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Clinical case

Clinical case. Laurent CASTERA. Service d ’ Hépatologie Hôpital Beaujon, Université Paris-7, Clichy, France. 5th PHC, Paris, January 31 2012. Patient Case: 43-year-old male. Previous intravenous drug user Alcohol intake > 50 g/day HCV RNA 6 log10 copies/ml Genotype 1

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Clinical case

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  1. Clinical case Laurent CASTERA Service d’Hépatologie Hôpital Beaujon, Université Paris-7, Clichy, France 5th PHC, Paris, January 31 2012

  2. Patient Case: 43-year-old male • Previous intravenous drug user • Alcohol intake > 50 g/day • HCV RNA 6 log10 copies/ml • Genotype 1 • HBV and HIV negative • Weight 90 Kg; height 170 cm

  3. Patient Case: past history • In 1997: liver biopsy indicates chronic “active” hepatitis (i.e. METAVIR A2F2) • Treatment with IFN 3M IU thrice a week • Treatment stopped after 3 months because of poor tolerance and depression • Normalisation of ALT but no information on HCV RNA • Lost to follow-up until 2002

  4. 2002: Laboratory & morphologic results HB (g/dl) WBC (/mm3) Platelet count (/mm3) AST (IU/L) ALT (IU/L) GGT (IU/L) AP (IU/L) Total bilirubin (µmol/L) PT 14 6000 100 000 120 70 500 150 15 80% Liver US: steatosis, heterogenous parenchyma

  5. Patient Case: liver biopsy • Metavir F3 with steatosis and NASH

  6. ULN Time (Weeks) Patient Case: 1st retreatment Pegylated interferon alfa-2b 135 µg/w Ribavirin 1200mg/day 108 250 106 200 ALT (UI/L) 150 HCV-RNA (log10) IU/mL 104 100 102 50 0 0

  7. ULN Time (Weeks) Patient Case: 1st retreatment Pegylated interferon alfa-2b 135 µg/w Ribavirin 1200mg/day 108 250 RBV 600 mg 106 200 ALT (UI/L) 150 HCV-RNA (log10) IU/mL 104 100 102 50 0 0 4

  8. ULN Time (Weeks) Patient Case: 1st retreatment Pegylated interferon alfa-2b 135 µg/w Ribavirin 1200mg/day 108 250 RBV 600 mg 106 200 PEG-IFN 100 µg ALT (UI/L) 150 HCV-RNA (log10) IU/mL 104 103 100 102 50 0 0 4 12

  9. ULN Time (Weeks) Patient Case: 1st retreatment Pegylated interferon alfa-2b 135 µg/w Ribavirin 1200mg/day 108 250 RBV 600 mg 106 200 PEG-IFN 100 µg ALT (UI/L) 150 HCV-RNA (log10) IU/mL 104 103 103 100 102 50 0 0 4 12 24

  10. VIRUS • Genotype 1 • High viral load • Viral kinetics • Quasispecies • DISEASE • Cirrhosis • HIV coinfection • HBV coinfection • HOST • Ethnicity • Insulin-resistance • Poor adherence • Alcohol Failure • TREATMENT • IFN dosage • RBV dosage • Ttt duration Factors associated with treatment failure

  11. Diet Withdrawal Education Failure EPO Factors associated with treatment failure Can be modified Cannotbemodified • HOST • Ethnicity • HOST • Insulin-resistance • Poor adherence • Alcohol • TREATMENT • IFN dosage • RBV dosage • Ttt duration • VIRUS • Genotype 1 • High viral load • Viral kinetics • Quasispecies • DISEASE • Cirrhosis • HIV coinfection • HBV coinfection

