Transcript hepatitis update - Microsoft Office

Viral Hepatitis for the Generalist
Thursday 20th May
Dr Allister Grant
Leicester Liver Unit
Viral Hepatitis- Objectives
• Name the common viral infections affecting the liver
• Understand the epidemiology, natural history,
investigation and treatment of the chronic viral
infection of the liver
– Hepatitis B
– Hepatitis C
• Gain an insight of the role of Hepatitis B in patients
undergoing immunosupression
Viral Infections and Abnormal LFT’s
• Herpes Viruses
– CMV
– EBV
– But also
• VZV
• Herpes Simplex virus
• HHV 6,7,8…..
• Adenovirus
• Influenza
• Hepatitis Viruses
– Acute
• Hepatitis A
• Hepatitis E
• Hepatitis B
– Chronic
• Hepatitis B
• Hepatitis C
• Delta Virus
• HIV
} “Infectious”
Type of Hepatitis
A
Source of
virus
Route of
transmission
Chronic
infection
Prevention
B
C
D
E
feces
blood/
blood/
blood/
blood-derived blood-derived blood-derived
body fluids
body fluids
body fluids
feces
fecal-oral
percutaneous percutaneous percutaneous
permucosal
permucosal
permucosal
fecal-oral
no
yes
pre/postexposure
immunization
pre/postexposure
immunization
yes
yes
blood donor
pre/postscreening;
exposure
risk behavior immunization;
modification risk behavior
modification
no
ensure safe
drinking
water
Hepatitis A - Clinical
Features

Incubation period:
Average 30 days
Range 15-50 days

Jaundice by
age group:
<6 yrs, <10%
6-14 yrs, 40%-50%
>14 yrs, 70%-80%

Complications:

Chronic sequelae:
Fulminant hepatitis
Cholestatic hepatitis
Relapsing hepatitis
None
Hepatitis A Infection
Typical Serological Course
Total anti-HAV
Symptoms
Titre
ALT
Faecal
HAV
IgM anti-HAV
0
1
2
3
4
5
Months after exposure
6
12
24
Hepatitis E - Clinical Features

Incubation period:

Case-fatality rate:

Illness severity:
Average 40 days
Range 15-60 days
Overall, 1%-3%
Pregnant women,
15%-25%
Increased with age

Chronic sequelae:
None identified
Hepatitis E Virus Infection
Typical Serologic Course
Symptoms
ALT
IgG anti-HEV
Titer
IgM anti-HEV
Virus in
stool
0 1
2 3 4 5 6 7 8 9 10 11 1 13
2
Weeks after Exposure
Viral Infections and Abnormal LFT’s
• Herpes Viruses
– CMV
– EBV
– But also
• VZV
• Herpes Simplex virus
• HHV 6,7,8…..
• Adenovirus
• Influenza
• Hepatitis Viruses
– Acute
• Hepatitis A
• Hepatitis E
• Hepatitis B
} “Infectious”
– Chronic
• Hepatitis B
• Hepatitis C
• Delta Virus
• HIV
World
Hepatitis
Day
May 19th
World
Hepatitis
Alliance
Did You Know?
500 million people
worldwide are infected
with Hepatitis B or C
Hepatitis B and C kills
1.5 million people/year
One in 3 people on
the planet have been
exposed to one or both
Viruses
Most of the 500 million
infected do not know
HBV Infection
Acute HBV= cIgM+
Immunity= sAb+
Previous exposure= cAb+
Chronic infection= sAg+
2 Billion Infected with HBV Worldwide
•
Almost half of the world’s
population lives in an area
with high HBV prevalence
2 billion with
evidence of
HBV infection
World population
6 billion
15–25% die of
cirrhosis or
liver cancer
350 million with chronic HBV

