Comment optimiser le traitement de l h patite chronique virale C CAS CLINIQUES

1. Comment optimiser le traitement de l’hépatite chronique virale C ?CAS CLINIQUES Denis OUZAN Olivier NOUEL

4. Cas n° 1 : Mr. B… Patrick : 58 ans, 59 kg Consulte en 2005 pour la découverte fortuite d’un anti VHC + ALT 8 N , GGT 10 N Plaquettes : 98 000/mm³Génotype 3 ARN : 7 974 000 UI/ml (7,52 log) Alcool : 80 g/j arrêt depuis 6 mois

6. Evaluation de la fibrose (2005) Fibrotest F : 0,92 : F4 Fibroscan 10 mesures KPa : 36,4 IQR : 3,0 TdR : 100 %

7. Examens complémentaires (2005) Echographie : foie à contours bosselés homogène Gastroscopie : absence de VO

8. IFNPeg + RBV 800 mg/j J0 ARN : 7, 52 Log S4 (5ème injection) ARN : 215 UI/ml S12 ARN : < 43 UI/ml

9. Quelle durée totale de traitement proposeriez-vous chez ce patient cirrhotique de génotype 3, dontl' ARN devient indétectable entre S4 et S12 ? 24 sem 48 sem

10. La durée du traitement a été 48 semaines  J0 ARN : 7 974 000 UI/ml S4 : (5 eme inj ) ARN : 215 UI/ml S12 ARN < 43 UI/ml S48 Fin du traitement

11. Une meilleure connaissance des profils de réponse virologique sous traitement

12. PROPHESYS : PEG-IFNa-2a + RBV% de patients ayant une réponse précoce

13. Schéma de l’étude ACCELERATEShiffman, NEJM 2007

14. Impact de la RVR sur la Réponse soutenuedans l’étude ACCELERATE 65 % des patients ont une RVR

15. RVS en fonction de l’existence d’une cirrhose chez les maladies qui n’ont pas de RVR

19. 573 patients traités par PEG-IFN + RBV Evaluation ARN-VHC à S12 et S24 post-traitement (Seuil = 10U (TMA))

20. un mois après la fin du traitement ARN du VHC : 3 450 UI/ml

21. Chez ce patient motivé, F4, proposeriez-vous d’emblée un nouveau traitement ? OUI NON

22. Si oui : quelle durée totale de retraitement proposeriez-vous ? 48 sem 72 sem

23. Le patient est retraité 72 semaines : PegIFN + RBV 800 mg J0 ARN : 3 450 UI/ml S4 ARN : 85 400 UI/ml S12 ARN < 43 UI/ml S 72 Fin du traitement

24. 1 et 3 mois après le second traitement Avril 08 ARN du VHC < 43 MU/ml Juin 08 ARN du VHC < 191885 MU/ml Juin 08 Apparition de 4 nodules hépatique mesurés à 10,15, 25 et 27 mm

25. Algorithme de traitement du CHC

26. Suite thérapeutique Juillet 2008 1ere séance de chimioembolisation Inscription sur liste de T HO Septembre 2008 Reprise du traitement antiviral Janvier 2009 : après 4mois de traitement THO Absence de rechute

27. Traitement antiviral avant transplantation hépatique pour cirrhose viral C 12/15 patients ARN du VHC <0 avant THO le restent après (Everson et al Hepatology 2005) 9/12 patients ARN du VHC <0 avant THO le restent après (Forns et al J of Hepatol 2003)

28. Suivi après transplantation Janvier 2009 THO Janvier 2011 ARN du VHC < 43 UI/ml Fibroscan : 4.7 Kpa Foie homogène

29. Conclusion Une virémie indétectable est obtenue chez la plupart des malades de génotype 2,3 qui de ce fait sont guérissables par le traitement standard. La durée du traitement doit être adaptée au degré de fibrose et au délai de disparition de l’ARN viral.

