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Ratziu virus et immunosuppression du 2012

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Ratziu virus et immunosuppression du 2012

  1. 1. Immunosuppression et Inféction par les Virus des Hépatites <ul><li>VHB </li></ul><ul><li>VHC </li></ul>
  2. 2. Circonstances de Survenue des Réactivations Virales B <ul><li>En cours de chimiothérapie pour tumeurs solides </li></ul><ul><li>En cours de chimiothérapie pour lymphome </li></ul><ul><li>Risque majoré en cas de traitement corticoïde </li></ul><ul><li>Après greffe de moelle </li></ul><ul><li>Après traitement par anti-TNF-alfa </li></ul>
  3. 3. Réactivation Virale B en Cours d’Immunosuppression <ul><li>Phase initiale: augmentation de la réplication virale; infection généralisée des hépatocytes </li></ul><ul><li>Phase secondaire: restauration de la réponse immunitaire: destruction immuno-médiée des hépatocytes infectés (hépatite aigue, insuffisance hépatique, décès) </li></ul>
  4. 4. GB hépatite chimio HBVDNA t chimio chimio
  5. 5. Chimiothérapie chez les Porteurs de l’AgHBs <ul><li>Charge virale élevée avant chimiothérapie </li></ul><ul><li>Immunosuppression marquée </li></ul><ul><li>Corticoides et anthracyclines, rituximab </li></ul><ul><li>Risque faible mais réel chez les patients AgHBs neg, anti-HBs pos </li></ul>Facteurs de risque de réactivation virale
  6. 6. Hépatites chez les Porteurs d’AgHBs en Chimiothérapie <ul><li>Etude prospective, Hong-Kong </li></ul><ul><li>626 patients atteints de cancer (sein, digestif, poumon, lymphome, ORL, gynécologique, leucémies) </li></ul><ul><li>Portage AgHBs: 12% </li></ul><ul><li>Hépatite chez les porteurs AgHBs: 44% </li></ul>Yeo, J Med Virol 2000
  7. 7. Hépatites chez les Porteurs d’AgHBs en Chimiothérapie <ul><li>Gravité: </li></ul><ul><ul><li>20% ictériques </li></ul></ul><ul><ul><li>20% sévère </li></ul></ul><ul><li>Facteurs de risque: </li></ul><ul><ul><li>Lymphome (40% vs. 14%, p=0.03) </li></ul></ul><ul><ul><li>Age plus jeune </li></ul></ul><ul><ul><li>Anthracyclines, corticoïdes, alcaloïdes </li></ul></ul><ul><ul><li>AgHBe positif </li></ul></ul>
  8. 8. Causes d’Hépatite chez les Porteurs d’AgHBs en cours de Chimiothérapie HBV : 44% Chimiothérapie : 32% HBV chronique 3% HCV : 3% Infiltration néoplasique : 6% Inconnue : 12% N=34 Yeo, J Med Virol 2000
  9. 9. Etude Prospective Réactivation VHB et Lymphome <ul><li>100 patients Chinois atteints de LNH </li></ul>AgHBs (n=27) antiHBc (n=18) antiHBs (n=33) Tout neg (n=27) % avec hépatite 67 11 21 5 Dont réactivation HBV (%) 72 9* 5* 0 Lok, Gastro 1991 * Séroréversion AgHBs <ul><li>Hépatites ictériques 6/13, mortelles 2/13 </li></ul><ul><li>Surviennent entre 1ere et 5 e cure chimio </li></ul>
  10. 10. Corticoïdes et VHB <ul><li>Interactions moléculaires: </li></ul><ul><ul><li>Région de réponse aux corticoïdes dans le promoteur du VHB </li></ul></ul><ul><ul><li>Activation de l’expression du VHB par les corticoïdes in vitro </li></ul></ul><ul><li>Traitement forte dose: </li></ul><ul><ul><li>Augmentation de la réplication et de l’expression de l’AgHBs et HBc </li></ul></ul><ul><ul><li>Diminution de la fonction cellulaire T </li></ul></ul><ul><li>Sevrage: </li></ul><ul><ul><li>Rebond de la cytotoxicité T </li></ul></ul><ul><ul><li>Baisse de l’HBVDNA </li></ul></ul><ul><ul><li>Élévation des ALAT, hépatite avec nécrose parfois sévère </li></ul></ul>
  11. 11. Etude Randomisée Chimio +/- Corticoides chez LNH AgHBs + <ul><li>Réactivation B </li></ul><ul><li>Hépatite sévère </li></ul><ul><li>(ALT >10 N) </li></ul>72% 44% 38% 13% 0.02 0.03 Corticoides Ss Corticoides Cheng, Hepatology 2003 p Chimiothérapie