  12. Patient Case • Lost to follow-up until 2007. • New evaluation

  13. Patient Case: ultrasound Splenomegaly, heterogenous parenchyma

  14. Patient Case: FibroScan 20.0

  15. Patient Case: upper GI endoscopy

  16. Patient Case • Not keen to start new antiviral treatment because of side effects. • What would you do ?

  17. Options • Retreatment with PegIFN+ RBV with optimization • Maintenance therapy with PegIFN monotherapy • Follow-up without treatment

  18. Patient Case • Alcohol withdrawal for 6 months • Strict Diet with weight loss: 90 -> 75 kg • Psychiatric care

  19. 250 200 ALT (UI/L) 150 100 50 ULN 0 Time (Weeks) Patient Case: 2nd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1400mg/day EPO 30 000 IU/w Paroxetine 20 mg/d 108 106 HCV-RNA (log10) IU/mL 104 102 0

  20. 250 200 ALT (UI/L) 150 100 50 ULN 0 Time (Weeks) Patient Case: 2nd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1400mg/day EPO 30 000 IU/w Paroxetine 20 mg/d 108 106 105 HCV-RNA (log10) IU/mL 104 102 0 4

  21. 250 200 ALT (UI/L) 150 100 50 ULN 0 Time (Weeks) Patient Case: 2nd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1400mg/day EPO 30 000 IU/w Paroxetine 20 mg/d 108 106 105 HCV-RNA (log10) IU/mL 104 103 102 0 4 12

  22. 250 200 ALT (UI/L) 150 100 50 ULN 0 Time (Weeks) Patient Case: 2nd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1400mg/day EPO 30 000 IU/w Paroxetine 20 mg/d 108 106 105 HCV-RNA (log10) IU/mL 104 103 102 0 4 24 12

  23. 250 200 ALT (UI/L) 150 100 50 ULN 0 Time (Weeks) Patient Case: 2nd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1400mg/day EPO 30 000 IU/w Paroxetine 20 mg/d 108 106 105 HCV-RNA (log10) IU/mL 104 103 102 0 4 24 12 48

  24. 250 200 ALT (UI/L) 150 100 50 ULN 0 72 Time (Weeks) Patient Case: 2nd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1400mg/day EPO 30 000 IU/w Paroxetine 20 mg/d 108 106 105 HCV-RNA (log10) IU/mL 104 103 102 0 4 24 12 48

  25. Patient Case • What would you do ?

  26. Triple therapy in genotype 1 non SVR Boceprevir Relapsers Partial responders Telaprevir Relapsers Partial responders Nullresponders + 50% + 60% + 45% + 40% + 25%

  27. TLR in treatment-experienced patientsREALIZE study: design TVR 750 mg q8h + Peg-IFN2a + RBV Peg-IFN2a + RBV Follow-up N = 260 TVR 750 mg q8h + Peg-IFN2a + RBV Peg-IFN2a + RBV Follow-up Peg-IFN2a + RBV N = 260 Peg-IFN2a + RBV Follow-up N = 130 48 60 72 4 12 24 28 0 36 Weeks *eRVR = HCV RAN undetectable at W4 et W12 Zeuzem et al. NEJM 2011

  28. 16 Proportion of patients with cirrhosisREALIZE 169 cirrhotic patients N=663 patients Zeuzem et al. NEJM 2011

  29. SVR REALIZE study Relapsers Partial Responders Null responders SVR (%) T12/PR48 LI T12/PR48 Pbo/PR48 LI T12/PR48 Pbo/PR48 LI T12/PR48 T12/PR48 T12/PR48 Pbo/PR48 N=663 patients Zeuzem et al. NEJM 2011

  30. 16 SVR according to Fibrosis Pol et al. AASLD 2011

  31. Boceprevir in previouslytreated patients RESPOND-2 N=403 patients Bacon et al. NEJM 2011

  32. Proportion of patients withcirrhosis RESPOND-2 49 cirrhotic patients N=403 patients Bacon et al. NEJM 2011

  33. 90 75 60 45 30 7 15 0 SVR with BOC in non respondersRESPOND-2 study Relapsers Partial responders RVS (%) 75 69 52 40 29 PR48 BOC TGR BOC/PR48 PR48 BOC TGR BOC/PR48 N=403 patients Bacon et al. NEJM 2011