30. Cas N°2 : A. Irina : 48 ans, 68 kg Consulte en 2007 pour la découverte fortuite d’un anti VHC + ALT 3 N , GGT 5 N ARN : 6 900 000 UI/ml (6,52 log) Génotype 1a PBF : A2F2

31. Peg-IFN + RBV 1000 mg/j J0 ARN : 6, 52 Log S4 (5ème injection) ARN : 1330 UI/ml S12 ARN : < 43 UI/ml Hg : 13 g/L (J0) 10.5 (S12)

32. Quelle durée totale de traitement proposeriez-vous chez ce patient de génotype 1, dontl' ARN devient indétectable entre S4 et S12 ? 48 sem 72 sem

33. La durée du traitement a été 48 semaines  J0 ARN : 6 900 000 UI/ml S4 : (5 eme inj ) ARN : 215 UI/ml S12 ARN < 43 UI/ml S48 Fin du traitement

34. Etude IDEAL: (3070 patients G1 naïfs) proportions de patients ayant une PCR négative

36. Etude IDEAL :Effets Indésirables

37. Comment améliorer l’observance ? Motivation du patient Information du patient Suivi du patient Gestion des effets secondaires

38. Taux de RVS selon que les patients ont béneficié ou non d’une éducation thérapeutique

39. Anémie associée à RVS (Essai IDEAL) Background: Anemia due to PEG/RBV affects ~30% of persons treated. Epoetin alfa has been used to increase hemoglobin (Hb) levels to improve quality of life and RBV dose. The relationship of anemia, EPO use and sustained viral response (SVR) is unknown. Methods: 3070 HCV genotype 1 infected patients (pts) were randomized (1:1:1) and treated for 48 weeks with PEG2b 1.5ìg/kg/week or PEG2b 1.0ìg/kg/wk + RBV 800-1400mg/day, or PEG2a 180ìg/wk + RBV 1000- 1200mg/day. Patients with virologic failure at treatment weeks 12 or 24 stopped therapy. Anemia was defined as Hb <10 g/dL. Anemic patients underwent protocol-defined RBV dose reduction after which EPO was permitted at investigator discretion. Viral response rates (ITT) were assessed in 3 groups: 1) No anemia; 2) Anemia/No EPO; 3)Anemia/EPO. Results: No anemia was observed in 2158 pts (70%); of whom, 67% were male; 83% were older than 40 years; median Hb maximum decline was -3.60 g/dL. Anemia was observed in 865 pts (28%); of whom, 41% were male; 90% were older than 40 years; median Hb maximum decline was -4.65 to -5.20 g/dL. EPO was used in 449 (52%) anemic pts. Median nadir Hb level and median Hb maximum decline were similar in anemic pts with and without EPO use. Median RBV exposure (mg/kg/day) during treatment: (PEG2b1.5/PEG2b1.0/PEG2a, respectively) – No anemia, 12.6/12.6/13.5, Anemia/No EPO, 11.7/12.0/12.6 Anemia/ EPO, 11.9/11.9/12.5. The proportion of pts completing = 12 weeks of therapy: No anemia, 94%; Anemia/No EPO, 92%; Anemia/EPO, 99%. Discontinuation due to adverse events (AEs)/virologic non-response: No anemia, 10%/31%; Anemia/No EPO, 18%/20%; Anemia/EPO, 12%/19%. Endof- treatment, relapse, and SVR rates are shown in the Table. Pvalue <0.0001 using Mantel-Haenszel test for the association of Anemia with SVR adjusting for treatment. Conclusions: Compared to those with no anemia, anemic pts were less likely to have virologic nonresponse and significantly more likely to achieve SVR despite receiving less RBV (mg/kg/day) during treatment. Although potential selection bias for comparing the groups may exist, this suggests that other host and treatment factors (e.g., plasma RBV concentration) contribute to viral response in this group. Among anemic pts, EPO use was associated with lower AE-related discontinuation and higher ontreatment viral response but not higher SVR rate.Background and aims: Peginterferon (Peg)/ribavirin (RBV) causes significant hemoglobin (Hb) decline leading to side effects and RBV reduction in ~30% of patients (pts). The effect of Hb loss on sustained viral response (SVR) is unknown. Methods: 3070 HCV genotype-infected pts were treated for 48 weeks with Peg2b 1.5 or 1.0mcg/kg/wk + RBV 800-1400mg/day, or Peg2a 180mcg/wk + RBV 1000-1200mg/day. Anemia was defined as Hb < 10 g/dL; erythropoietin (EPO) was permitted in anemic pts after protocol-defined RBV reduction. Viral response rates (ITT) were assessed according to maximum Hb decline. Results: 3023 pts had baseline and at least one Hb measurement during therapy. Anemia occurred in 865 (28%) pts, of whom 449 (52%) used EPO. Among all pts, mean maximum Hb decline was 4.0g/dL (±1.4). SVR was associated with the magnitude of the Hb decline (Figure): >3 g/dL, 43.7% (984/2250); =3 g/dL, 29.9% (231/773) (P< 0.0001). EPO was associated with higher SVR rate in pts with early anemia (=8 weeks): Anemia/no EPO, 25.9% (37/143); Anemia/EPO, 45.0% (107/238); P=0.0002, but not among pts with late anemia (>8 weeks): Anemia/no EPO, 59.3% (162/273); Anemia/EPO, 55.0% (116/211); P=0.33. Among anemic pts, EPO was