Marcellin tt vhb final

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  • Marcellin P et al . Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348:808 − 816. Lai CL et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med . 2007;357:2576−2588. Chang TT et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001−1010. Heathcote J et al. A randomized, double blind, comparison of tenofovir DF (TDF) versus adefovir diprivoxil (ADV) for the treatment of HBeAg positive chronic hepatitis B (CHB): study GS-US-174−0103. Hepatology . 2007;46(4 suppl 1):861A (Abstract LB6). Hadziyannis S et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen- negative chronic hepatitis B. N Engl J Med . 2003;348:800−807. Lai CL et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med . 2006;354:1011−1020. Marcellin P et al. A randomized, double blind, comparison of tenofovir DF (TDF) versus adefovir diprivoxil (ADV) for the treatment of HBeAg negative chronic hepatitis B (CHB): study GS-US-174-0102. Hepatology . 2007;46(4 suppl 1):290A−291A (Abstract LB2).
  • Therapeutic Response HBV DNA suppressed to ≤ 5 log 10 , with ALT normalized OR HBeAg loss
  • Therapeutic Response HBV DNA suppressed to ≤ 5 log 10 , with ALT normalized OR HBeAg loss
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  • Patients were selected for HBsAg analysis, who reached week 24 of study There were no significant differences between the 3 treatment arms
  • Marcellin tt vhb final

    1. 1. TRAITEMENTDE L’HÉPATITE B Patrick Marcellin
    2. 2. L’HÉPATITE B EN FRANCE - 0,7% (300.000) porteurs chroniques* - 3ème cause de cirrhose et CHC - Mortalité: 1500/an** - < 150 000 dépistés - 15 000 traités - 1500 nouveaux traités par an* InVS 2005 ** INSERM CépiDC, FPRH, AFEF, InVS Marcellin et al. J Hepatol 2008
    3. 3. POURQUOI TRAITER?
    4. 4. OBJECTIFS DU TRAITEMENT DE L’HÉPATITE CHRONIQUE B?- 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
    5. 5. OBJECTIFS DU TRAITEMENT Anti-Hbe Anti-HBs AgHBeADN VHB négatif positif AgHBs positif négatif négatif TEMPS
    6. 6. SEROCONVERSION HBs:LE CHAMPION DES CRITÈRES Seroconversion HBs SeroconversionADN VHB HBe négatif 1 3 2
    7. 7. QUI TRAITER
    8. 8. COMMENT OPTIMISER LE TRAITEMENT DE L’HÉPATITE CHRONIQUE B?-Traiter les malades qui en ont besoin(risque de complications)- Traiter les malades qui ont de bonneschances de répondre
    9. 9. HEPATITE CHRONIQUE B =MULTIPLICATION VIRALE/RÉPONSE IMMUNITAIRE MULTIPLICATION RÉPONSE VIRALE IMMUNITAIRE
    10. 10. PHASE DE TOLÉRANCE IMMUNITAIRE = MAUVAISE RÉPONSE ADN VHB > 7 log ALAT < N AgHBe + PBH = A1F1 RÉPONSE IMMUNITAIRE MULTIPLICATION VIRALE
    11. 11. PHASE DE RÉACTION IMMUNITAIRE = BONNE RÉPONSEADN VHB < 7 log ALAT > NAgHBe +/- PBH > A1F1 MULTIPLICATION VIRALE RÉPONSE IMMUNITAIRE
