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 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%

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

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

Where do carriers come from?

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

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:

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:

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:

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

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

HBV Notifications in England & Wales

HBV Notifications in England & Wales (1990 to 2003)

HBeAg+ve HIGH-LEVEL REPLICATION LOW-LEVEL REPLICATION

HBeAg+ve HBeAg-ve HIGH-LEVEL REPLICATION LOW-LEVEL REPLICATION

HIGH-LEVEL REPLICATION LOW-LEVEL REPLICATION HBeAg+ve HBeAg-ve

HBeAg+ve HBeAg-ve HIGH-LEVEL REPLICATION LOW-LEVEL REPLICATION

HBeAg+ve HBeAg-ve HIGH-LEVEL REPLICATION LOW-LEVEL REPLICATION

HBV DEATH HBeAg+ve HBeAg-ve HIGH-LEVEL REPLICATION LOW-LEVEL REPLICATION

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

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

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.

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

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

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

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

HBeAg 8% per annum Spontaneous HBeAg Seroconversion Italian children Bortolotti et al J Hep HBeAg +ve Median age 5 at entry

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

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

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

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

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?

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

HBV DEATH 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

HBV DEATH 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

HBV DEATH 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

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

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

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?

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

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

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

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

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

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

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

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

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

HBeAg Seroconversion Spontaneous vs Nucleosides vs Interferon

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

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

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

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

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

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

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

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

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

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

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

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?