Mais conteúdo relacionado Semelhante a Hépatite C_Résistance aux traitements.ppt (20) Hépatite C_Résistance aux traitements.ppt4. 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) 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. 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. 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. 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. 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) 19. SNP and SVR in the IDEAL Trial (Ge et al, Nature, 2009;461:399-401) IL28B 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) 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. 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. -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. 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 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. 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) 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. Asp168 Ala156 Arg155 Thr54 Val36 (Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: 205-219) Amino Acid Substitutions Associated with PI Resistance 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. 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. 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. 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. 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. 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 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. 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. 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. 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 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. 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. 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. 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. 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. 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) 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. DAA Resistance -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL) 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. 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. Triple Combo Failure -5 -4 -3 -2 -1 0 1 Study Time Median HCV RNA Change from Baseline (Log 10 IU/mL) 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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 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. 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 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. 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. 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. 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. 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 Notas do Editor Thereafter, the viral quasispecies distribution continued to fluctuate. Thereafter, the viral quasispecies distribution continued to fluctuate.