Una sintesi dello stato dell'arte sull'epatite B

1. Epatite da Virus B Cosa c’è di nuovo ? 17 dicembre 2011 _______________________________________ Ambulatorio di Epatologia Divisione di Medicina Interna Ospedale di Biella Paolo Scivetti

4. Acute self-limited HBV infection subclinical hepatitis

5. 2 4 6 8 10 12 14 16 18 1 10 100 HBV HBV-DNA copies x 10 6 /mL ALT U/L 1,000 2,000 ALT 0 Poor induction of early intracellular innate responses 1 Efficient and timely induction of adaptive responses 3 Early HBV-DNA clearance by non-cytolytic mechanisms 4 Liver damage and elimination of infected cells by cythopatic mechanisms 5 NK cells activation 2 0 Early Immune Events in HBV Infection Ferrari C, Mondelli M, 2009 Intrahepatic HBV specific CD8 – T cells

6. SELF-LIMITED HBV Infection Vigorous, Th1-oriented, multispecific acute phase responses Long-lasting protective antibody responses

7. Occult HBV infection (OBI) Does HBV infection ever resolve?

8. The molecular basis of OBI is the persistence of HBV ccc-DNA in the nuclei of hepatocytes

13. Almost all OBI cases are infected in the liver with replication-competent HBV A few are due to replication-defective or HBsAgsynthesis-defective HBV mutants

14. OBI - mechanisms STRONG IMMUNOLOGICAL SUPPRESSION OF VIRAL REPLICATION AND GENE EXPRESSION Anti-HBc + : typical protective immunological memory Resolved infection with immunologic control of the virus Zerbini, 2008

15. Graft survival in 316 HCV-RNA positive transplant recipients according to the HBcAb status of the donor – Turin 2002-2009 Centro Trapianto Fegato “E.S.Curtoni” Università degli Studi di Torino Direttore : Prof. M. Salizzoni

20. Chronic HBV infection

22. Highly deficient HBV-specific T-cell response

24. Chronic evolution Inefficient acute phase immune responses Progressive impairment of protective responses

25. HBeAg  / anti-HBe + chronic HBV infection

28. CONCLUSIONS HBV-DNA T cell efficiency +++ ++ + Immune subjects Asymptomatic carriers Chronic patients Chronic HBV infection comprises a wide spectrum of different virological and immunological situations which are the expression of a complex natural history, where levels of virus replication and levels of T cell reactivity appear to be inversely correlated and where HBV persistence is likely caused by the synergistic effect of different mechanisms, including exhaustion by high antigen concentrations. ALT

30. Therapeutic strategies for CHB

31. Antivirali Inibitori RT e DNApol Therapeutic strategies for CHB

32. Antivirali Inibitori RT e DNApol Specifici  pochi effetti collaterali Terapia soppressiva  life time? Resistenza Therapeutic strategies for CHB

33. Antivirali Inibitori RT e DNApol Specifici  pochi effetti collaterali Terapia soppressiva  life time? Resistenza Therapeutic strategies for CHB

34. Interferoni Antivirali Inibitori RT e DNApol Specifici  pochi effetti collaterali Terapia soppressiva  life time? Resistenza Therapeutic strategies for CHB

35. Interferoni Antivirali Inibitori RT e DNApol Aspecifici  molti effetti collaterali Terapia finita  obiettivo: anti HBs o anti HBe Specifici  pochi effetti collaterali Terapia soppressiva  life time? Resistenza Therapeutic strategies for CHB

36. Indication to HBV Treatment is an Integrated Decision VIRUS LIVER DISEASE STAGE PATIENT PROFILE Treat active virus with active disease Do not treat but observe carefully active virus without disease Stresa Guidelines Individualised strategy

37. Chronic Anti-HBe + Hepatitis B: ALT pattern 0 12 24 months With flares and normalization Without flares With flares and without normalization 73 pts (44.5%) 59 pts (36%) 32 pts (19.5%) A L T Biochemical patterns in 164 untreated patients, 23 months (range 12-36) monthly monitoring Brunetto MR, J Hepatol, 2002

38. Grading and staging necessary before starting treatment + Not necessary for diagnosis Possible use of non invasive methods ? Liver Biopsy in the era of non invasive methods Castera L. et al, Gut 2010

39. HBV DNA : >20.000 UI/L >15 UI/mL ALT: > UNL qualsiasi ALT Considerare il trattamento Trattare Pazienti naïve con epatite cronica HBeAg-positiva PEG IFN o trattamento finito con NA Trattamento indefinito con NA Carosi et al. Dig Liver Dis 2011 Epatite cronica Cirrosi Cirrosi scompensata Fibrosi No Lieve Moderata Severa METAVIR Ishak F0 S0 F1 S 1-2 F2 S3 F3 S4 F4 S5-6

40. Pazienti naïve con epatite cronica HBeAg-negativa HBV DNA : > 2000 UI/mL > 15 UI/mL ALT: > UNL qualsiasi ALT Attività necro- infiammatoria > A2 (METAVIR) qualsiasi PEG IFN Trattamento indefinito con analoghi Considerare il trattamento Trattare Carosi et al. Dig Liver Dis 2011 Epatite cronica Cirrosi Cirrosi scompensata Fibrosi No Lieve Moderata Severa METAVIR Ishak F0 S0 F1 S 1-2 F2 S3 F3 S4 F4 S5-6

41. “… .therapy must reduce HBV DNA to as low a level as possible…. … .to ensure a degree of virological suppression that will lead to biochemical remission, histological improvement and prevention of complications …”

42. L’elevata carica virale si associa ad un’aumentata incidenza di cirrosi

43. L’elevata carica virale si associa ad un’aumentata incidenza di epatocarcinoma

44. Trattamento dell’epatite cronica HBeAg-negativa

45. Real-world study: Italy cohort Virological response to Entecavir (month 30) (HBVDNA < 12 UI/ml) Virological response to Tenofovir (month 18) (HBVDNA undetectable by PCR ) Pts on f-u 418 399 377 334 255 158 Pts on f-u 178 185 176 160 128 88 Lampertico P. et al, AASLD 2010

47. Progressione di malattia nei pazienti trattati con lamivudina rispetto ai trattati con placebo

49. Comparsa di HCC nei pazienti con cirrosi in funzione della risposta virologica a lamivudina

53. La soppressione virologica durante trattamento riduce lo sviluppo e la progressione di varici esofagee nei pazienti con cirrosi HBeAg negativa

55. Regressione istologica della cirrosi nei pazienti trattati a lungo termine con entecavir 0 1 2 3 4 5 6 7 8 9 10 Punteggio fibrosi Ishak 1 2 3 4 5 6 0 n=10 Pazienti (n) Basale Sett 48 Long-term 1. Adapted from Chang T-T et al. Hepatology. 2010 (Article in Press) DOI: 10.1002/hep.23785. Data on File. Bristol-Myers Squibb. Princeton, NJ. # BARA 001 . * Miglioramento: riduzione ≥1 punto

57. Regressione della cirrosi nei pazienti trattati con entecavir