1. TRAITEMENT DE L’HÉPATITE B Patrick Marcellin

3. POURQUOI TRAITER?

4. - Arrêter la multiplication virale - Diminuer l’activité de l ’hépatite chronique - Arrêter l’évolution de la fibrose (régression?) - Prévenir l’évolution vers la cirrhose - Prévenir les complications - Prévenir le CHC - Prévenir la mortalité OBJECTIFS DU TRAITEMENT DE L’HÉPATITE CHRONIQUE B?

5. TEMPS AgHBe négatif ADN VHB négatif Anti-Hbe positif AgHBs négatif Anti-HBs positif OBJECTIFS DU TRAITEMENT

6. SEROCONVERSION HBs: LE CHAMPION DES CRITÈRES ADN VHB négatif Seroconversion HBe Seroconversion HBs 1 3 2

7. QUI TRAITER

9. HEPATITE CHRONIQUE B = MULTIPLICATION VIRALE/RÉPONSE IMMUNITAIRE MULTIPLICATION VIRALE RÉPONSE IMMUNITAIRE

10. PHASE DE TOLÉRANCE IMMUNITAIRE = MAUVAISE RÉPONSE ADN VHB > 7 log ALAT < N AgHBe + PBH = A1F1 MULTIPLICATION VIRALE RÉPONSE IMMUNITAIRE

11. PHASE DE RÉACTION IMMUNITAIRE = BONNE RÉPONSE ADN VHB < 7 log ALAT > N AgHBe +/- PBH > A1F1 MULTIPLICATION VIRALE RÉPONSE IMMUNITAIRE

12. 10 10 2 10 3 10 4 10 5 10 6 10 7 10 8 10 9 10 10 Hépatite chronique AgHBe - Porteur inactif Martinot et al. J Hepatol 2002 CHARGE VIRALE ET STADE DE L’HC B

13. 10 10 2 10 3 10 4 10 5 10 6 10 7 10 8 10 9 10 10 1 2 3 4 Années Hépatite chronique AgHBe - Porteur inactif 5 COMMENT DISTINGUER LE PORTAGE INACTIF DE L’HCA AgHBe - LE SUIVI +++ Asselah et al. GCB 2005

15. QUI TRAITER Guidelines EASL AgHBe + et AgHBe - EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009

16. QUI TRAITER Guidelines EASL AgHBe + et AgHBe - EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009 ADN VHB < 4 log ALAT = N

17. QUI TRAITER Guidelines EASL AgHBe + et AgHBe - Surveiller EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009 ADN VHB < 4 log ALAT = N

18. QUI TRAITER Guidelines EASL AgHBe + et AgHBe - Surveiller EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009 ADN VHB < 4 log ALAT = N ADN VHB > 4 log et/ou ALAT > N PBH > A1/F1

19. QUI TRAITER Guidelines EASL AgHBe + et AgHBe - Surveiller EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009 ADN VHB < 4 log ALAT = N ADN VHB > 4 log Et/ou ALAT > N PBH > A1F1 Traiter

20. COMMENT TRAITER

21. TREATMENT OF CHRONIC HEPATITIS B Two Strategies - Analogues : pure antivirals maintained response - Interferon : antiviral + immune modulator sustained response

23. RESULTS WITH ANALOGUES

24. VIROLOGICAL RESPONSE AT 1 YEAR HBeAg-positive HBeAg-negative LAM 2 ADV 1 ETV 3 LdT 2 TDF 4 LAM 2 ADV 5 ETV 6 LdT 2 TDF 4 21% 51% 40% 71% 67% 90% 60% 88% 73% 93% 0 20 40 60 80 100 1. Marcellin et al . N Engl J Med. 2003 2. Lai et al. N Engl J Med. 2007 3. Chang et al. N Engl J Med . 2006 4. Marcellin et al. N Engl J Med. 2008 5. Hadziyannis et al. N Engl J Med. 2003 6. Lai et al. N Engl J Med. 2006 Negative PCR (%)

26. ENTECAVIR

27. ENTECAVIR ADN VHB NÉGATIF A 1 et 3-5 ANS . 55% 94% AgHBe + AgHBe - Chan et al. Hepatology 2010 Shouval et al. AASLD 2008 95% 94%