500,000 -1,200,000 deaths
yearly due to HBV
complications
Lavanchy D. J Viral Hepatitis 2004; 11: 97-107
The Stages of Chronic HBV Infection
HBeAg
Anti-HBe
HBV-DNA
ALT
immune immune
tolerance clearance
inactive
carrier
reactivation
Inactive carrier?
HBeAg(-)
CHB
Detection limit
HBV DNA
HBeAg(-)
Inactive
carrier
Detection limit
0
3mo
6mo
9mo
12mo
Serum HBV DNA (IU/ml)
HBV DNA Thresholds
1010
109
108
107
106
105
104
103
102
10
HBeAg (+)
CHB
HBeAg (-)
CHB
Inactive
Carrier
State
Management of eAg Negative Hepatitis B
HBsAg +ve, HBeAg -ve
HBV DNA < 2000 IU/ml
Normal ALT
Possible chronic inactive state
s-seroconversion 1-3%/yr
Monitor
ALT/ HBV DNA 3 monthly for 12/12
then if normal ALT every 6-12/12
HBV DNA > 2000 IU/ml
and ALT > 2 x ULN
(or persistently 1-2 x ULN)
ALT abnormal
Liver biopsy
Measure HBV DNA
(unless clinical evidence of cirrhosis
or contraindication)
Advanced fibrosis/ Cirrhosis
(F5-6)
Start indefinite NUC therapy
(ETV* or TDF)
Consider combination therapy
(TDF/ ETV or TDF/LAM)
Moderate or severe
necroinflammation (Metavir ≥ A2,
Ishak grade ≥ 5) and/or fibrosis
(Metavir ≥ F2, Ishak stage ≥ F2)
Start indefinite NUC
monotherapy (ETV* or TDF) unless
s seroconversion
(then consider discontinuing after 612/12)
Draft EM Guidelines based on EASL Guidelines 2009
Mild inflammation (Metavir
A0/1, Ishak grade <5)
and/or No/ Mild Fibrosis
(Metavir/Ishak 0 or 1)
Monitor
3-6/12 ALT/ HBV DNA
If ALT remains abnormal +
HBV DNA > 2000 IU/ml
repeat biopsy after 2-5 yrs
(or annual fibroscan if
available)
Prevalence of HBeAg Negative
Chronic HBV in Italy
HBeAg positive
1975-85: 539 patients
HBeAg negative
2001: 837 patients
10%
42%
58%
Giusti et al, 1991
90%
Gaeta et al, 2003
Where do carriers
come from?
Acute infection
<5% risk
Chronic infection
“carrier”
Where do carriers
come from?
Acute infection
~5% risk
Chronic infection
“carrier”
“carrier” from abroad
Transmission of HBV in England & Wales
Hahné 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%)
QE Hepatitis Database 2005/6
Ethnicity of HBV Patients
HBV Notifications in England & Wales
Cumulative Incidence of Liver Cirrhosis
REVEAL HBV Study
Cumulative incidence of liver
cirrhosis
.4
Baseline HBV DNA Level, copies/mL
37.1%
1.0 x 106 n=627
1.0-9.9x105 n=344
1.0-9.9x104 n=649
300-9.9x103 n=1210
<300 n=944
.3
n=3,774
23.0%
.2
.1
10.0%
6.3%
5.2%
0
0
1
2
3
4
5
6
7
8
Year of follow-up
Uchenna H. I, et al. Gastroenterology 2006; 130:678-686
9
10
11
12
13
P value for log-rank test, <0.001
High Serum HBV DNA Levels are Associated
with Increased Risk of HCC Mortality
HBV DNA
Negative
HBV DNA Low
< 105 copies/mL
RR = 1.7 (0.5-5.7)
p < 0.001 across viral categories
Chen G, et al. J Hepatology 2005; 42 (suppl 2):477A.
Chen G, et al. Hepatology 2005; 40 (suppl 1):594A.
HBV DNA High
> 105 copies/mL
RR = 11.2 (3.6-35.0)
HCV- Natural History
100 Infected HCV Ab pos
80 Develop Chronic Hepatitis
20 Clear the HCV
HCV Ab pos
PCR neg
HCV Ab pos & PCR pos
20 No Harmful Effects
60 Signs/symptoms
20% at 20yrs
50% at 30yrs
Transplantation
Liver Failure
3.9% pa
Liver Cancer
1.4% pa
CIRRHOSIS
Age
Gender
Alcohol
Prevalence of Hepatitis C virus
2001 WHO
UK HCV Prevalence <1%
IV Drug Use
Blood Donation
Screening 1991
2-400,000
Migration
QE Hepatitis Database 2005/6
Hepatitis C
Natural Hx of HCV Cirrhosis
liver fibrosis score
(degree of scarring)
cirrhosis
6
3
0
10
20
30
60
years
liver fibrosis score
(degree of scarring)
6
HCV-pos
(median time 38 years)
cirrhosis
3
0
10
20
30
60
years
liver fibrosis score
(degree of scarring)
6
cirrhosis
immune
suppression
end-stage
renal disease
?
3
0
10
20
30
60
years
Antiviral Therapy
HBV
• Aim is suppression of
replication
 rarely elimination
• HIV treatment paradigm
 suppression prevents disease
• Indefinite treatment
 ? lifelong
• Treatment well tolerated
Antiviral Therapy
HBV
• Aim is suppression of
replication
 rarely elimination
• HIV treatment paradigm
 suppression prevents disease
• Indefinite treatment
 ? lifelong
• Treatment well tolerated
HCV