associated with less early (< 0.001). Conclusions: Among HCV genotype 1-infected pts treated with Peg/RBV, the magnitude of Hb decline is strongly associated with the likelihood of SVR. The effect of EPO varied by time to anemia; no benefit was observed for pts who became anemic after treatment week 8. These data suggest that Hb decline may be a pharmacodynamic marker of treatment effectiveness and that the primary effect of EPO was to prevent treatment discontinuation in pts with early anemia. Background: Anemia due to PEG/RBV affects ~30% of persons treated. Epoetin alfa has been used to increase hemoglobin (Hb) levels to improve quality of life and RBV dose. The relationship of anemia, EPO use and sustained viral response (SVR) is unknown. Methods: 3070 HCV genotype 1 infected patients (pts) were randomized (1:1:1) and treated for 48 weeks with PEG2b 1.5ìg/kg/week or PEG2b 1.0ìg/kg/wk + RBV 800-1400mg/day, or PEG2a 180ìg/wk + RBV 1000- 1200mg/day. Patients with virologic failure at treatment weeks 12 or 24 stopped therapy. Anemia was defined as Hb <10 g/dL. Anemic patients underwent protocol-defined RBV dose reduction after which EPO was permitted at investigator discretion. Viral response rates (ITT) were assessed in 3 groups: 1) No anemia; 2) Anemia/No EPO; 3)Anemia/EPO. Results: No anemia was observed in 2158 pts (70%); of whom, 67% were male; 83% were older than 40 years; median Hb maximum decline was -3.60 g/dL. Anemia was observed in 865 pts (28%); of whom, 41% were male; 90% were older than 40 years; median Hb maximum decline was -4.65 to -5.20 g/dL. EPO was used in 449 (52%) anemic pts. Median nadir Hb level and median Hb maximum decline were similar in anemic pts with and without EPO use. Median RBV exposure (mg/kg/day) during treatment: (PEG2b1.5/PEG2b1.0/PEG2a, respectively) – No anemia, 12.6/12.6/13.5, Anemia/No EPO, 11.7/12.0/12.6 Anemia/ EPO, 11.9/11.9/12.5. The proportion of pts completing = 12 weeks of therapy: No anemia, 94%; Anemia/No EPO, 92%; Anemia/EPO, 99%. Discontinuation due to adverse events (AEs)/virologic non-response: No anemia, 10%/31%; Anemia/No EPO, 18%/20%; Anemia/EPO, 12%/19%. Endof- treatment, relapse, and SVR rates are shown in the Table. Pvalue <0.0001 using Mantel-Haenszel test for the association of Anemia with SVR adjusting for treatment. Conclusions: Compared to those with no anemia, anemic pts were less likely to have virologic nonresponse and significantly more likely to achieve SVR despite receiving less RBV (mg/kg/day) during treatment. Although potential selection bias for comparing the groups may exist, this suggests that other host and treatment factors (e.g., plasma RBV concentration) contribute to viral response in this group. Among anemic pts, EPO use was associated with lower AE-related discontinuation and higher ontreatment viral response but not higher SVR rate.Background and aims: Peginterferon (Peg)/ribavirin (RBV) causes significant hemoglobin (Hb) decline leading to side effects and RBV reduction in ~30% of patients (pts). The effect of Hb loss on sustained viral response (SVR) is unknown. Methods: 3070 HCV genotype-infected pts were treated for 48 weeks with Peg2b 1.5 or 1.0mcg/kg/wk + RBV 800-1400mg/day, or Peg2a 180mcg/wk + RBV 1000-1200mg/day. Anemia was defined as Hb < 10 g/dL; erythropoietin (EPO) was permitted in anemic pts after protocol-defined RBV reduction. Viral response rates (ITT) were assessed according to maximum Hb decline. Results: 3023 pts had baseline and at least one Hb measurement during therapy. Anemia occurred in 865 (28%) pts, of whom 449 (52%) used EPO. Among all pts, mean maximum Hb decline was 4.0g/dL (±1.4). SVR was associated with the magnitude of the Hb decline (Figure): >3 g/dL, 43.7% (984/2250); =3 g/dL, 29.9% (231/773) (P< 0.0001). EPO was associated with higher SVR rate in pts with early anemia (=8 weeks): Anemia/no EPO, 25.9% (37/143); Anemia/EPO, 45.0% (107/238); P=0.0002, but not among pts with late anemia (>8 weeks): Anemia/no EPO, 59.3% (162/273); Anemia/EPO, 55.0% (116/211); P=0.33. Among anemic pts, EPO was associated with less early (< 0.001). Conclusions: Among HCV genotype 1-infected pts treated with Peg/RBV, the magnitude of Hb decline is strongly associated with the likelihood of SVR. The effect of EPO varied by time to anemia; no benefit was observed for pts who became anemic after treatment week 8. These data suggest that Hb decline may be a pharmacodynamic marker of treatment effectiveness and that the primary effect of EPO was to prevent treatment discontinuation in pts with early anemia.