    12. 12. CHARGE VIRALE ET STADE DE L’HC B10 1010 910 810 7 Hé patite10 6 chronique10 510 4 AgHBe - Porteur10 310 2 inactif10 Martinot et al. J Hepatol 2002
    13. 13. COMMENT DISTINGUER LE PORTAGE INACTIF DE L’HCA AgHBe - 10 10 LE SUIVI +++10 910 8 Hé patite chronique AgHBe -10 710 610 510 410 3 Porteur inactif10 210 1 2 Années 3 4 5 Asselah et al. GCB 2005
    14. 14. QUI TRAITER Guidelines EASL 1. Indications semblables pour HC AgHBe + ou AgHBe - 2. Indication dépend de: - ADN VHB - ALAT - PBHEASL 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 - ADN VHB < 4 log ALAT = NEASL Clinical Practice Guidelines: Management of chronic hepatitis B.J Hepatol 2009
    17. 17. QUI TRAITER Guidelines EASL AgHBe + et AgHBe - ADN VHB < 4 log ALAT = N SurveillerEASL Clinical Practice Guidelines: Management of chronic hepatitis B.J Hepatol 2009
    18. 18. QUI TRAITER Guidelines EASL AgHBe + et AgHBe - ADN VHB < 4 log ADN VHB > 4 log ALAT = N et/ou ALAT > N PBH > A1/F1 SurveillerEASL Clinical Practice Guidelines: Management of chronic hepatitis B.J Hepatol 2009
    19. 19. QUI TRAITER Guidelines EASL AgHBe + et AgHBe - ADN VHB < 4 log ADN VHB > 4 log ALAT = N Et/ou ALAT > N PBH > A1F1 Surveiller TraiterEASL Clinical Practice Guidelines: Management of chronic hepatitis B.J Hepatol 2009
    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 NUCs IFN- Finite duration - +- Sustained response - +- No resistance +/- +- Oral administration + -- Good tolerance + -- Low cost - +?
    23. 23. RESULTS WITH ANALOGUES
    24. 24. VIROLOGICAL RESPONSE AT 1 YEAR HBeAg-positive HBeAg-negative 100 90% 88% 93% 80 73% 71% 67% Negative PCR 60% 60 51% 40% 40 21% (%) 20 0 ADV 1 LAM 2 ETV 3 LdT 2 TDF 4 ADV 5 LAM 2 ETV 6 LdT 2 TDF 41. Marcellin et al. N Engl J Med. 2003 2. Lai et al. N Engl J Med. 20073. Chang et al. N Engl J Med. 2006 4. Marcellin et al. N Engl J Med. 20085. Hadziyannis et al. N Engl J Med. 2003 6. Lai et al. N Engl J Med. 2006
    25. 25. ANALOGUES REGISTERED FOR THETREATMENT OF CHRONIC HEPATITIS B - Lamivudine - - Adefovir - - Telbivudine + - Entecavir +++ - Tenofovir +++
    26. 26. ENTECAVIR
    27. 27. ENTECAVIR ADN VHB NÉGATIF A 1 et 3-5 ANS 94% 94% 95% 55% AgHBe + AgHBe -. Chan et al. Hepatology 2010 Shouval et al. AASLD 2008
    28. 28. ENTECAVIR DANS L’HC AgHBe + ADN VHB négatif10080 85% 90% 91% 94%6040 55%20 N=146 N=140 N=134 N=112 N=94 0 1 an 2 ans 3 ans 4 ans 5 ans Chan et al. Hepatology 2010
    29. 29. TENOFOVIR
    30. 30. TENOFOVIR ADN VHB NÉGATIF A 1 et 5 ANS 93% 87%* 73% 65%* *98% Per protocol AgHBe + AgHBe -. Marcellin et al. NEJM 2008 Marcellin et al. AASLD 2011
    31. 31. Histologie à 5 ans de Traitement n=348 100% Ishak Fibrosis Score 90% 6 5 80%s 4 3 70% 2 60% 1 0 50% 40% 30%Pognacerfti 20% 10% 0 Baselin e Year 1 Year 5 Marcellin et al. AASLD 2011
    32. 32. Cumulative incidence of HBV resistance100%90% Year 1 Year 280% Year 370% 70% Year 4 67% Year 560% 49%50%40% 38% 29%30% 24% 22%20% 18% 11%10% 4% 3% 0% 0.2% 1.2% 1.2% 1.2% 0% 0% 0% 0% 0% 0% LAM ADV ETV LdT TDF
