when, how and which patient to treat with hbv infection
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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) - PowerPoint PPT PresentationTRANSCRIPT
When, how and which patient to treat with HBV infection.
David MutimerQueen Elizabeth Hospital
Birmingham, England.
BSG Post-graduate CourseMarch 20th 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 MutimerQueen Elizabeth Hospital
Birmingham, England.
BSG Post-graduate CourseMarch 20th 2006.
= who?
Where do carriers come from?
Where do carriers come from?
Acute infection
Chronic infection“carrier”
<5% risk
Acute HBV infectionn=2,876
Resolution & immunityn=2,660
Chronic infectionn=216
Transmission of HBV in England & WalesHahné et al J Clin Virol 2004;29:211-220.
To E & W From E & WNet
migration
Migrants 300,820 210,600 90,220
Migrants with chronic
HBV9,922 3,351 6,571
Transmission of HBV in England & WalesHahné et al J Clin Virol 2004;29:211-220.
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 & WalesHahné et al J Clin Virol 2004;29:211-220.
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
0
100
200
300
400
500
600
700
800
1990 1992 1994 1996 1998 2000 2002 2004
year
notif
icat
ions
male female
HBV Notifications in England & Wales (1990 to 2003)
0
500
1000
1500
2000
2500
3000
3500
4000
notif
icat
ions
<1 1 to 4 5 to 9 10 to14
15 to24
25 to34
35 to44
45 to54
55 to64
> 64
age group
0 20 40 50
HBeAg+ve HIGH-LEVEL REPLICATION
LOW-LEVEL REPLICATION
0 20 40 50
HBeAg+ve
HBeAg-ve
HIGH-LEVEL REPLICATION
LOW-LEVEL REPLICATION
HIGH-LEVEL REPLICATION
LOW-LEVEL REPLICATION
0 20 40 50
HBeAg+ve
HBeAg-ve
0 20 40 50
HBeAg+ve
HBeAg-ve
HIGH-LEVEL REPLICATION
LOW-LEVEL REPLICATION
0 20 40 50
HBeAg+ve
HBeAg-ve
HIGH-LEVEL REPLICATION
LOW-LEVEL REPLICATION
HBV DEATH
0 20 40 50
HBeAg+ve
HBeAg-ve
HIGH-LEVEL REPLICATION
LOW-LEVEL REPLICATION
0
20
40
60
80
100
120
0 to 10
11 to 20
21 to 30
31 to 40
41 to 50
51 to 60
61 to 70
> 70
num
ber
tran
spla
nted
male female
Liver Transplantation for Chronic HBV
UK Transplant data : 1990-2003
Male:female297:47 (6:1)
Median age 50
When , how and which patient to treat with HBV infection.
David MutimerQueen Elizabeth Hospital
Birmingham, England.
BSG Post-graduate CourseMarch 20th 2006.
= who?
When , how and which patient to treat with HBV infection.
David MutimerQueen Elizabeth Hospital
Birmingham, England.
BSG Post-graduate CourseMarch 20th 2006.
0 20 40 50
HBeAg+ve
Aim of Treatment• HBeAg seroconversionChoice of treatment• Interferon• Lamivudine• AdefovirBut!• High rate of spontaneous seroconversion• Little increase with treatment• A lot of females!
HIGH-LEVEL REPLICATION
0 20 40 50
HBeAg+ve
Aim of Treatment• HBeAg seroconversionChoice of treatment• Interferon• Lamivudine• AdefovirBut!• High rate of spontaneous seroconversion• Little increase with treatment• A lot of females!
HIGH-LEVEL REPLICATION
0 20 40 50
HBeAg+ve
Aim of Treatment• HBeAg seroconversionChoice of treatment• Interferon• Lamivudine• AdefovirBut!• High rate of spontaneous seroconversion• Little increase with treatment• A lot of females!
