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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 Marcellin tt vhb final Presentation Transcript

  • TRAITEMENTDE L’HÉPATITE B Patrick Marcellin
  • 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
  • POURQUOI TRAITER?
  • 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
  • OBJECTIFS DU TRAITEMENT Anti-Hbe Anti-HBs AgHBeADN VHB négatif positif AgHBs positif négatif négatif TEMPS
  • SEROCONVERSION HBs:LE CHAMPION DES CRITÈRES Seroconversion HBs SeroconversionADN VHB HBe négatif 1 3 2
  • QUI TRAITER
  • 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
  • HEPATITE CHRONIQUE B =MULTIPLICATION VIRALE/RÉPONSE IMMUNITAIRE MULTIPLICATION RÉPONSE VIRALE IMMUNITAIRE
  • PHASE DE TOLÉRANCE IMMUNITAIRE = MAUVAISE RÉPONSE ADN VHB > 7 log ALAT < N AgHBe + PBH = A1F1 RÉPONSE IMMUNITAIRE MULTIPLICATION VIRALE
  • PHASE DE RÉACTION IMMUNITAIRE = BONNE RÉPONSEADN VHB < 7 log ALAT > NAgHBe +/- PBH > A1F1 MULTIPLICATION VIRALE RÉPONSE IMMUNITAIRE
  • 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
  • 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
  • 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
  • QUI TRAITER Guidelines EASL AgHBe + et AgHBe -EASL Clinical Practice Guidelines: Management of chronic hepatitis B.J Hepatol 2009
  • QUI TRAITER Guidelines EASL AgHBe + et AgHBe - ADN VHB < 4 log ALAT = NEASL Clinical Practice Guidelines: Management of chronic hepatitis B.J Hepatol 2009
  • 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
  • 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
  • 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
  • COMMENT TRAITER
  • TREATMENT OF CHRONIC HEPATITIS B Two Strategies- Analogues: pure antivirals maintained response- Interferon: antiviral + immune modulator sustained response
  • NUCs vs IFN NUCs IFN- Finite duration - +- Sustained response - +- No resistance +/- +- Oral administration + -- Good tolerance + -- Low cost - +?
  • RESULTS WITH ANALOGUES
  • 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
  • ANALOGUES REGISTERED FOR THETREATMENT OF CHRONIC HEPATITIS B - Lamivudine - - Adefovir - - Telbivudine + - Entecavir +++ - Tenofovir +++
  • ENTECAVIR
  • 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
  • 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
  • TENOFOVIR
  • 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
  • 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
  • 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
  • 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-
  • 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
  • WHY HBsAg IS THE MAINOBJECTIVE OF THERAPY
  • 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
  • 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
  • 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
  • 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
  • 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
  • RESULTS WITH INTERFERON
  • 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
  • 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
  • PEG IFNHBeAg negative CHB
  • 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
  • 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
  • HOW TO TREAT EASL Guidelines HBeAg + or HBeAg -• EASL Clinical Practice Guidelines: Management of chronic hepatitis B.J Hepatol 2009
  • 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
  • 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
  • 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
  • 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
  • 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
  • THE ROLE OF HBsAg QUANTIFICATION
  • HBsAg ACCORDING TO TREATMENT Weeks LAMMedian log10 IU/mL PEG-IFNα-2a + LAM PEG-IFNα-2a Treatment Marcellin et al. Hepatology International. In press
  • HBsAg Kinetics: PEG IFNSVR (+) HBsAg (Log10 U/ml)HBV DNA (Log10 copies/ml) Treatment Moucari et al. Hepatology 2009
  • HBsAg Kinetics: PEG IFNSVR (-) HBsAg (Log10 U/ml)HBV DNA (Log10 copies/ml) Moucari et al. Hepatology 2009
  • 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
  • THE FUTURE OF THERAPYFOR HBV PEG IFN + NUC
  • 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
  • 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
  • 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
  • HBsAg kinetics according to treatment responseLog10 IU/mlMarcellin et al. AASLD 2011
  • SVR patient with HBsAg lossLog10 IU/ml Marcellin et al. AASLD 2011
  • 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.
  • PERSPECTIVAS L’AVENIR?
  • PERSPECTIVASTraitement individualisé