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How to manage G1 relapsers and non-responders

How to manage G1 relapsers and non-responders. George V. Papatheodoridis, MD Associate Professor in Medicine & Gastroenterology 2nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital, Athens, Greece. Case 1 - AM. 01/2008

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How to manage G1 relapsers and non-responders

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  1. How to manage G1 relapsers and non-responders George V. Papatheodoridis, MD Associate Professor in Medicine & Gastroenterology 2nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital, Athens, Greece

  2. Case 1 - AM 01/2008 • Male, 42 y.o., H: 1.75 m, W 77 Kg, BMI 25.1 Kg/m2, no other disease G1a, HCV RNA 1,200,000 IU/mL, Fibroscan 6.3 (0.9) kPa • Peg-IFNa-2a (180 μg/wk) + RBV (1.2 g/d) x48 wks • HCV RNA (-) at 12 & 48 wks, (+) at 72 wks 2009-2011 • No therapy - Transient, mild ALT elevations 12/2011 • HCV RNA 2,200,000 IU/mL, Fibroscan 6.0 (1.0) kPa

  3. Case 1 – AM – Question 1 Would you retreat this patient today? (BOC/TPV available) No Yes a. Peg-IFN + RBV b. Peg-IFN + RBV + BOC/TPV

  4. RESPOND-2: SVR after ΒΟC based therapyin G1 relapsers 4-wk PR + 32-wk BOC+PR ± 12-wk PR 4-wk PR + 44-wk BOC+PR 48-wk PR SVR (%) FO/F1/F2/F3 Relapsers F4 All relapsers N= 42 87 81 6 14 14 Ν= 51 105 103 Bacon BR et al. ΝΕJM 2011; 364: 1207-17

  5. PROVE 3 / REALIZE: SVR under TPV based therapy in G1 relapsers 100 P< .0001 P< .0001 88 83 80 76 69 60 SVR (%) 40 24 20 20 0 12-wk TPV+PR 24-wk TPV+PR 48-wk PR + 12-wk PR + 24-wk PR 12-wk TPV+PR 4-wk PR + 48-wk PR + 36-wk PR 12-wk TPV+PR + 32-wk PR REALIZE trial PROVE 3 trial McHutchison JG et al. NEJM 2010;362:1292-303. Zeuzem S et al. NEJM 2011;364:2417-28.

  6. Pooled T12/PR48 Pbo/PR48 REALIZE: SVR in G1 prior relapsers by baseline fibrosis stage Patients with SVR, % n/N 145/167 12/38 53/62 2/15 48/57 1/15 Stage No, minimal or portal Bridging fibrosis Cirrhosis fibrosis Pol S et al. Hepatology 2011;54(Suppl. S1): 374A-375A.

  7. Case 1 – AM – Question 2 If you retreat this patient with a triple combination, do you think that the virological response during a 4-week lead-in period with only Peg-IFN+RBV might offer useful information even in case of TPV based triple therapy? No Yes

  8. REALIZE (telaprevir): SVR by Week 4 on-treatment response according to prior response category <1 log10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase ≥1 log10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase P=0.001 SVR (%) Prior null responders15/28 Prior relapsers8/13 Prior partial responders10/18 Prior relapsers106/113 Prior partial responders16/27 Prior null responders6/41 n/N = Foster GR et al. J Hepatol 2011; 54 (Suppl.): S3.

  9. SVR by Week 4 on-treatment response in the LI T12/PR48 arm in prior relapsers Proportions of patients in each group 2% 8% 10% 14% 66% SVR (%) 0-0.5 0.5-1.0 1.0-1.5 1.5-2.0 >2.0 Reduction in HCV RNA at Week 4, log10 IU/mL n/N= 2/3 6/10 11/12 16/18 79/83 Zeuzem S et al. Hepatology 2011; 54 (Suppl. S1): 986A-987A.

