Upload
peregrine-cole
View
235
Download
5
Tags:
Embed Size (px)
Citation preview
Viral Hepatitis for the Generalist
Thursday 20th May
Dr Allister GrantLeicester 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”
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
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
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
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
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
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”
World Hepatitis
DayMay 19th
World HepatitisAlliance
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
HBV Infection
Acute HBV= cIgM+Immunity= sAb+ Previous exposure= cAb+Chronic infection= sAg+
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
The Stages of Chronic HBV Infection
immunetolerance
immuneclearance
inactivecarrier
reactivation
HBeAgAnti-HBe
HBV-DNA
ALT
Inactive carrier?
Detection limit
Detection limit
HBeAg(-)CHB
HBeAg(-)Inactivecarrier
HBV DNA
0 3mo 6mo 9mo 12mo
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
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
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%
Where do carriers come from?
Acute infection
Chronic infection“carrier”
<5% risk
Where do carriers come from?
Acute infection
Chronic infection“carrier”
~5% risk
“carrier” from abroad
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.
QE Hepatitis Database 2005/6Ethnicity of HBV Patients
HBV Notifications in England & Wales
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
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.
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
Prevalence of Hepatitis C virus
2001 WHO
UK HCV Prevalence <1%
IV Drug Use
Migration
Blood Donation
2-400,000
Screening 1991
QE Hepatitis Database 2005/6Hepatitis C
Natural Hx of HCV Cirrhosis
liver fibrosis score(degree of scarring)
0
6
3
years10 20 30 60
cirrhosis
liver fibrosis score(degree of scarring)
0
6
3
years10 20 30 60
cirrhosis
HCV-pos(median time 38 years)
liver fibrosis score(degree of scarring)
0
6
3
years10 20 30 60
cirrhosisend-stage
renal disease
?
immune suppression
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
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
HBV Genotypes
AD
D
DD Ba
CC
Bj
F
D
E
AD
BC
F
F
Fung & Lok, Hepatology 2004;40:790-2
A
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 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
TDF
ADV
ETV
LAM FTC
Genetic Barrier
Pot
ency
Nucleoside analogue
Nucleotide analogue
IFN
Anti-HBV drugs
LdT
UK Transplantation for Viral Hepatitis
Total HCV
recipients
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 anaemiaThrombocytopeniaHeadacheGI disturbance AlopeciaAnxiety, depression, memory loss, irritability, insomniaChest painCoughGout
HCV Antiviral Treatment
IFN
Pegylated IFN
IFN & ribavirin
Peg-IFN & ribavirin
efficacy
tolerability
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
Peg-IFN & Ribavirin(normal renal function)
Caucasian
QE Hepatitis Database 2005/6Hepatitis C genotype
Asian
QE Hepatitis Database 2005/6Hepatitis C genotype
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