40. EPO Hors AMM Ordonnance spécifique, dispensé en officine de ville Hémoglobine < 10 g/dl Néorecormon 30 000 UI / semaine Suivi de sécurité : risque de thrombose stimulation de prolifération tumorale Surveillance NFS : arrêt si Hb > 12 g/

41. Genotype 1: Doses cumulées de ribavirine et RVS

42. Genotype 1: Doses cumulées de ribavirine et RVS Analyse retrospective de 3 essais de PegIFN alfa-2a/RBV pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response.   The drug exposure in patients maintaining their ribavirin through treatment completion is important as well. A correlation between ribavirin exposure and SVR rate in patients completing treatment was demonstrated in a retrospective study by Reddy and colleagues. In this analysis the group compared peginterferon alfa-2a and ribavirin exposure levels of patients from a number of phase III trials with virologic response. As cumulative ribavirin exposure increased, the SVR rate increased and the relapse rate decreased. pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response.   The drug exposure in patients maintaining their ribavirin through treatment completion is important as well. A correlation between ribavirin exposure and SVR rate in patients completing treatment was demonstrated in a retrospective study by Reddy and colleagues. In this analysis the group compared peginterferon alfa-2a and ribavirin exposure levels of patients from a number of phase III trials with virologic response. As cumulative ribavirin exposure increased, the SVR rate increased and the relapse rate decreased.

43. Réponse virologique rapide (S4) et concentration sérique de ribavirine à S4

47. 1 et 3 mois après le traitement 1 mois ARN du VHC < 43 MU/ml 3mois ARN du VHC < 26983 MU/ml

48. Taux de rechute en fonction de la cinétique virale précoce chez les malades de génotype 1 263 pts de génotype 1 traités par Peg-IFNa + ribavirine 48s

49. Génotype 1 : Optimisation de la durée du traitement 

52. Chez cette patient motivé, F2, proposeriez-vous d’emblée un nouveau traitement ? OUI NON

53. Si oui : quelle durée totale de retraitement proposeriez-vous ? 48 sem 72 sem

54. Durée du traitement La patiente a été retraitée 72 semaines

55. 1 et 3 et 6 mois après le second traitement de 72 semaines. 1 mois ARN du VHC < 43 MU/ml 3 mois ARN du VHC < 43 MU/ml 6 mois ARN du VHC < 43 MU/ml

60. Facteurs prédictifs de réponse à la bithérapie

61. « Certaines informations de ce document sont susceptibles de ne pas être validées par la Commission d’AMM de l’AFSSAPS »

62. Recherche de SNP associés à la réponse au traitement 1 polymorphisme situé sur le chromosome 19 «rs 12979860» fortement lié à la RVS, situé en amont du gène de l’IL28B (IFN ?-3) 2 allèles (C et T) Polymorphisme de l’IL28B

63. Association du gène de l’IL28B à la RVS Parmi les patients tjrs virémiques à S4, les chances de RVS sont très > chez les homozygotes CC Parmi les patients tjrs virémiques à S4, les chances de RVS sont très > chez les homozygotes CC

64. Etude IDEAL : RVS en fonction du génotype de l’IL28B - SNP rs12979860

66. Répartition des allèles C et T dans la population mondiale

67. Est il utile de réaliser un génotype de l’IL28B chez les malades de génotype 1 jamais traités ?