HBV_The First GI Conference in Palestine
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Transcript of HBV_The First GI Conference in Palestine
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Rifaat Safadi, M.D.Liver & Gastroenterology Units
Division of MedicineJerusalem
HBV current treatment
guidelines
The First GI conference in Palestine(20-22) May 2010
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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
Chronicity no yes yes yes no
Prevention pre/post-exposure
immunization
pre/post-exposure
immunization
blood donorscreening;
risk behaviormodification
pre/post-exposure
immunization;risk behavior
modification
ensure safedrinkingwater
Viral HepatitisA DB C E
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HBsAg Prevalence8% - High
2-7% - Intermediate
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2 Billion Infected with HBV Worldwide
1525% die ofcirrhosis orliver cancer
World population6 billion
2 billion withevidence of
HBV infection
350 millionchronic HBV
Adapted from Lavanchy D. J Viral Hepatitis2004;11:97-107.
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1525% die of Cirrhosis or HCC
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Hepatitis B Vaccines
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MiddleSurfaceAntigen
LargeSurfaceAntigen
Small SurfaceAntigen
Hepatitis B Virus Structure
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1st
Plasma-derived
-HBsAg, Pre-S
3rd
Mammalian cell d.
-HBsAg, Pre-S2
-HBsAg, Pre-S2, Pre-S1
2nd
Yeast-derived,
-HBsAg
recom
binant
Generations
History of Hepatitis B Vaccines
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11
2
13055
6074
3211
722
Months
GMTmIU/ml
*p
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Sci- B-Vac in > 20 Clinical Trials
Sci-B-Vac is safe & highly immunogenic
Rapid (earlier/higher) immune responses
High seroprotection rates
Induces seroconversion in:
high-risk patients
in non-responders
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HBV Vertical Transmission
Universal HBV vaccination for
all newborns since 1992 :
Active for all neonates
Passive if maternal HBsAg+
Vertical
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Epidemiology: Age dependent
350M chronically infected
1M cases of death per year 5-10% of liver transplant
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HBV vertical trans mission inEast Jerusalem During 2005
HBcAb+:8.4% (14/165)Of them: 3+4 Brothers
HBsAg+:4.4% (8/182)Of them: 4 Brothers
Safadi R et. al., Unpublished
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Arauz-Ruiz P, et al. J Gen Virol. 2002;83:2059-2073. Bell SJ, et al. J Clin Virol. 2005;32:122-127.Chu CJ, et al. Gastroenterology. 2003;125:444-451. Kidd-Ljunggren K, et al. J Gen Virol.
2002;83:1267-1280. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.
Global Distribution of 8 HBVGenotypes
A, B, C,D, G
F
A, D, E
B, C
AG D
H, F
D
A, B, C, D
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HBV:
Pre treatment
evaluation
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Clinical Sequelae of HBV
Acute HepatitisClinical illness
(jaundice):
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Clinical Sequelae of Chronic HBV
Chronic Hepatitis B
Active (High)Replication
Low ViralReplication
ProgressiveLiver Injury
AsymptomaticInfection
Fibrosis & Cirrhosis Hepatocellular Ca
Death 15%-25%
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IgM anti-HBc
Total anti-HBc
HBsAg
Acute
HBeAg
Chronic
anti-HBe
0 4 8 12 16 20 24 28 32 36 52 Years
HBVDNA
Chronic Hepatitis B
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Chronic HBV with Viral Replication
No evidence of acute infection
Anti-HBc IgM -
Some immuneresponse to the virus
Anti-HBc IgG +
Anti-HBs -
Anti-HBe - +
Viral markers presentfor > 6 months
HBsAg +
HBeAg + -
HBV DNA + (>100,000c/ml)
ALT, AST
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Indications for treatment
The indications for treatment are generally the same
for both HBeAg+ & HBeAgnegative CHB.
Based mainly on the combination of 3 criteria:
Serum HBV DNA levels > 2000 IU/ml (~10,000copies/ml)
Serum aminotransferase levels > upper limit of
normal (ULN)
Histological grade & stage (or non-invasivemarkers) shows moderate to severe active
necroinflammation and/or fibrosis (at least A2 or F2
by METAVIR scoring) (A1)
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Pre therapeutic assessmentBiochemical markers, AST, ALT, GGT, Alk. Phos., albumin,
INR, CBC & hepatic ultrasound (A1).