28. ENTECAVIR DANS L’HC AgHBe + ADN VHB négatif 0 20 40 60 100 80 1 an 2 ans 3 ans 55% 85% 90% Chan et al. Hepatology 2010 4 ans 91% N=146 N=140 N=134 N=112 5 ans 94% N=94

29. TENOFOVIR

30. TENOFOVIR ADN VHB NÉGATIF A 1 et 5 ANS . 73% 93% AgHBe + AgHBe - Marcellin et al. NEJM 2008 Marcellin et al. AASLD 2011 87%* 65%* *98% Per protocol

31. Histologie à 5 ans de Traitement n=348 Marcellin et al. AASLD 2011

32. Cumulative incidence of HBV resistance 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 24% 0% LAM ADV ETV LdT TDF 0% Year 1 Year 2 Year 3 Year 4 Year 5 0% 0% 0% 0% 38% 49% 67% 70% 4% 22% 3% 11% 18% 29% 0% 1.2% 1.2% 0.2% 1.2%

35. WHY HBsAg IS THE MAIN OBJECTIVE OF THERAPY

36. - Ultimate goal of therapy - Closest to cure - Not HBV eradication but associated with improved prognosis Marcellin et al. Annals Intern Med 1990 Loriot et al. Hepatology 1992 THE IMPORTANCE OF HBsAg LOSS

38. No HBsAg loss 20 40 60 80 100 Survival (%) HBsAg loss P<0.001 309 cirrhotics with a mean follow-up of 6 years Fattovich et al. Am J Gastroenterology 1998 Time (years) 1 2 3 4 5 6 7 HBsAg Loss is Associated with Improved Survival

39. INCIDENCE DE LA NÉGATIVATION DE L’AgHBs EN FONCTION DE LA SÉROCONVERSION HBe Moucari et al. J Hepatol 2009 64% 17% p <0,001

41. RESULTS WITH INTERFERON

42. PEG IFN HBeAg negative CHB

43. HBsAg LOSS after PEG IFN ± LAM 1 an 2 ans 3 ans 4 ans % 5 6 9 11 0 Marcellin et al. NEJM 2004 Marcellin et al. Gastroenterology 2009 Marcellin et al. Hepatology International. In press 12 5 ans

44. HBsAg LOSS 1 an 2 ans 3 ans 4 ans % 5 6 9 11 0 Marcellin et al. NEJM 2004 Marcellin et al. Gastroenterology 2009 Marcellin et al. APASL 2009 12 5 ans 64% of the patients HBV DNA negative

51. THE ROLE OF HBsAg QUANTIFICATION

52. HBsAg ACCORDING TO TREATMENT Treatment Weeks LAM PEG-IFN  -2a PEG-IFN  -2a + LAM Median log 10 IU/mL Marcellin et al. Hepatology International. In press

53. HBV DNA (Log 10 copies/ml) HBsAg (Log 10 U/ml) Treatment HBsAg Kinetics: PEG IFN SVR (+) Moucari et al. Hepatology 2009

54. HBV DNA (Log 10 copies/ml) HBsAg (Log 10 U/ml) Treatment HBsAg Kinetics: PEG IFN SVR (-) Moucari et al. Hepatology 2009

55. Quantification of HBsAg: “Stopping Rule” Early Serological Response = 0 .5 log at W12 48 Patients treated with PEG IFN a2a ESR - PPV = 89 % NPV = 90 % Moucari et al. Hepatology 2009 ESR + SVR Sustained Virological response

57. PEG IFN + LAM SERUM HBV DNA Study week On-treatment Mean HBV DNA (log 10 cp/mL) 2 3 4 5 6 7 0 6 12 18 24 30 36 42 48 – 4.1 – 5.0 – 4.2 Marcellin et al. NEJM 2004 0.9 log PEG IFN a2a + placebo lamivudine + lamivudine PEG IFN a2a

58. PEG IFN + Telbivudine HBsAg decline baseline to week 24 Baseline 42 46 16 Week 12 42 46 16 Week 24 42 46 16 PEG LDT LDT+PEG Time on treatment Marcellin et al. EASL 2010

60. Log 10 IU/ml HBsAg kinetics according to treatment response Marcellin et al. AASLD 2011

61. SVR patient with HBsAg loss Log 10 IU/ml Marcellin et al. AASLD 2011

63. PERSPECTIVAS L’AVENIR?

64. PERSPECTIVAS Traitement individualisé