  12. 12. Profils Cliniques de Réactivation B en cours de Chimiothérapie Cheng, Hepatology 2003
  13. 13. Hépatite B Occulte et Chimiothérapie <ul><li>244 pts AgHBs neg devant avoir une chimiothérapie pour lymphome (2000-2005) </li></ul><ul><li>62% antiHBc + </li></ul><ul><li>Incidence des hépatites « de novo » (N=8) </li></ul>Chimio thérapie HBVDNA (2log) AgHBs+ (sero reversion) ALT 10 sem 8 sem Lau, Gastroenterology 2006
  14. 14. Portage Occulte du VHB et Hépatite de Novo 100 21 Hepatite De novo Pas d’Hepatite De novo PORTAGE OCCULTE VHB <ul><li>Portage occulte: PCR </li></ul><ul><li>nichée positive sur 2 des </li></ul><ul><li>3 primers </li></ul><ul><li>Sur prélèvements avant </li></ul><ul><li>la chimiothérapie </li></ul>Lau, Gastroenterology 2006
  15. 15. Portage Occulte du VHB - Conséquences en Extrême-Orient <ul><li>Transfusion (Liu, J Hepatol 2006) </li></ul><ul><ul><li>Receveurs naïfs pour le VHB (transas N, AgHBs neg, PCR neg) </li></ul></ul><ul><ul><li>Incidence hépatite transfusionnelle B: 1% (5/327) soit 7-40 fois plus que dans les pays Occidentaux </li></ul></ul><ul><ul><li>Même chez les enfants vaccinés; peu sévères </li></ul></ul><ul><li>Greffe de moelle (Hui J Hepatol 2005) </li></ul><ul><ul><li>15% de portage occulte du B parmi les donneurs de moelle; pas de prédiction par l’anti HBc; faible charge virale (<400 copies/ml) </li></ul></ul><ul><ul><li>Transmission du VHB possible, hépatite aigue chez le receveur </li></ul></ul>
  16. 16. Stratégies Thérapeutiques
  17. 17. Stratégies thérapeutiques Analogues Nucléosi(ti)diques <ul><li>Préventive précoce </li></ul>Traitements par excès Durée prolongée (YMDD) <ul><li>Préventive retardée </li></ul><ul><li>Symptomatique </li></ul>Échecs Surveillance mal définie Échecs, formes graves Inconvénients
  18. 18. Réactivation virale symptomatique en cours de chimiothérapie <ul><li>30 patients </li></ul><ul><li>Chimiothérapie pour lymphome </li></ul><ul><li>Prévention ou traitement retardé par la lamivudine </li></ul><ul><li>Surveillance HBVDNA toutes les 2 semaines </li></ul>Lau Gastroenterology, 2003
  19. 19. Prévention par la Lamivudine de la Réactivation virale B en cours de Chimiothérapie Réactivation virale (%) Hépatite, n (%) Prophylaxie (AgHBs, n=15) Retardée (AgHBs, n=15) 0 53 0 7/8 (88) Délai réactivation (médiane, sem) 16 Délai réactivation hépatite (médiane, extrêmes, sem) 1 (0-11) !!! - - Lau, Gastroenterology 2003
  20. 20. Prévention par la Lamivudine de la Réactivation virale B en cours de chimiothérapie <ul><li>Continuer l’administration de la lamivudine jusqu’à 6-9 mois après la dernière cure de chimiothérapie </li></ul><ul><li>Continuer la surveillance 4 mois après l’arrêt de la lamivudine </li></ul>
  21. 21. Chimioembolisation et Réactivation VHB <ul><li>Cirrhoses virale B avec CHC et ALT<2.5 N, HBVDNA<log7 copies/ml; (75% PCR +) </li></ul>Jang, Hepatology 2006 <ul><li>Réactivation après un délai médian de 3.5 mois; HBVDNA > log 4 facteur prédictif </li></ul>Réactivation B Hépatite clinique B Lamivudine (n=36) Contrôle (n=37) 3% (1/36) 41% (15/37) 3% (1/36) 30% (11/37)
  22. 22. Greffe de Moelle et VHB
  23. 23. Greffe de Moelle chez les Patients AgHBs: Epidémiologie et Clinique <ul><li>Prévalence de l’Ag HBs chez les receveurs de greffe de moelle: </li></ul><ul><ul><li>Europe: 3.5% </li></ul></ul><ul><ul><li>Asie (Hong-Kong) 10% </li></ul></ul><ul><li>Immunosupression en préparation à la greffe, en entretien après allogreffe, chimiothérapie ponctuelle pour complications de la greffe </li></ul><ul><li>Réactivation virale B; augmentation risque GVH </li></ul>
  24. 24. Réactivation VHB et Greffe de Moelle <ul><li>137 patients Chinois consécutifs ayant eu une greffe de moelle </li></ul>AgHBs (n=23) antiHBs (n=37) Tout neg (n=77) Hépatite (due VHB) 13(11) 5(1) 14(1) Ictère/ déces 3/4 0/0 3/0 Lau, Blood 2002