HBV DNA level is essential for the diagnosis, decision to treat &monitoring (A1).
Follow-up using real-time PCR quantification assays is strongly
recommended (A1). The WHO has defined an internationalstandard for normalization of expression of HBV DNAconcentrations.
Other causes of chronic liver disease should be systematicallylooked for including coinfection with HDV, HCV and/or HIV.Co-morbidities, including alcoholic, autoimmune, metabolicliver disease with steatosis or steato-hepatitis should beassessed (A1).
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Liver biopsy is recommendedDetermining the degree of necroinflammation & fibrosis in either
increased ALT or HBV DNA >2000 IU/ml (or both) (A1).
To evaluate other possible causes of liver disease.
The risk of severe complications is very low (1/4,00010,000).
The size of the needle biopsy specimen should be large enoughto precisely analyze the degree of liver injury & fibrosis (A1).
A liver biopsy is usually not required in patients with clinicalevidence of cirrhosis or in those in whom treatment isindicated irrespective of activity grade/ fibrosis stage (A1).
There is growing interest in the use of non-invasive methods
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Factors forprogressivefibrogenesis
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25-year survival rates in untreated CHB
0
100
80
60
40
20
0 5 10 15 20 25
Sur
vivalprobability(%)
Inactive CHB
HBeAg-/HBV DNA+
HBeAg+ persistence
Fattovich et al. Gut 2008 Time (years)
HBeAg Status
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HBsAg
RNA
d antigen
Hepatitis D Virus
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Cumulative Incidence of Liver Cirrhosisfor Five HBV DNA Categories
Iloeje UH et al, Gastroenterology 2006;130:678-86
2.5
1.4
1.0
5.6
6.5
Pvalue for log-rank test,
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HBV DNA Levels Predict Risk of HCC(REVEAL-HBV Study)
P
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HBVtherapy
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Anti-HBV Active Compounds
/3
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Goal of therapy
To improve quality of life & survival by preventing progression to cirrhosis, decompensated cirrhosis, HCC & death.
HBV infection cant be completely eradicateddue to persistence of covalently closedcircular DNA (cccDNA) in the nucleus of
infected hepatocytes.
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HBV-Triggered Immune Responses
Modified from:Ganem D, et al. N Engl J Med. 2004;350:1118-1129.
MHC
class II
HBVpeptides
HBV
MHCclass I
MHCclass I
TNF-Interferon-
gamma
Down-regulationsof viral
replication
HBV DNA
HBsAg
HBVpeptides
CD8+T cell
Antigen-presenting cell
CD8+T cell
InfectedHepatocyte
HBV cores
HBV RNA
HBVantigens
CD4+T cell
Stellate cell activation
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2 4 6 8 10 1200
2
4
6
810
12
HAI
Baseline HBV DNA Level(log10 copies/mL)
1 2 3 4 5
2
1
0
1
2
3
4
5
Median log10 HBV DNA Decrease
MedianImprovement
in HAI
Correlation between HAI andHBV DNA in untreated patients
(r=0.78; P=0.0001)
Correlation between change inHBV DNA and HAI with Lamtreatment (r=0.96; P
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Lamivudine for patients with chronic
HBV & advanced liver disease
Liaw YF et al. N Engl J Med 2004;351:1521-1531.
Increase in Child-Pugh Score(% of patients)
Diagnosis of HCC(% of patients)
Disease Progression(% of patients)
PlaceboLamivudine
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Liaw YF et al. Lamivudine for patients with chronic hepatitis Band advanced liver disease. N Engl J Med 2004;351:1521-31.
Dienstag JL et al. Histological outcome during long-termlamivudine therapy. Gastroenterology 2003;124:105-117.
Hadziyannis SJ et al. Long-term therapy with adefovir dipivoxilfor HBeAg-negative chronic hepatitis B for up to 5 years.
Gastroenterology 2006;131:1743-1751.