  10. Case 1 – AM – Question 4 Would you retreat this patient with? • BOC based triple therapy • TPV based triple therapy • Any of the above combinations

  11. BOC or TPV in G1 prior relapsers without cirrhosis Stop treatment at Week 24 if RNA undetectable at Week 4 and 12 PR TPV + PR PR if RNA detectable at Week 4 or 12 Weeks 0 4 12 24 36 48 HCV RNA If >1000 IU/mL at Week 4 or 12: discontinue all drugs If detectable at Week 24 or 36:discontinue PR PR PRlead-in BOC + PR 36 Weeks 24 0 4 48 12 HCV RNA If ≥100 IU/mL: If detectable: Discontinue all drugs Boceprevir, Telaprevir EU SmPC

  12. Case 2 - GS 02/2009 • Female, 58 years, H 1.60 m, W 70 Kg, BMI 27.3 Kg/m2, Diabetes G1b, HCV RNA 2,000,000 IU/mL, Fibroscan 14.3 (1.9) kPa • Peg-IFNa-2b (100 μg/wk) +RBV (1.0 g/d) • HCV RNA 1,200,000 IU/mL at 12 wks – stop treatment 05/2009-12/2011 • Moderate ALT elevations, increased γ-globulin 12/2011 • HCV RNA 1,000,000 IU/mL, Fibroscan 17.5 (2.5) kPa

  13. Would you retreat this patient today? (BOC/TPV available) No Yes a. Peg-IFN + RBV b. Peg-IFN + RBV + BOC/TPV Case 2 – GS – Question 1

  14. REALIZE: SVR under TPV based therapy in G1 null responders P<0.001 Patients with SVR, % n/N 21/72 25/37 2/37 12-wk TPV+PR 4-wk PR + 48-wk PR + 36-wk PR 12-wk TPV+PR + 32-wk PR Zeuzem S et al. NEJM 2011;364:2417-28.

  15. REALIZE: SVR in G1 prior null responders by baseline fibrosis stage Pooled T12/PR48 Pbo/PR48 Patients with SVR, % n/N 24/59 1/18 16/38 0/9 7/50 1/10 Stage No, minimal or portal Bridging fibrosis Cirrhosis fibrosis Pol S et al. Hepatology 2011;54(Suppl. S1): 374A-375A.

  16. BOC in G1 null responders to PR PROVIDE study: prospective, one arm Patients Ν= 37 from SPRINT-2 (naive) N= 11 fromRESPOND-2 N= 42 HCV RNA >800.000 IU/ml N=31 G1a Duration of PR discontinuation: 5-112wks Patients, % n/N= 20/43 16/42 3/19 Vierling J et al. Hepatology 2011; 54 (Suppl. S1): 796A-797A.

  17. PROVIDE: SVR rates by baseline patient characteristics* Vierling J et al. Hepatology 2011; 54 (Suppl. S1): 796A-797A.

  18. Case 2 – GS – Question 2 If you retreat this patient with a triple combination, do you think that the virological response during a 4-week lead-in period with only Peg-IFN+RBV might offer useful information even in case of TPV based triple therapy? No Yes

  19. SVR rates ofnull responderstoPR under BOC+PR in relation to virological response during the lead-in period Proportions of patients in each group 76% 24% 38% 38% 21% 3% SVR (%) <1.0 ≥1.0 <0.5 0.5-<1.0 1.0-<1.5 1.5-2.0 Reduction in HCV RNA at Week 4, log10 IU/mL n/N= 11/32 5/10 6/16 5/16 5/9 0/1 Vierling J et al. Hepatology 2011; 54 (Suppl. S1): 796A-797A.

  20. REALIZE (telaprevir): SVR by Week 4 on-treatment response according to prior response category P=0.001 <1 log10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase ≥1 log10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase SVR (%) Prior null responders15/28 Prior relapsers8/13 Prior partial responders10/18 Prior relapsers106/113 Prior partial responders16/27 Prior null responders6/41 n/N = Foster GR et al. J Hepatol 2011; 54 (Suppl.): S3.

  21. SVR by Week 4 on-treatment response in the LI T12/PR48 arm in prior null responders Proportions of patients in each group 23% 36% 26% 7% 7% SVR (%) <0.5 0.5-1.0 1.0-1.5 1.5-2.0 >2.0 Reduction in HCV RNA at Week 4, log10 IU/mL n/N= 1/16 5/25 8/18 3/5 4/5 Zeuzem S et al. Hepatology 2011; 54 (Suppl. S1): 986A-987A.

  22. Case 2 – GS – Question 3 Would you retreat this patient with? BOC based triple therapy TPV based triple therapy Any of the above combinations

  23. BOC or TPV in G1 prior null responders PR TPV + PR Weeks 0 4 12 24 36 48 HCV RNA If >1000 IU/mL at Wk 4 or 12: discontinue all drugs If detectable at Wk 24 or 36:discontinue PR PRlead-in BOC + PR 24 Weeks 0 4 48 12 If ≥100 IU/mL If detectable HCV RNA Discontinue all drugs Boceprevir, Telaprevir EU SmPC

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