Viral Hepatitis for the Generalist Thursday 20 th May Dr Allister Grant Leicester Liver Unit.
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Transcript of Viral Hepatitis for the Generalist Thursday 20 th May Dr Allister Grant Leicester Liver Unit.
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Viral Hepatitis for the Generalist
Thursday 20th May
Dr Allister GrantLeicester Liver Unit
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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
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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”
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Source ofvirus
feces blood/blood-derived
body fluids
blood/blood-derived
body fluids
blood/blood-derived
body fluids
feces
Route oftransmission
fecal-oral percutaneouspermucosal
percutaneouspermucosal
percutaneouspermucosal
fecal-oral
Chronicinfection
no yes yes yes no
Prevention pre/post-exposure
immunization
pre/post-exposure
immunization
blood donorscreening;
risk behaviormodification
pre/post-exposure
immunization;risk behaviormodification
ensure safedrinking
water
Type of HepatitisA B C D E
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Incubation period: Average 30 days
Range 15-50 days
Jaundice by <6 yrs, <10%age group: 6-14 yrs, 40%-50%
>14 yrs, 70%-80%
Complications: Fulminant hepatitisCholestatic
hepatitisRelapsing hepatitis
Chronic sequelae: None
Hepatitis A - Clinical Features
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FaecalHAV
Symptoms
0 1 2 3 4 5 6 12 24
Hepatitis A Infection
Total anti-HAV
Titre ALT
IgM anti-HAV
Months after exposure
Typical Serological Course
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Incubation period: Average 40 days
Range 15-60 days Case-fatality rate: Overall, 1%-3%
Pregnant women, 15%-25%
Illness severity: Increased with age Chronic sequelae: None identified
Hepatitis E - Clinical Features
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Symptoms
ALTIgG anti-HEV
IgM anti-HEVVirus in
stool
0 1 2 3 4 5 6 7 8 9 10 11 1213
Hepatitis E Virus InfectionTypical Serologic Course
Titer
Weeks after Exposure
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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”
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World Hepatitis
DayMay 19th
World HepatitisAlliance
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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 millioninfected do not know
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HBV Infection
Acute HBV= cIgM+Immunity= sAb+ Previous exposure= cAb+Chronic infection= sAg+
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2 Billion Infected with HBV Worldwide
500,000 -1,200,000 deaths 500,000 -1,200,000 deaths yearly due to HBV yearly due to HBV complicationscomplications
• Almost half of the world’s population lives in an area with high HBV prevalence
15–25% die of cirrhosis or liver cancer
World population 6 billion
2 billion with evidence of HBV infection
350 million with chronic HBV
Lavanchy D. J Viral Hepatitis 2004; 11: 97-107
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The Stages of Chronic HBV Infection
immunetolerance
immuneclearance
inactivecarrier
reactivation
HBeAgAnti-HBe
HBV-DNA
ALT
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Inactive carrier?
Detection limit
Detection limit
HBeAg(-)CHB
HBeAg(-)Inactivecarrier
HBV DNA
0 3mo 6mo 9mo 12mo
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HBV DNA Thresholds
InactiveCarrierState
HBeAg (+)CHB
Ser
um
HB
V D
NA
(IU
/ml)
HBeAg (-)CHB
102
103
106
107
108
109
1010
104
105
10
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Management of eAg Negative Hepatitis B
HBsAg +ve, HBeAg -ve
HBV DNA < 2000 IU/mlNormal ALT
Possible chronic inactive states-seroconversion 1-3%/yr
MonitorALT/ HBV DNA 3 monthly for 12/12 then if normal ALT every 6-12/12
HBV DNA > 2000 IU/mland ALT > 2 x ULN
(or persistently 1-2 x ULN)
Liver biopsy (unless clinical evidence of cirrhosis or
contraindication)
ALT abnormalMeasure HBV DNA
Advanced fibrosis/ Cirrhosis(F5-6)
Moderate or severe necroinflammation (Metavir ≥ A2,
Ishak grade ≥ 5) and/or fibrosis (Metavir ≥ F2, Ishak stage ≥ F2)
Mild inflammation (Metavir A0/1, Ishak grade <5)
and/or No/ Mild Fibrosis (Metavir/Ishak 0 or 1)
Start indefinite NUC therapy (ETV* or TDF)
Consider combination therapy(TDF/ ETV or TDF/LAM)
Start indefinite NUC monotherapy (ETV* or TDF) unless
s seroconversion (then consider discontinuing after 6-
12/12)
Monitor3-6/12 ALT/ HBV DNA
If ALT remains abnormal + HBV DNA > 2000 IU/ml
repeat biopsy after 2-5 yrs (or annual fibroscan if
available)
Draft EM Guidelines based on EASL Guidelines 2009
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HBeAg positive HBeAg negative
Giusti et al, Giusti et al, 1991
1975-85: 539 patients
Prevalence of HBeAg Negative Chronic HBV in Italy
58%42%
Gaeta et al, 2003Gaeta et al, 2003
2001: 837 patients
10%
90%
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Where do carriers come from?
Acute infection
Chronic infection“carrier”
<5% risk
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Where do carriers come from?
Acute infection
Chronic infection“carrier”
~5% risk
“carrier” from abroad
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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.