Marcellin P et al. Long-term efficacy and safety of adefovirdipivoxil for the treatment of hepatitis B e antigen-positive
chronic hepatitis B. Hepatology 2008;48:750-758.
Cirrhosis Reversal followingAnti viral therapy in HBV
Distribution of Ishak fibrosis scores at phase III baseline
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Distribution of Ishak fibrosis scores at phase III baseline,after 48 weeks of entecavir treatment, and at the time of
the long-term biopsy(median: 6 years entecavir treatment [range 37 years]) among histologically
evaluable patients in the Long-Term Histology Cohort (N=57).
Ishak Fibrosis Score
12
3
4
5
6
Missing
0
0
10
20
30
40
50
60
Baseline Week 48 Long-term
Nu
mberofpatients
Reduction in fibrosis following long-term entecavir
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Reduction in fibrosis following long-term entecavirtherapy in a 60 yo, HBeAg-negative, Caucasian male.The baseline biopsy shows an Ishak score of 6, indicating cirrhosis, which isunchanged at Week 48, and the Week 268 biopsy shows an Ishak score of 2,
indicating minimal fibrosis
268 week
48 week
Baseline
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Virological Endpoint of Therapy
Inhibition of HBV replication:
As profound as possible As sustained as possible
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Sensitivity of HBV DNA
AssaysTest Method Range of quantification
Dot blot Rapid test
Abbott Liquid hybridisation
Digene RNA-DNA hybrid
Chiron Branched DNA
Amplicor Quantitative PCRMonitor
106
105
103
102
104
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End-points of therapy(1) In HBeAg+ & HBeAgnegative patients, the ideal is
sustained HBsAg loss with/out seroconversion toanti-HBs. Associated with a definitive remission of
HBV & an improved long-term outcome (A1).
(2) In HBeAg+ patients, durable HBe seroconversion
is associated with improved prognosis (A1).
(3) To reduce HBV DNA as possible, ideally < thelower limit of detection (1015 IU/ml), then lead to:
o biochemical remission,
o histological improvement
o prevention of complications.
Response Rates in CHB
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Response Rates in CHB:Randomized clinical trials
63
72
51
90 8892
0
1020
30
40
50
60
70
80
90
100
PEG LA AD ET Ld TD
Undetectable HBV DNA
HBeAg(-) HBeAg(+)
25
39
21
67
60
74
0
10
20
30
40
50
60
70
80
PEG LA AD ET Ld TD
Rates of mutations increased in
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UndetectableHBVDNA
%
Rates of mutations increased indifferent NUCs
24
0
0.2
4
0
38
3
0.5
22
49
11
1.2
67
18
1.2
70
29
1.2
0
10
20
30
40
50
60
70
LA AD ET Ld TD
Year 1
Year 2
Year 3
Year 4
Year 5
EASL Clinical Practice Guidelines
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Risk of Resistance Development Increases
with Suboptimal Viral Suppression
8%13%
32%
64%
0
20
40
60
80
100
200 3 log10 4 log10 >4 log10
HBV DNA levels at 24 weeks (copies/mL)
Patientswith
LamivudineResistance
(%)
Yuen MF et al. Hepatology. 2001;34:785-791.
Analysis of 159 HBeAg-
positive patients treated
with Lamivudinefor median
29 months follow-up
0
20
40
60
80
100
< 3 log 3 - 6 log > 6 log
4%
26%
67%
Locarnini S, et al. J Hepatology2005;42(Suppl 2):16,Abstract 36.
HBV DNA level at week 48 (copies/mL)
Patientswith ADV
Resistanceat
Week 144(%)
Analysis of 114 HBeAg-
negative patients treated
with Adefovir
Response Rates in CHB:
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Response Rates in CHB:Randomized clinical trials
63
72
51
90 8892
0
10
20
30
40
50
60
70
80
90
100
PEG LA AD ET Ld TD
Undetectable HBV DNA
HBeAg(-) HBeAg(+)
25
39
21
67
60
74
0
10
20
30
40
50
60
70
80
PEG LA AD ET Ld TD
Main respective advantages & disadvantages of
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Main respective advantages & disadvantages ofPEG- interferon & NUCs in the treatment of CHB
Advantages
Disadvant.