• Aim is viral eradication
• Treatment of finite duration
• Treatment is poorly tolerated
Pegylated IFN in HBV
Advantages
Disadvantages
Mainly used for eAg positive
disease
• Finite duration of Rx
• Cant use in Cirrhosis
• Stopping rule at 12 weeks
• Side effects ++
• Can seroconvert to eAg
negative disease (30%)
• 48 week course of Rx
• But some do sAg seroconvert
(3%) + some late
• Not good for all genotypes
AB>CD
HBV Genotypes
F
A
C
D
A
B
D
D
D
E
F
A
Fung & Lok, Hepatology 2004;40:790-2
D
C
D Ba
F
C
Bj
Pegylated Interferon
•
•
•
•
•
•
•
•
•
•
•
Neuropsychiatric (aggression, anxiety, depression)
Lethargy
Flu-like symptoms
Neutropenia
Rashes
Anorexia and weight loss
Alopecia
Thyroid dysfunction
Nephrotoxic
Cardiac disturbance (high/low BP or arrhythmia)
Ocular effects
Therapy For HBV is Rapidly Evolving
•
Approved Drugs
–
–
–
–
–
–
•
Conventional Interferons (IFNs)
Pegylated Interferon a-2a (PEG-IFN)
Lamivudine (LMV)
Adefovir (ADV)
Entecavir (ETV) -NICE 2009
Tenofovir (TDF) -NICE 2009
Future Options
–
–
–
–
–
–
X Telbivudine (LdT)- turned down by NICE 2009
Clevudine
Pradefovir
Emtricitabine (Truvada= TDF+Emtricitabine)
Valtorcitabine
…………
Rebound of serum
HBV DNA
>1 log10
cpm
Incidence of Resistance
Incidence of HBV Resistance
Lamivudine resistance (rtL180M+rtM204V/I)
Adefovir resistance (rtN236T/rtA181V)
80%
70%
70%
70%
60%
53%
50%
42%
40%
30%
29%
24%
18%
20%
11%
10%
0%
0%
year 1
3%
year 2
year 3
year 4
year 5
Lai CL, Clin Infect Dis 2003;36:687.
Locarnini et al., EASL 2005.
Potency
Nucleoside analogue
Nucleotide analogue
Anti-HBV drugs
LdT
LAM
ETV
TDF
FTC
ADV
Genetic Barrier
IFN
UK Transplantation for Viral Hepatitis
recipients
Total HCV
Total HBV
Hepatitis C Treatment
• Aim is viral eradication
• Treatment of finite duration
HCV Genotypes
• 6 main genotypes
• Nucleotide diversity > 20%
• Little effect on natural history
• Geographical variation
• Most important determinant of
response to treatment
Ribavirin- adverse effects
Haemolytic anaemia
Thrombocytopenia
Headache
GI disturbance
Alopecia
Anxiety, depression, memory loss, irritability, insomnia
Chest pain
Cough
Gout
HCV Antiviral Treatment
IFN
efficacy
Pegylated IFN
tolerability
IFN & ribavirin
Peg-IFN & ribavirin
Treatment of Chronic Hepatitis C
•
´90 IFNa 3x3 MU x 24 Wk.
Davis et al., NEJM 1989
54-63%
40% 39%
16%
•
´96 IFNa 3x3 MU x 48 Wk.
Poynard et al., NEJM 1995
Poynard et al., Hepatology 1996
•
´98 IFNa + Ribavirin
McHutchison et al., NEJM 1998
Poynard et al., Lancet 1998
•
´00 PEG-IFNa2a
Zeuzem et al., NEJM 2000
•
´01 PEG-IFNa2b + RBV
Manns et al., Lancet 2001
•
´01 PEG-IFNa2a + RBV
Fried et al., NEJM 2002
•
´02 PEG-IFNa2a + RBV
Hadzyannis et al Ann Intern Med
2004
6%
1990
2005
Protease Inhibitors-Telapravir and Bocepravir Trials awaited
Peg-IFN & Ribavirin
(normal renal function)
QE Hepatitis Database 2005/6
Hepatitis C genotype
Caucasian
QE Hepatitis Database 2005/6
Hepatitis C genotype
Asian
Chemotherapy and HBV
• HBV reactivation is common among patients receiving
• chemotherapy haematological malignancy > solid
• malignant tumors.
• 21% to 53% of patients who are HBsAg positive will
• have a flare with chemotherapy.
• HBsAg-positive patients are at the highest risk.
Chemotherapy and HBV
• Patients with resolved HBV infection (ie, HBsAg-neg,
HBcAb pos and HBsAb-pos) may have reactivation with
immunosuppression.
• Worse if
–
–
–
–
–
HBeAg-positivity
High pretreatment HBV load
Male sex
Young age
High pretreatment serum ALT
• The risk for hepatic decompensation is greatest during
recovery from immunosuppression
Current Advice
• All patients undergoing chemotherapy should be
screened for HBV Infection. (Flares have been seen
with the use of immunomodulatory drugs such as
infliximab / rituximab)
• Consider Rx in Hepatitis B cAb+ve patients
• sAg positive patients should be started on
Lamivudine 3 weeks before treatment
• Patients should have Lamivudine for 3 months after
the completion of chemotherapy
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