  34. 100 80 60 SVR (%) 40 20 0 SVR according to response at W4 of Lead in phase 100 79 73 80 60 SVR (%) 34 33 40 25 0 20 17/67 80/110 90/114 0/12 15/46 15/44 0 PR48 BOC TGR PR48 BOC TGR BOC/PR48 BOC/PR48 Decrease <1 log Decrease ≥ 1 log

  35. Tolerance TelaprevirBoceprevir Rash (37%) Anemiax 2 (50%) (Severe7%) AnemiaDysgueusia Discontinuation AE: 13-20% Discontinuation AE: 9-19%

  36. Patient Case • What would you do ?

  37. 250 200 ALT (UI/L) 150 100 50 ULN 0 Time (Weeks) Patient Case: 3rd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1200 mg/day TVR 2250 mg/d 108 106 HCV-RNA (log10) IU/mL 104 102 0 4 24 12 48

  38. 250 200 ALT (UI/L) 150 100 50 ULN 0 Time (Weeks) Patient Case: 3rd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1200 mg/day TVR 2250 mg/d 108 106 HCV-RNA (log10) IU/mL 104 102 0 4 24 12 48

  39. REALIZE: Laboratory Abnormalities Pol et al, AASLD 2011

  40. Tolerance in F3-F4 non respondersthe French CUPIC observatory Interimanalysis TVR + Peg-IFN α-2a + RBV Peg-IFN α-2a + RBV Follow-up Peg-IFN + RBV BOC + Peg-IFN α-2b + RBV Follow-up BOC : 800 mg/8h; peg-IFNα-2b : 1,5 µg/kg/week; RBV : 800 -1400 mg/d TVR : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : 1000 à 1200 mg/d 72 36 4 0 12 16 48 8 Weeks

  41. CUPIC: preliminary safety findings Telaprevir Hézode C, et al, Hepdart 2011

  42. CUPIC: preliminary safety findings Telaprevir Hézode C, et al, Hepdart 2011

  43. CUPIC: preliminary safety findings Boceprevir Hézode C, et al, Hepdart 2011

  44. CUPIC: preliminary safety findings Boceprevir Hézode C, et al, Hepdart 2011

  45. 250 200 ALT (UI/L) 150 100 50 ULN 0 Time (Weeks) Patient Case: 3rd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1200 mg/day TVR 2250 mg/d 108 106 HCV-RNA (log10) IU/mL 104 102 0 4 24 12 48

  46. Patient Case: rash

  47. CutaneousreactionwithTelaprevir phase II & III studies 100 > 90% mild or moderate 80 55 60 Incidence of rash (%) Incidence of rash (%) 33 40 20 (n=1346) (n=764) 0 Mild Moderate severe control TLR Cacoub P et al, J Hepatol 2012;56:455-63

  48. 250 200 ALT (UI/L) 150 100 50 ULN 0 Time (Weeks) Patient Case: 2nd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1200 mg/day TVR 2250 mg/d 108 106 HCV-RNA (log10) IU/mL 104 102 0 4 24 12 48

  49. Rectal burningwithTelaprevir phase II & III studies • In clinical trials, the majority of these events (e.g., haemorrhoids, anorectal discomfort, anal pruritus, and rectal burning) were mild to moderate, very few led to treatment discontinuation and resolved after completion of telaprevir dosing2 1. http://www.fda.gov/downloads/AdvisoryCommittees/Committees/MeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf2. Telaprevir EU SmPC

  50. 250 200 ALT (UI/L) 150 100 50 ULN 0 Time (Weeks) Patient Case: 2nd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1200 mg/day TVR 2250 mg/d 108 106 HCV-RNA (log10) IU/mL 104 102 0 4 24 12 48

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