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Marcellin tt vhb du 2012

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Marcellin tt vhb du 2012

  1. 1. TRAITEMENT DE L’HÉPATITE B Patrick Marcellin
  2. 2. L’HÉPATITE B EN FRANCE <ul><li>0,7% (300.000) porteurs chroniques* </li></ul><ul><li>- 3ème cause de cirrhose et CHC </li></ul><ul><li>Mortalité: 1500/an** </li></ul><ul><li>< 150 000 dépistés </li></ul><ul><li>15 000 traités </li></ul><ul><li>1500 nouveaux traités par an </li></ul>* InVS 2005 ** INSERM CépiDC, FPRH, AFEF, InVS Marcellin et al. J Hepatol 2008
  3. 3. POURQUOI TRAITER?
  4. 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. 5. TEMPS AgHBe négatif ADN VHB négatif Anti-Hbe positif AgHBs négatif Anti-HBs positif OBJECTIFS DU TRAITEMENT
  6. 6. SEROCONVERSION HBs: LE CHAMPION DES CRITÈRES ADN VHB négatif Seroconversion HBe Seroconversion HBs 1 3 2
  7. 7. QUI TRAITER
  8. 8. COMMENT OPTIMISER LE TRAITEMENT DE L’HÉPATITE CHRONIQUE B? <ul><li>Traiter les malades qui en ont besoin (risque de complications) </li></ul><ul><li>- Traiter les malades qui ont de bonnes chances de répondre </li></ul>
  9. 9. HEPATITE CHRONIQUE B = MULTIPLICATION VIRALE/RÉPONSE IMMUNITAIRE MULTIPLICATION VIRALE RÉPONSE IMMUNITAIRE
  10. 10. PHASE DE TOLÉRANCE IMMUNITAIRE = MAUVAISE RÉPONSE ADN VHB > 7 log ALAT < N AgHBe + PBH = A1F1 MULTIPLICATION VIRALE RÉPONSE IMMUNITAIRE
  11. 11. PHASE DE RÉACTION IMMUNITAIRE = BONNE RÉPONSE ADN VHB < 7 log ALAT > N AgHBe +/- PBH > A1F1 MULTIPLICATION VIRALE RÉPONSE IMMUNITAIRE
  12. 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. 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
  14. 14. QUI TRAITER Guidelines EASL <ul><li>Indications semblables pour </li></ul><ul><li>HC AgHBe + ou AgHBe - </li></ul><ul><li>2. Indication dépend de: </li></ul><ul><li>- ADN VHB </li></ul><ul><li>- ALAT </li></ul><ul><li>- PBH </li></ul>EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009
  15. 15. QUI TRAITER Guidelines EASL AgHBe + et AgHBe - EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009
  16. 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. 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. 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. 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. 20. COMMENT TRAITER
  21. 21. TREATMENT OF CHRONIC HEPATITIS B Two Strategies - Analogues : pure antivirals maintained response - Interferon : antiviral + immune modulator sustained response
  22. 22. NUCs vs IFN <ul><li> NUCs IFN </li></ul><ul><li>- Finite duration - + </li></ul><ul><li>- Sustained response - + </li></ul><ul><li>No resistance +/- + </li></ul><ul><li>Oral administration + - </li></ul><ul><li>Good tolerance + - </li></ul><ul><li>Low cost - +? </li></ul>
  23. 23. RESULTS WITH ANALOGUES
  24. 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 (%)
  25. 25. ANALOGUES REGISTERED FOR THE TREATMENT OF CHRONIC HEPATITIS B <ul><li>Lamivudine - </li></ul><ul><li>Adefovir - </li></ul><ul><li>Telbivudine + </li></ul><ul><li>Entecavir +++ </li></ul><ul><li>Tenofovir +++ </li></ul>
  26. 26. ENTECAVIR
  27. 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. 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. 29. TENOFOVIR
  30. 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. 31. Histologie à 5 ans de Traitement n=348 Marcellin et al. AASLD 2011
  32. 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%
  33. 33. NO CORRELATION BETWEEN ANTIVIRAL POTENCY AND HBs SEROCONVERSION* <ul><li>HBV DNA HBs </li></ul><ul><li> decrease (log) loss </li></ul><ul><li>- Lamivudine 5.0 0% </li></ul><ul><li>- Adefovir 4.0 0% </li></ul><ul><li>Entecavir 7.0 2%** </li></ul><ul><li>- Telbivudine 6.5 0% </li></ul><ul><li>- Tenofovir 5.5 3%** </li></ul>* One year ** Only in HBeAg-positive patients
  34. 34. TREATMENT OF CHRONIC HEPATITIS B WITH ANALOGUES: LIMITATIONS <ul><li>HBV DNA must be undetectable to prevent resistance </li></ul><ul><li>HBe seroconversion inconstant despite virological response </li></ul><ul><li>Risk of resistance on the long term? </li></ul><ul><li>Tolerance on the long term? </li></ul><ul><li>Importance of compliance </li></ul><ul><li>When to stop? </li></ul><ul><li>HBsAg loss rare </li></ul>