  25. 25. Réactivation B après Greffe de Moelle <ul><li>La moitié des patients porteurs de l’AgHBs avant la greffe de moelle feront une réactivation B; délai 3-4 mois </li></ul><ul><li>Des rares cas de réactivation existent chez les patients AgHBs neg, Ac anti HBs et anti-HBc positifs surtout si PCR positive </li></ul>Lau, Blood 2002
  26. 26. Etude Cas-Témoins Lamivudine en Prévention de la Réactivation B après Greffe de Moelle Hépatite par réactivation virale B Préventive par Lamivudine (n=20) Pas de Prévention (n=20) 5% (1/20) 45% (9/20) Délai réactivation (moy, j) 117 252 Lau Hepatology, 2002
  27. 27. Prévention par la Lamivudine de la Réactivation B après Greffe de Moelle Lau Hepatology, 2002 Lamivudine: seul fact indépendant de l’absence de réactivation B 94% 54% 1 an
  28. 28. Hepatitis outcomes of 110 CD20+ lymphoma patients receiving rituximab-based treatment Pei , Ann Hematol 2010; 89:255–262
  29. 29. Clinical features of the four patients with de novo hepatitis B Pei , Ann Hematol 2010; 89:255–262
  30. 30. Prévention de la réactivation B en hémato-oncologie Lalazar Br J Hematol 2007
  31. 31. Immunosuppression et Inféction par les Virus des Hépatites <ul><li>VHB </li></ul><ul><li>VHC </li></ul>
  32. 32. <ul><li>Leucémie aigue myeloide: 4 % </li></ul><ul><li>Leucémies chroniques, myelome, lymphomes: 3 % </li></ul>Prévalence Actuelle (>1993) de l’infection VHC chez les Candidats à la Greffe de Moelle
  33. 33. Chimiothérapie et Portage du VHC <ul><li>Maladies hématologiques malignes (n=33): </li></ul><ul><ul><li>Élévation ALT 50% cas </li></ul></ul><ul><ul><li>Délai 2-3 semaines après arrêt chimiothérapie </li></ul></ul><ul><ul><li>1 seul cas > 10N </li></ul></ul><ul><li>REACTIVATIONS PLUS RARES ET BEAUCOUP MOINS SEVERES QUE POUR LE VHB </li></ul>
  34. 34. Corticothérapie et Portage du VHC <ul><li>Diminution des transaminases, augmentation de la charge virale en cours de corticothérapie </li></ul><ul><li>Rebond asymptomatique des transaminases à l’arrêt </li></ul><ul><li>PAS D’EFFET SUR L’ÉVOLUTION DE L’HEPATITE CHRONIQUE C SI CORTICOTHÉRAPIE DE COURTE DURÉE </li></ul>
  35. 35. Risques induits par l’infection VHC après Greffe de Moelle <ul><li>Maladie veino-occlusive </li></ul><ul><ul><li>Risque accru de MVO sévère (X10) </li></ul></ul><ul><ul><li>Si F3, F4 gros risque de MVO sévère, MOF et mortalité: CID greffe </li></ul></ul><ul><li>Poussée d’hépatite </li></ul><ul><li>Progression d’une hépatopathie chronique C </li></ul>
  36. 36. VHC et Greffe de Moelle <ul><li>Chimiothérapie d’induction: </li></ul><ul><ul><li>Baisse des transaminases, élévation de la charge virale VHC </li></ul></ul><ul><ul><li>Sans effets pathogènes hépatiques </li></ul></ul><ul><li>Élévation asymptomatique des transaminases 60 à 120 j après la greffe (reconstitution immunitaire) </li></ul><ul><li>Diagnostic différentiel avec la GVH (+++ car Trt IS) </li></ul><ul><li>Transitoire (cas sévères exceptionnels, rechercher HSV, VZV, adenovirus) </li></ul><ul><li>Hépatite chronique C chez les greffés de moelle: impact négatif (mortalité par cirrhose) seulement à partir de la deuxième décennie après la greffe </li></ul>
  37. 37. Diagnostics Différentiels Hépatite Post Greffe <ul><li>Maladie veino-occlusive </li></ul><ul><li>Maladie du greffon contre l’hôte </li></ul><ul><li>Sepsis </li></ul><ul><li>Insuffisance cardiaque </li></ul><ul><li>Infiltration tumorale </li></ul><ul><li>Hépatite à CMV </li></ul><ul><li>Hépatite à Herpes Virus </li></ul><ul><li>Hépatite médicamenteuse </li></ul>

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