PEG-interferon : NUCs:
Finite duration Potent antiviral effect
Absence of resistance Good tolerance
Higher rates of HBe & Oral administration
HBs seroconversion
Moderate antiviral effect Indefinite duration
Poor tolerance Risk of resistance
Subcutaneous injections Lower rates of
HBe/ HBs
seroconversion
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How effective are nucleoside treatmentstrategies at achieving HBsAg clearance?
PEG-IFN LAM ADV ETV LdT
HBsAg loss in
HBeAg-neg CHB3%
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Predictors of response for IFN
Pre-treatment factors for HBe seroconversion:
low viral load (3 times ULN), &
high activity scores on liver biopsy (A2) (B2).
During treatment, an HBV DNA decrease to 3 times ULN),
high activity scores on liver biopsy (at least A2).
During treatment with Lam, Adv or LdT, a virological
response at 24 or 48 weeks (undetectable HBVDNA) is associated with a lower incidence of
resistance, i.e. an improved chance of maintained
virological response, and HBe seroconversion in
HBeAg+ patients (B1).
HBV genotypedoesnt influence the response to any
NUC.
Treatment failure
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Treatment failure
It is important to checkfor compliance!
Definitions of response on NUC therapy
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Definitions of response on NUC therapy
Virological breakthrough: a confirmed increase in
HBV DNA level > 1 log10 IU/ml compared to thenadir (lowest value) HBV DNA level on therapy; it
usually precedes a biochemical breakthrough. The
main causes of virological breakthrough on NUC
therapy are poor adherence to therapy & selectionof drug-resistant HBV variants (resistance) (A1).
HBV resistance to NUCs: selection of HBV variants
with amino acid substitutions that confer reducedsusceptibility to the administered NUC(s).
Resistance may result in primary treatment failure or
virological breakthrough on therapy (A1).
Treatment failure
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Treatment failure(1) Primary non-response:
Rare with Lam., telbivudine, entecavir or tenofovir.
More frequent with adefovir (~20%). A rapid switch
to tenofovir or entecavir is recommended (B1).
In a compliant patient, identification of resistance
mutations can formulate a rescue strategy based on
an early change to a more potent drug that is active
against the resistant variant (B1).
Treatment failure
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Treatment failure(2) Partial virological response:
o With all available NUCs.o In lamivudine, adefovir or telbivudine with apartial virological response at week 24:
Change to entecavir or tenofovir Or addition of a more potent drug that
does not share cross-resistance:
add tenofovir to lamivudine or telbivudine add entecavir to adefovir (A1).
HBV Mutants: Total of 44 tests, Hadassah
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WT;18; 39%
Lam;15; 33%
Adf; 3; 7%
Ent; 2; 4%
NoViremia;8; 17%
HBV Mutants: Total of 44 tests, HadassahT. Saadi & R. Safadi, 2009
C R i t With HBV D
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V173L L180M A181V A184G S202I M204I M204V N236T M250V
LAMLamivudine
ETVEntecavir
LdTTelbivudine
FTCEmtricitabine
ADVAdefovir
YMDD
Cross Resistance With HBV Drugs
Yang H. et al. Hepatology 2003;38:705A; Lai CL et al Hepatology 2003;38:262A
TDTenofovir
Special groups of patients
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Special groups of patients
Immunotolerant patients: most patients under 30
years of age with persistently normal ALT levels anda high HBV DNA level (usually above 107 IU/ml),
without any suspicion of liver disease and without a
family history of HCC or cirrhosis do not require
immediate liver biopsy or therapy. Follow-up is
mandatory (B1).
Patients with mild CHB: patients with slightlyelevated ALT (less than 2 times ULN) and mild
histological lesions (less than A2/F2) may not
require therapy. Follow-up is mandatory (B1).
Patients with cirrhosis
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Patients with cirrhosis
Compensated & detectable HBV DNA may be
considered for treatment even if ALT levels arenormal &/or HBV DNA levels
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Thank YouRifaat Safadi M.D
Definitions of response on interferon-
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Definitions of response on interferon-
Primary non-response: