1. When, how and which patient to treat with HBV infection. David Mutimer Queen Elizabeth Hospital Birmingham, England. BSG Post-graduate Course March 20 th 2006.

2. WHO Global Burden of Disease 2000 Cirrhosis (all causes) 785,000 deaths per annum from liver failure (cirrhosis, all causes)  HBV 40%  HCV 25%  Other causes 35% 600,000 deaths per annum from HCC  HBV 57%  HCV18%  Other causes 25%

3. WHO Global Burden of Disease 2000 Mortality from HBV & HCV 1 million deaths per annum  including deaths from cirrhosis and/or liver cancer HBV causes 644,000 deaths per annum HCV causes 325,000 deaths per annum

5. When, how and which patient to treat with HBV infection. David Mutimer Queen Elizabeth Hospital Birmingham, England. BSG Post-graduate Course March 20 th 2006. = who?

6. Where do carriers come from?

7. Where do carriers come from? Acute infection Chronic infection “carrier” <5% risk

8. Acute HBV infection n=2,876 Resolution & immunity n=2,660 Chronic infection n=216 Transmission of HBV in England & Wales Hahné et al J Clin Virol 2004;29:211-220.

9. To E & WFrom E & W Net migration Migrants300,820210,60090,220 Migrants with chronic HBV 9,9223,3516,571 Transmission of HBV in England & Wales Hahné et al J Clin Virol 2004;29:211-220.

10. New chronic infections in England & Wales (per annum) Arising in E & W  n = 216 (3%) Coming from abroad  n = 6,571 (97%) Transmission of HBV in England & Wales Hahné et al J Clin Virol 2004;29:211-220.

11. Where do carriers come from? Acute infection Chronic infection “carrier” <5% risk “carrier” from abroad

12. Where do carriers come from? Acute infection Chronic infection “carrier” <5% risk “carrier” from abroad

14. HBV Notifications in England & Wales

15. HBV Notifications in England & Wales (1990 to 2003)

18. 0 20 40 50 HBeAg+ve HIGH-LEVEL REPLICATION LOW-LEVEL REPLICATION

19. 0 20 40 50 HBeAg+ve HBeAg-ve HIGH-LEVEL REPLICATION LOW-LEVEL REPLICATION

20. HIGH-LEVEL REPLICATION LOW-LEVEL REPLICATION 0 20 40 50 HBeAg+ve HBeAg-ve

21. 0 20 40 50 HBeAg+ve HBeAg-ve HIGH-LEVEL REPLICATION LOW-LEVEL REPLICATION

22. 0 20 40 50 HBeAg+ve HBeAg-ve HIGH-LEVEL REPLICATION LOW-LEVEL REPLICATION

23. HBV DEATH 0 20 40 50 HBeAg+ve HBeAg-ve HIGH-LEVEL REPLICATION LOW-LEVEL REPLICATION

24. Liver Transplantation for Chronic HBV UK Transplant data : 1990-2003 Male:female 297:47 (6:1) Median age 50

25. When, how and which patient to treat with HBV infection. David Mutimer Queen Elizabeth Hospital Birmingham, England. BSG Post-graduate Course March 20 th 2006. = who?

27. When, how and which patient to treat with HBV infection. David Mutimer Queen Elizabeth Hospital Birmingham, England. BSG Post-graduate Course March 20 th 2006.

28. 0 20 40 50 HBeAg+ve Aim of Treatment HBeAg seroconversion Choice of treatment Interferon Lamivudine Adefovir But! High rate of spontaneous seroconversion Little increase with treatment A lot of females! HIGH-LEVEL REPLICATION

29. 0 20 40 50 HBeAg+ve Aim of Treatment HBeAg seroconversion Choice of treatment Interferon Lamivudine Adefovir But! High rate of spontaneous seroconversion Little increase with treatment A lot of females! HIGH-LEVEL REPLICATION

30. 0 20 40 50 HBeAg+ve Aim of Treatment HBeAg seroconversion Choice of treatment Interferon Lamivudine Adefovir But! High rate of spontaneous seroconversion Little increase with treatment A lot of females! HIGH-LEVEL REPLICATION

31. Spontaneous HBeAg Seroconversion Italian children Bortolotti et al J Hep 1998 168 HBeAg +ve Median age 5 at entry

32. HBeAg seroconversion @ 8% per annum Spontaneous HBeAg Seroconversion Italian children Bortolotti et al J Hep 1998 168 HBeAg +ve Median age 5 at entry

33. Case 1 20 year old Asian lady HBeAg-positive ALT 50, other LFT’s normal ? liver biopsy

34. Case 1 20 year old Asian lady HBeAg-positive ALT 50, other LFT’s normal ? liver biopsy – I wouldn’t

35. Case 1 20 year old Asian lady HBeAg-positive ALT 50, other LFT’s normal ? liver biopsy – I wouldn’t ? antiviral treatment

36. Case 1 20 year old Asian lady HBeAg-positive ALT 50, other LFT’s normal ? liver biopsy – I wouldn’t ? antiviral treatment – I wouldn’t

37. Case 1 20 year old Asian lady HBeAg-positive ALT 50, other LFT’s normal ? liver biopsy – I wouldn’t ? antiviral treatment – I wouldn’t what happened next?