    33. 33. NO CORRELATION BETWEEN ANTIVIRAL POTENCY AND HBs SEROCONVERSION* HBV DNA HBs decrease (log) loss- Lamivudine 5.0 0%- Adefovir 4.0 0%- Entecavir 7.0 2%**- Telbivudine 6.5 0%- Tenofovir 5.5 3%** * One year ** Only in HBeAg-
    34. 34. TREATMENT OF CHRONIC HEPATITIS B WITH ANALOGUES: LIMITATIONS- HBV DNA must be undetectable to preventresistance- HBe seroconversion inconstant despitevirological response- Risk of resistance on the long term?- Tolerance on the long term?- Importance of compliance- When to stop?- HBsAg loss rare
    35. 35. WHY HBsAg IS THE MAINOBJECTIVE OF THERAPY
    36. 36. THE IMPORTANCE OF HBsAg LOSS - 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
    37. 37. HBsAg AND THE RISK OF HCC 11,893 men in TaiwanHBsAg HBeAg ALT Relative Risk -- -- normal 1 -- -- elevated 5 + -- normal 10 + -- elevated 30 + + normal 60 + + elevated 110 Yang et al. NEJM 2002
    38. 38. HBsAg Loss is Associated with ImprovedSurvival309 cirrhotics with a mean follow-up of 6 years 100 HBsAg loss 80 60 P<0.001 No HBsAg Survival (%) 40 loss 20 2 1 (years)3 4 5 6 7 Time Fattovich et al. Am J Gastroenterology 1998
    39. 39. Cumulative Incidence of HBsINCIDENCE DE LA NÉGATIVATION DE L’AgHBs EN FONCTION DE LA SÉROCONVERSION HBe Seroconversion 1,0 0,8 64% 0,6 p<0,001 0,4 17% 0,2 0,0 0 5 10 15 Tim ( ea ) e Y rs Moucari et al. J Hepatol 2009
    40. 40. EVOLUTION (10 ans) APRÈS TRAITEMENT IFN AgHBs+ AgHBs-• CHC : 6 0• Ascite : 5 0• Hemorhagie: 0 0• Transplantation: 0 0• Mortalité (CHC): 4 0 Moucari et al. J Hepatol 2009
    41. 41. RESULTS WITH INTERFERON
    42. 42. INCIDENCE OF HBsAg LOSS ACCORDING TO RESPONSE TO IFN (HBe seroconversion) 1,0 0,8 Réponse : 64% 0,6 p<.001 0,4 Seroconversion Non réponse : 17% 0,2 Cumulative Incidence of HBsAg 0,0 0 5 10 15 Tim (Y rs e ea ) Moucari et al. J Hepatol 2009
    43. 43. OUTCOME (10 years) AFTER IFN THERAPY HBsAg+ HBsAg- • HCC : 6 0 • Ascitis : 5 0 • Hemorhage: 0 0 • Transplantation: 0 0 • Mortality (HCC): 4 0 Moucari et al. J Hepatol 2009
    44. 44. PEG IFNHBeAg negative CHB
    45. 45. HBsAg LOSS after PEG IFN ± LAM 12 11 9 6 5 0% 1 an 2 ans 3 ans 4 ans 5 ansMarcellin et al. NEJM 2004Marcellin et al. Gastroenterology 2009Marcellin et al. Hepatology International. In press
    46. 46. HBsAg LOSS 64% of the patients HBV DNA negative 12 11 9 6 5 0% 1 an 2 ans 3 ans 4 ans 5 ansMarcellin et al. NEJM 2004Marcellin et al. Gastroenterology 2009Marcellin et al. APASL 2009
    47. 47. HOW TO TREAT EASL Guidelines HBeAg + or HBeAg -• EASL Clinical Practice Guidelines: Management of chronic hepatitis B.J Hepatol 2009
    48. 48. HOW TO TREAT EASL Guidelines HBeAg + or HBeAg -PEG IFNHBV DNA < 7 log (copies)*ALT > 3N • 2 million IU • EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009