  35. 35. WHY HBsAg IS THE MAIN OBJECTIVE OF THERAPY
  36. 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
  37. 37. HBsAg AND THE RISK OF HCC <ul><li>HBsAg HBeAg ALT Relative Risk </li></ul><ul><li>-- -- normal 1 </li></ul><ul><li>-- -- elevated 5 </li></ul><ul><li>+ -- normal 10 </li></ul><ul><li>+ -- elevated 30 </li></ul><ul><li>+ + normal 60 </li></ul><ul><li>+ + elevated 110 </li></ul>Yang et al. NEJM 2002 11,893 men in Taiwan
  38. 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. 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
  40. 40. EVOLUTION (10 ans) APRÈS TRAITEMENT IFN <ul><li> AgHBs+ AgHBs- </li></ul><ul><li>CHC : 6 0 </li></ul><ul><li>Ascite : 5 0 </li></ul><ul><li>Hemorhagie: 0 0 </li></ul><ul><li>Transplantation: 0 0 </li></ul><ul><li>Mortalité (CHC): 4 0 </li></ul>Moucari et al. J Hepatol 2009
  41. 41. RESULTS WITH INTERFERON
  42. 42. PEG IFN HBeAg negative CHB
  43. 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. 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
  45. 45. HOW TO TREAT EASL Guidelines HBeAg + or HBeAg - <ul><li>EASL Clinical Practice Guidelines: Management of chronic hepatitis B. </li></ul><ul><li>J Hepatol 2009 </li></ul>
  46. 46. HOW TO TREAT EASL Guidelines HBeAg + or HBeAg - <ul><li>2 million IU </li></ul><ul><li>EASL Clinical Practice Guidelines: Management of chronic hepatitis B. </li></ul><ul><li>J Hepatol 2009 </li></ul>PEG IFN HBV DNA < 7 log (copies)* ALT > 3N
  47. 47. HOW TO TREAT EASL Guidelines HBeAg + or HBeAg - <ul><li>2 million IU </li></ul><ul><li>EASL Clinical Practice Guidelines: Management of chronic hepatitis B. </li></ul><ul><li>J Hepatol 2009 </li></ul>PEG IFN HBV DNA < 7 log (copies)* ALT > 3N HBV DNA < 1 log at S12
  48. 48. HOW TO TREAT EASL Guidelines HBeAg + or HBeAg - ANALOGUE Entecavir or Tenofovir or Telbivudine <ul><li>2 million IU </li></ul><ul><li>EASL Clinical Practice Guidelines: Management of chronic hepatitis B. </li></ul><ul><li>J Hepatol 2009 </li></ul>PEG IFN HBV DNA < 7 log (copies)* ALT > 3N HBV DNA < 1 log at S12
  49. 49. HOW TO TREAT EASL Guidelines HBeAg + or HBeAg - ANALOGUE Entecavir or Tenofovir or Telbivudine <ul><li>2 million IU </li></ul><ul><li>EASL Clinical Practice Guidelines: Management of chronic hepatitis B. </li></ul><ul><li>J Hepatol 2009 </li></ul>PEG IFN HBV DNA < 7 log (copies)* ALT > 3N HBV DNA < 1 log at S12
  50. 50. HOW TO TREAT EASL Guidelines HBeAg + or HBeAg - ANALOGUE Entecavir or Tenofovir or Telbivudine If HBV DNA + at S24-48 Change analogue <ul><li>2 million IU </li></ul><ul><li>EASL Clinical Practice Guidelines: Management of chronic hepatitis B. </li></ul><ul><li>J Hepatol 2009 </li></ul>PEG IFN HBV DNA < 7 log (copies)* ALT < 3N HBV DNA < 1 log at S12
  51. 51. THE ROLE OF HBsAg QUANTIFICATION
  52. 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. 53. HBV DNA (Log 10 copies/ml) HBsAg (Log 10 U/ml) Treatment HBsAg Kinetics: PEG IFN SVR (+) Moucari et al. Hepatology 2009
  54. 54. HBV DNA (Log 10 copies/ml) HBsAg (Log 10 U/ml) Treatment HBsAg Kinetics: PEG IFN SVR (-) Moucari et al. Hepatology 2009
  55. 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
  56. 56. <ul><li>PEG IFN + NUC </li></ul>THE FUTURE OF THERAPY FOR HBV
  57. 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. 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
  59. 59. <ul><li>36 patients - 8 (22%) with HBsAg drop > 0.5 log at 2 4 weeks - All with SVR - 4 (11%) HBsAg negative at 24 weeks post-TX </li></ul>PEG IFN + Tenofovir Marcellin et al. AASLD 2011
  60. 60. Log 10 IU/ml HBsAg kinetics according to treatment response Marcellin et al. AASLD 2011
  61. 61. SVR patient with HBsAg loss Log 10 IU/ml Marcellin et al. AASLD 2011
  62. 62. Conclusion <ul><li>La quantification de l’AgHBs a une forte VPN: </li></ul><ul><li>AgHBs à J0 > 3000 UI: 89% </li></ul><ul><li>AgHBs diminué de moins de 0,5 log à S24: 86% </li></ul><ul><li>Ces résultats suggèrent qu’il est possible de sélectionner les bons répondeurs avant traitement et de considérer un arrêt à S24. </li></ul>
  63. 63. PERSPECTIVAS L’AVENIR?
  64. 64. PERSPECTIVAS Traitement individualisé

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