38. Case 1 20 year old Asian lady HBeAg-positive ALT 50, other LFT’s normal ? liver biopsy – I wouldn’t ? antiviral treatment – I wouldn’t what happened next?  annual review  spontaneous HBeAg seroconversion 2 years later

39. HBV DEATH 0 20 40 50 HBeAg+ve HBeAg-ve Replication after 40 Death wish Always treat! Aim of treatment HBV suppression (HBeAg seroconversion) Choice of treatment Lamivudine Adefovir (Interferon) HIGH-LEVEL REPLICATION

40. HBV DEATH 0 20 40 50 HBeAg+ve HBeAg-ve Replication after 40 Death wish Always treat! Aim of treatment HBV suppression (HBeAg seroconversion) Choice of treatment Lamivudine Adefovir (Interferon) HIGH-LEVEL REPLICATION

41. HBV DEATH 0 20 40 50 HBeAg+ve HBeAg-ve Replication after 40 Death wish Always treat! Aim of treatment HBV suppression (HBeAg seroconversion) Choice of treatment Lamivudine Adefovir (Interferon) HIGH-LEVEL REPLICATION

42. Case 2 47 year old Chinese male HBeAg-negative ALT 55 what else?

43. Case 2 47 year old Chinese male HBeAg-negative ALT 55 what else?  HBV DNA 500,000 copies/ml  US heterogeneous liver  liver biopsy

45. Case 2 47 year old Chinese male HBeAg-negative ALT 55 what else?  HBV DNA 500,000 copies/ml  US heterogeneous liver  liver biopsy antiviral treatment?

46. Case 2 47 year old Chinese male HBeAg-negative ALT 55 what else?  HBV DNA 500,000 copies/ml  US heterogeneous liver  liver biopsy antiviral treatment?  definitely – with nucleosides

47. 0 20 40 50 Treat? High risk population Lowest risk have “self-sorted” Males > females 30’s > 20’s Suppression prevents fibrosis Indefinite suppression possible! Observe? Further spontaneous selection likely Females > males 20’s > 30’s Reduces costs (indefinite duration of treatment) Reduces toxicity (cumulative) Family planning Fibrosis is reversible! HBeAg+ve HBeAg-ve HIGH-LEVEL REPLICATION

48. 0 20 40 50 Treat? High risk population Lowest risk have “self-sorted” Males > females 30’s > 20’s Suppression prevents fibrosis Indefinite suppression possible! Observe? Further spontaneous selection likely Females > males 20’s > 30’s Reduces costs (indefinite duration of treatment) Reduces toxicity (cumulative) Family planning Fibrosis is reversible! HBeAg+ve HBeAg-ve HIGH-LEVEL REPLICATION

49. 0 20 40 50 Treat? High risk population Lowest risk have “self-sorted” Males > females 30’s > 20’s Suppression prevents fibrosis Indefinite suppression possible! Observe? Further spontaneous selection likely Females > males 20’s > 30’s Reduces costs (indefinite duration of treatment) Reduces toxicity (cumulative) Family planning Fibrosis is reversible! HBeAg+ve HBeAg-ve HIGH-LEVEL REPLICATION

50. 0 20 40 50 Treat? High risk population Lowest risk have “self-sorted” Males > females 30’s > 20’s Suppression prevents fibrosis Indefinite suppression possible? Observe? Further spontaneous selection likely Females > males 20’s > 30’s Fibrosis is reversible? Reduces costs (indefinite duration of treatment) Reduces toxicity (cumulative) Family planning HBeAg+ve HBeAg-ve HIGH-LEVEL REPLICATION

51. 0 20 40 50 Treat? High risk population Lowest risk have “self-sorted” Males > females 30’s > 20’s Suppression prevents fibrosis Indefinite suppression possible! Observe? Further spontaneous selection likely Females > males 20’s > 30’s Fibrosis is reversible! Reduces costs (indefinite duration of treatment) Reduces toxicity (cumulative) Family planning HBeAg+ve HBeAg-ve HIGH-LEVEL REPLICATION

52. 0 20 40 50 Treat? High risk population Lowest risk have “self-sorted” Males > females 30’s > 20’s Suppression prevents fibrosis Indefinite suppression possible! Observe? Further spontaneous selection likely Females > males 20’s > 30’s Fibrosis is reversible! Reduces costs (indefinite duration of treatment) Reduces toxicity (cumulative) Family planning LIVER BIOPSY! HBeAg+ve HBeAg-ve HIGH-LEVEL REPLICATION

