (i.e. the failure to eradicate HCV infection) with the triple combination of Peg-IFN, ribavirin and a protease inhibitor is due to an inadequate response to IFN and ribavirin• The outgrowth of viral populations resistant to the protease inhibitor is the consequence of treatment failure, not its cause
  89. 89. Treatmentfailure and resistance in Phase III trials
  90. 90. Boceprevir Resistance in Patients withTreatmentFailure 300 250 32 Dominant virus at 200 Patients, n the time of failure 150 117 No sequence available 100 Dominant resistant virus 15 Dominant wild-type virus 38 50 97 43 0 1a 1b Total n=342*(Zeuzem S., et al., EASL 2011)
  91. 91. Boceprevir Resistance in Patients withTreatmentFailure Frequency and distribution of resistance substitutionsaccording to the subtype (% substitutions detected by subtype) 100 90 Subtype 1a 80 Subtype 1b 70 68 61 Variants, % 60 50 42 40 37 32 30 24 26 19 20 10 6 8 5 5 75 5 33 3 3 3 43 3 03 03 10 0 0 0 10 10 0 0 0(Zeuzem S., et al., EASL 2011)
  92. 92. Treatment Failure-PROVE2 H28Q+R155K 100% H28Q+R155K+S54T+Y52C % of variants in the quasispecies 80% H28Q+R155K+S54T+Y52C+V36M+H5 7L+P96H 60% 8 40% HCV RNA(Log10 IU/mL) 6 20% 0% 4 0 2 29 0 57 Days of therapy 85 Viral populations *PyroLink®(Chevaliez S., et al., EASL 2011)
  93. 93. Summary• In Phase III trials, approximatelyhalf of the patients whofailed to eradicate HCV wereinfected by dominant viral populations thatwereresistant to telaprevir or boceprevirat the time of viral escape, depending on the ability of therapy to clearwild-type, sensitive virusesat the time of failure
  94. 94. Post-treatmentfailureoutcome
  95. 95. Long-Term Follow-Up After Treatment Failure (EXTEND) Median follow-up 22 months (range 5-35) 100 100 100 92 % of samples with no detectable 89 88 85 variant at end of follow-up 80 60 40 20 0 Overall 36 54 155 156 36+155 NS3 variant positions(Zeuzem et al., AASLD 2010)
  96. 96. Probability of Telaprevir- Resistant Variant Detection 1.0 0.9 Median time to wild-type by population 0.8 sequencing =7 months (95% CI: 5-8) 0.7 Probability 0.6 median 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)(Sullivan et al., EASL 2011)
  97. 97. Probability of Telaprevir- Resistant Variant Detection 1.0 0.9 0.8 1a 0.7 Probability 0.6 median 0.5 0.4 1b 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 Time after failure (months)(Sullivan et al., EASL 2011)
  98. 98. Treatment Failure-PROVE2 100% H28Q+R155K % of variants in the quasispecies H28Q+R155K+S54T+Y52C % of mutations in the whole quasispecies 80% H28Q+R155K+S54T+Y52C+V36M+H57 L+P96H V36M+R155K+H57L 60% R155K 40% 8 HCV RNA (Log10 IU/mL) HCV RNA (Log10 IU/mL) 20% 6 0% 0 4 29 57 85 2 182 595 0 Days of treatment Days of therapy 686 *PyroLink® 903 Viral populations(Chevaliez S., et al., EASL 2011)
  99. 99. Post-FailureFollow-up (Boceprevir) Genotype 1a Genotype 1b 100% 100% % resistant viral variants detected 90% 90% All % Variant viral résistantdétecté 80% 80% T54S T54A 70% 70% 60% 60% 50% 50% 40% 40% All 30% 30% T54S 20% R155K 20% 10% V36M 10% 0% 0% 0 0.5 1 1.5 2 0 0.5 1 1.5 2 Time after treatment failure (years) Time after treatment failure (years)(Barnard et al., CROI 2011)
  100. 100. Summary• The decrease of telaprevir- or boceprevir-resistant viral populations starts immediately after administration of the protease inhibitor is stopped• This decrease is slow and leads, after a few months to years, to their replacement by a wild-type (i.e. protease inhibitor-sensitive) dominant population, which coexists with minor populations made of resistant viruses, i.e. a situation similar to the pretherapeutic one
  101. 101. Practicalrole of HCV resistancetesting
  102. 102. Viral SequenceAnalysis Tools Population (direct) sequencing Reverse hybridization Reverse hybridization Cloning/sequencing Next-generation sequencing (UDPS)
  103. 103. Practical Recommendations• Prior to therapy: • All patients shouldbeconsidered as harboringminor viral populations that are resistant to telaprevir and boceprevir • There is no indication for resistancetestingatbaseline
  104. 104. Practical Recommendations• In case of treatmentfailure: • Proteaseinhibitor-resistant viral populations have been enriched in every patient treatedwithtelaprevir or boceprevirwhodid not clear infection • There is no indication for resistancetestingduring and aftertherapy, as the resultwill have no impact on treatmentdecisions • Resistance testingisrequired in clinical trials and global surveillance studies (research setting)
  105. 105. IVHCV Resistance inAll-oral, IFN-freeregimens
  106. 106. GS-9256 (PI) + Tegobuvir (NNI) 8 GS-9256 + tegobuvir 7 HCV RNA IU/mL (Log) 6 5 4 3 2 (<25 IU/mL) 1 0 0 7 14 21 28 Days(Zeuzem et al., AASLD 2010)
  107. 107. GS-9256 (PI) + Tegobuvir (NNI) 8 GS-9256 + tegobuvir 7 GS-9256 + tegobuvir + ribavirin HCV RNA IU/mL (Log) 6 5 4 3 2 (<25 IU/mL) 1 0 0 7 14 21 28 Days(Zeuzem et al., AASLD 2010)
  108. 108. BMS-650032 (PI) + BMS-790052 (NS5A) 7 HCV RNA (log10) 6 5 4 No Peg/ribavirin 3 2 1 0 1 2 3 4 6 8 10 12 Weeks 7 6 HCV RNA (log10) 5 4 +Peg/ribavirin 3 2 1 0 1 2 3 4 6 8 10 12 Weeks(Lok et al., AASLD 2010)
  109. 109. Danoprevir + RG7128 Combo INFORM-1 Trial Danoprevir, 900 mg bid + RG7128 Increasing doses of danoprevir and RG7128 Danoprevir, 900 mg bid + pegIFNand ribavirin Days Days Days(Gane et al., Lancet 2010; published online)
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×