    49. 49. HOW TO TREAT EASL Guidelines HBeAg + or HBeAg -PEG IFNHBV DNA < 7 log (copies)*ALT > 3N HBV DNA < 1 log at S12 • 2 million IU • EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009
    50. 50. HOW TO TREAT EASL Guidelines HBeAg + or HBeAg -PEG IFN ANALOGUEHBV DNA < 7 log (copies)* Entecavir or TenofovirALT > 3N or Telbivudine HBV DNA < 1 log at S12 • 2 million IU • EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009
    51. 51. HOW TO TREAT EASL Guidelines HBeAg + or HBeAg -PEG IFN ANALOGUEHBV DNA < 7 log (copies)* Entecavir or TenofovirALT > 3N or Telbivudine HBV DNA < 1 log at S12 • 2 million IU • EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009
    52. 52. HOW TO TREAT EASL Guidelines HBeAg + or HBeAg -PEG IFN ANALOGUEHBV DNA < 7 log (copies)* Entecavir or TenofovirALT < 3N or Telbivudine HBV DNA < 1 log at S12 If HBV DNA + at S24-48 • 2 million IU Change analogue • EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009
    53. 53. THE ROLE OF HBsAg QUANTIFICATION
    54. 54. HBsAg ACCORDING TO TREATMENT Weeks LAMMedian log10 IU/mL PEG-IFNα-2a + LAM PEG-IFNα-2a Treatment Marcellin et al. Hepatology International. In press
    55. 55. HBsAg Kinetics: PEG IFNSVR (+) HBsAg (Log10 U/ml)HBV DNA (Log10 copies/ml) Treatment Moucari et al. Hepatology 2009
    56. 56. HBsAg Kinetics: PEG IFNSVR (-) HBsAg (Log10 U/ml)HBV DNA (Log10 copies/ml) Moucari et al. Hepatology 2009
    57. 57. Quantification of HBsAg: “Stopping Rule”Early Serological Response = 0.5 log at W12 ESR + PPV = 89 % 48 Patients SVR treated with Sustained Virological PEG IFN a2a response ESR - NPV = 90 % Moucari et al. Hepatology 2009
    58. 58. THE FUTURE OF THERAPYFOR HBV PEG IFN + NUC
    59. 59. PEG IFN + LAM SERUM HBV DNA On-treatment 7 Mean HBV DNA (log10 cp/mL) PEG IFN a2a 6 + placebo 5 PEG IFN a2a + lamivudine 4 – 4.1 lamivudine 3 – 4.2 0.9 log – 5.0 2 0 6 12 18 24 30 36 42 48 Study weekMarcellin et al. NEJM 2004
    60. 60. PEG IFN + Telbivudine HBsAg decline baseline to week 24 Time on treatment Baseline Week 12 Week 24 PEG 42 42 42 LDT 46 46 46 LDT+PEG 16 16 16Marcellin et al. EASL 2010
    61. 61. PEG IFN + Tenofovir - 36 patients - 8 (22%) with HBsAg drop > 0.5 log at 24 weeks - All with SVR - 4 (11%) HBsAg negative at 24 weeks post-TXMarcellin et al. AASLD 2011
    62. 62. HBsAg kinetics according to treatment responseLog10 IU/mlMarcellin et al. AASLD 2011
    63. 63. SVR patient with HBsAg lossLog10 IU/ml Marcellin et al. AASLD 2011
    64. 64. ConclusionLa quantification de l’AgHBs a une forte VPN:- AgHBs à J0 > 3000 UI: 89%- AgHBs diminué de moins de 0,5 log à S24: 86%Ces résultats suggèrent qu’il est possible desélectionner les bons répondeurs avanttraitement et de considérer un arrêt à S24.
    65. 65. PERSPECTIVAS L’AVENIR?
    66. 66. PERSPECTIVASTraitement individualisé

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