53. IFN or Lamivudine or Adefovir? IFNLamivudineAdefovir HBeAg seroconversion superior but prolonged treatment associated with ongoing HBeAg loss HBsAg seroconversion superior reports of HBsAg loss (genotype dependent) prolonged suppression inferior until resistance (20% per annum) superior (resistance <5% pa) tolerabilityinferiorsuperior safety supervision autoimmunity excellent costexpensiveinexpensiveexpensive

54. IFN or Lamivudine or Adefovir? IFNLamivudineAdefovir HBeAg seroconversion superior but prolonged treatment associated with ongoing HBeAg loss HBsAg seroconversion superior reports of HBsAg loss (genotype dependent) prolonged suppression inferior until resistance (20% per annum) superior (resistance <5% pa) tolerabilityinferiorsuperior safety supervision autoimmunity excellent costexpensiveinexpensiveexpensive

55. HBeAg Seroconversion Spontaneous vs Nucleosides vs Interferon

56. Incidence Incidence of HBeAg Seroconversion in Patients Treated with Adefovir or Lamivudine

57. IFN or Lamivudine or Adefovir? IFNLamivudineAdefovir HBeAg seroconversion superior but prolonged treatment associated with ongoing HBeAg loss HBsAg seroconversion superior reports of HBsAg loss (genotype dependent) prolonged suppression inferior until resistance (20% per annum) superior (resistance <5% pa) tolerabilityinferiorsuperior safety supervision autoimmunity excellent costexpensiveinexpensiveexpensive

58. IFN or Lamivudine or Adefovir? IFNLamivudineAdefovir HBeAg seroconversion superior but prolonged treatment associated with ongoing HBeAg loss HBsAg seroconversion superior reports of HBsAg loss (genotype dependent) prolonged suppression inferior until resistance (20% per annum) superior (resistance <5% pa) tolerabilityinferiorsuperior safety supervision autoimmunity excellent costexpensiveinexpensiveexpensive

59. Incidence Incidence of Resistance in Patients Treated with Adefovir, Lamivudine, Entecavir, FTC, LdT Incidence of resistance

60. IFN or Lamivudine or Adefovir? IFNLamivudineAdefovir HBeAg seroconversion superior but prolonged treatment associated with ongoing HBeAg loss HBsAg seroconversion superior reports of HBsAg loss (genotype dependent) prolonged suppression inferior until resistance (20% per annum) superior (resistance <5% pa) tolerabilityinferiorsuperior safety supervision autoimmunity excellent costexpensiveinexpensiveexpensive

61. IFN or Lamivudine or Adefovir? IFNLamivudineAdefovir HBeAg seroconversion superior but prolonged treatment associated with ongoing HBeAg loss HBsAg seroconversion superior reports of HBsAg loss (genotype dependent) prolonged suppression inferior until resistance (20% per annum) superior (resistance <5% pa) tolerabilityinferiorsuperior safety supervision autoimmunity excellent costexpensiveinexpensiveexpensive

62. IFN or Lamivudine or Adefovir? IFNLamivudineAdefovir HBeAg seroconversion superior but prolonged treatment associated with ongoing HBeAg loss HBsAg seroconversion superior reports of HBsAg loss (genotype dependent) prolonged suppression inferior until resistance (20% per annum) superior (resistance <5% pa) tolerabilityinferiorsuperior safety supervision autoimmunity excellent costexpensiveinexpensiveexpensive

63. HBV Treatment Licensed options 2006 Non-cirrhoticCirrhotic Post-transplant HIV co-infected HBeAg- positive HBeAg- negative

64. HBV Treatment Licensed options 2006 Non-cirrhoticCirrhotic Post-transplant HIV co-infected HBeAg- positive IFN Nucleosides HBeAg- negative Nucleosides IFN

65. HBV Treatment Licensed options 2006 Non-cirrhoticCirrhotic Post-transplant HIV co-infected HBeAg- positive IFN Nucleosides HBeAg- negative Nucleosides IFN Nucleosides

66. HBV Treatment Licensed options 2006 Non-cirrhoticCirrhotic Post-transplant HIV co-infected HBeAg- positive IFN Nucleosides HBeAg- negative Nucleosides IFN Nucleosides

67. Who and how to treat HBV? The patient with likely progressive liver damage  requires viral replication over prolonged period  easier to identify as (s)he gets older  liver biopsy is useful Expert clinical guidelines rely heavily on published clinical trials  which cannot assess strategy of prolonged inhibition of viral replication  which rely on analysis after brief post-treatment follow-up  IFN or nucleosides?