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QE Hepatitis Database 2005/6Ethnicity of HBV Patients
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HBV Notifications in England & Wales
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Uchenna H. I, et al. Gastroenterology 2006; 130:678-686
Year of follow-up
Cu
mu
lati
ve in
cid
ence
of
liver
ci
rrh
osi
s
.2
.1
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0
.4
.3
Baseline HBV DNA Level, copies/mL
P value for log-rank test, <0.001
n=3,774
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
5.2%6.3%
10.0%
23.0%
37.1%
Cumulative Incidence of Liver CirrhosisREVEAL HBV Study
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High Serum HBV DNA Levels are Associated with Increased Risk of HCC Mortality
HBV DNA Negative
HBV DNA LowHBV DNA Low< 105 copies/mL copies/mL RR = 1.7 (0.5-5.7)RR = 1.7 (0.5-5.7)
HBV DNA HighHBV DNA High> 105 copies/mL copies/mL
RR = 11.2 (3.6-35.0)RR = 11.2 (3.6-35.0)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.
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60 Signs/symptoms
CIRRHOSIS
HCV- Natural History
20% at 20yrs50% at 30yrs
AgeGenderAlcohol
20 No Harmful Effects
TransplantationLiver Failure
Liver Cancer
3.9% pa
1.4% pa
20 Clear the HCV
80 Develop Chronic Hepatitis
HCV Ab pos & PCR pos
HCV Ab posPCR neg
100 Infected HCV Ab pos
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Prevalence of Hepatitis C virus
2001 WHO
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UK HCV Prevalence <1%
IV Drug Use
Migration
Blood Donation
2-400,000
Screening 1991
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QE Hepatitis Database 2005/6Hepatitis C
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Natural Hx of HCV Cirrhosis
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liver fibrosis score(degree of scarring)
0
6
3
years10 20 30 60
cirrhosis
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liver fibrosis score(degree of scarring)
0
6
3
years10 20 30 60
cirrhosis
HCV-pos(median time 38 years)
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liver fibrosis score(degree of scarring)
0
6
3
years10 20 30 60
cirrhosisend-stage
renal disease
?
immune suppression
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Antiviral Therapy
HBV• Aim is suppression of
replication rarely elimination
• HIV treatment paradigm suppression prevents disease
• Indefinite treatment ? lifelong
• Treatment well tolerated
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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
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Pegylated IFN in HBV
Advantages
Mainly used for eAg positive disease
• Finite duration of Rx
• Stopping rule at 12 weeks
• Can seroconvert to eAg negative disease (30%)
• But some do sAg seroconvert (3%) + some late
Disadvantages
• Cant use in Cirrhosis
• Side effects ++
• 48 week course of Rx
• Not good for all genotypes
AB>CD
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HBV Genotypes
AD
D
DD Ba
CC
Bj
F
D
E
AD
BC
F
F
Fung & Lok, Hepatology 2004;40:790-2
A
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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
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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– …………
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Rebound of serum HBV DNA
>1 log10
cpm
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Incidence of HBV Resistance
Lamivudine resistance (rtL180M+rtM204V/I)
Adefovir resistance (rtN236T/rtA181V)
Lai CL, Clin Infect Dis 2003;36:687.Locarnini et al., EASL 2005.
0%0%
10%10%
20%20%
30%30%
40%40%
50%50%
60%60%
70%70%
80%80%
year 1year 1 year 2year 2 year 3year 3 year 4year 4
0%0%
24%24%
3%3%
42%42%
11%11%
53%53%
70%70%
Inci
den
ce o
f R
esis
tan
ceIn
cid
ence
of
Res
ista
nce
18%18%
29%29%
70%70%
year 5year 5
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TDF
ADV
ETV
LAM FTC
Genetic Barrier
Pot
ency
Nucleoside analogue
Nucleotide analogue
IFN
Anti-HBV drugs
LdT
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UK Transplantation for Viral Hepatitis
Total HCV
recipients
Total HBV
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Hepatitis C Treatment
• Aim is viral eradication• Treatment of finite duration
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HCV Genotypes
• 6 main genotypes
• Nucleotide diversity > 20%
• Little effect on natural history
• Geographical variation
• Most important determinant of response to treatment
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Ribavirin- adverse effects
Haemolytic anaemiaThrombocytopeniaHeadacheGI disturbance AlopeciaAnxiety, depression, memory loss, irritability, insomniaChest painCoughGout
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HCV Antiviral Treatment
IFN
Pegylated IFN
IFN & ribavirin
Peg-IFN & ribavirin
efficacy
tolerability
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Treatment of Chronic Hepatitis C• ´90 IFN 3x3 MU x 24 Wk.
Davis et al., NEJM 1989
• ´96 IFN 3x3 MU x 48 Wk. Poynard et al., NEJM 1995
Poynard et al., Hepatology 1996
• ´98 IFN + Ribavirin McHutchison et al., NEJM 1998Poynard et al., Lancet 1998
• ´00 PEG-IFN2a Zeuzem et al., NEJM 2000
• ´01 PEG-IFN2b + RBV Manns et al., Lancet 2001
• ´01 PEG-IFN2a + RBV Fried et al., NEJM 2002
• ´02 PEG-IFN2a + RBV Hadzyannis et al Ann Intern Med 2004
s us t
a in
e d v
i ro
log
i cre
s po
n se
(%
)
6%16%
40% 39%
54-63%
Protease Inhibitors-Telapravir and Bocepravir Trials awaited
1990 2005
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Peg-IFN & Ribavirin(normal renal function)
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Caucasian
QE Hepatitis Database 2005/6Hepatitis C genotype
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Asian
QE Hepatitis Database 2005/6Hepatitis C genotype
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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.
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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
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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