HIGH-LEVEL REPLICATION
Spontaneous HBeAg SeroconversionItalian children
Bortolotti et al J Hep 1998168 HBeAg +veMedian age 5 at entry
HBeAg seroconversion @ 8% per annum
Spontaneous HBeAg SeroconversionItalian children
Bortolotti et al J Hep 1998168 HBeAg +veMedian 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
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
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
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
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
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
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
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
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
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
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
IFN or Lamivudine or Adefovir?IFN Lamivudine Adefovir
HBeAg seroconversion
superiorbut prolonged treatment associated with
ongoing HBeAg loss
HBsAg seroconversion
superiorreports of HBsAg loss (genotype dependent)
prolonged suppression
inferioruntil resistance
(20% per annum)superior
(resistance <5% pa)
tolerability inferior superior superior
safetysupervision
autoimmunityexcellent excellent
cost expensive inexpensive expensive
IFN or Lamivudine or Adefovir?IFN Lamivudine Adefovir
HBeAg seroconversion
superiorbut prolonged treatment associated with
ongoing HBeAg loss
HBsAg seroconversion
superiorreports of HBsAg loss (genotype dependent)
prolonged suppression
inferioruntil resistance
(20% per annum)superior
(resistance <5% pa)
tolerability inferior superior superior
safetysupervision
autoimmunityexcellent excellent
cost expensive inexpensive expensive
HBeAg SeroconversionSpontaneous vs Nucleosides vs Interferon
0%
5%
10%
15%
20%
25%
30%
HB
eAg
seoc
onve
rsio
n
spontaneous nucleosides interferon
spontaneous
nucleosides
interferon
Incidence
Incidence of HBeAg Seroconversion in Patients Treated with Adefovir or Lamivudine
0%
10%
20%
30%
40%
50%
60%
% s
eroc
onve
rsio
n
6 12 18 24 36 48
months
ADV
LAM (published)
LAM (B'ham data)
IFN or Lamivudine or Adefovir?IFN Lamivudine Adefovir
HBeAg seroconversion
superiorbut prolonged treatment associated with
ongoing HBeAg loss
HBsAg seroconversion
superiorreports of HBsAg loss (genotype dependent)
prolonged suppression
inferioruntil resistance
(20% per annum)superior
(resistance <5% pa)
tolerability inferior superior superior
safetysupervision
autoimmunityexcellent excellent
cost expensive inexpensive expensive
IFN or Lamivudine or Adefovir?IFN Lamivudine Adefovir
HBeAg seroconversion
superiorbut prolonged treatment associated with
ongoing HBeAg loss
HBsAg seroconversion
superiorreports of HBsAg loss (genotype dependent)
prolonged suppression
inferioruntil resistance
(20% per annum)superior
(resistance <5% pa)
tolerability inferior superior superior
safetysupervision
autoimmunityexcellent excellent
cost expensive inexpensive expensive
Incidence
Incidence of Resistance in Patients Treated with Adefovir, Lamivudine, Entecavir, FTC, LdT
0%
24%
0%
13%
5% 2%
42%
0%
18%
14% 4%
53%
15%
70%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
year 1 year 2 year 3 year 4
ADV
LAM
ENT
FTC
LdT
Incidence of resistance
IFN or Lamivudine or Adefovir?IFN Lamivudine Adefovir
HBeAg seroconversion
superiorbut prolonged treatment associated with
ongoing HBeAg loss
HBsAg seroconversion
superiorreports of HBsAg loss (genotype dependent)
prolonged suppression
inferioruntil resistance
(20% per annum)superior
(resistance <5% pa)
tolerability inferior superior superior
safetysupervision
autoimmunityexcellent excellent
cost expensive inexpensive expensive
IFN or Lamivudine or Adefovir?IFN Lamivudine Adefovir
HBeAg seroconversion
superiorbut prolonged treatment associated with
ongoing HBeAg loss
HBsAg seroconversion
superiorreports of HBsAg loss (genotype dependent)
prolonged suppression
inferioruntil resistance
(20% per annum)superior
(resistance <5% pa)
tolerability inferior superior superior
safetysupervision
autoimmunityexcellent excellent
cost expensive inexpensive expensive
IFN or Lamivudine or Adefovir?IFN Lamivudine Adefovir
HBeAg seroconversion
superiorbut prolonged treatment associated with
ongoing HBeAg loss
HBsAg seroconversion
superiorreports of HBsAg loss (genotype dependent)
prolonged suppression
inferioruntil resistance
(20% per annum)superior
(resistance <5% pa)
tolerability inferior superior superior
safetysupervision
autoimmunityexcellent excellent
cost expensive inexpensive expensive
HBV TreatmentLicensed options 2006
Non-cirrhotic CirrhoticPost-transplant
HIV co-infected
HBeAg-positive
HBeAg-negative
HBV TreatmentLicensed options 2006
Non-cirrhotic CirrhoticPost-transplant
HIV co-infected
HBeAg-positive
IFN
Nucleosides
HBeAg-negative
Nucleosides
IFN
HBV TreatmentLicensed options 2006
Non-cirrhotic CirrhoticPost-transplant
HIV co-infected
HBeAg-positive
IFN
NucleosidesNucleosides
HBeAg-negative
Nucleosides
IFNNucleosides
HBV TreatmentLicensed options 2006
Non-cirrhotic CirrhoticPost-transplant
HIV co-infected
HBeAg-positive
IFN
NucleosidesNucleosides Nucleosides
HBeAg-negative
Nucleosides
IFNNucleosides 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?