giovanni battista gaeta unità epatiti virali acute e croniche seconda università di napoli
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Paestum, 18 maggio 2006. Il portatore di HBV: inattivo o malato ?. Giovanni Battista Gaeta Unità Epatiti Virali Acute e Croniche Seconda Università di Napoli. Il progresso nella definizione della malattia da HBV. Anni ’50-’60 ’60 ’70 ‘90 2000. - PowerPoint PPT PresentationTRANSCRIPT
Giovanni Battista GaetaUnità Epatiti Virali Acute e CronicheSeconda Università di Napoli
Paestum, 18 maggio 2006
Il portatore di HBV: inattivo o malato ?
Il progresso nella definizionedella malattia da HBV
HBsAg (Antigene Australia)
ALT (epatite post-trasfusionale a lunga
incubazione, evoluzione in cronicità)
Istologia (Desmet, 1973)
Biologia Molecolare
Anni’50-’60
’60
’70
‘90
2000Alta sensibilità
The “healthy carrier”: the histology era
de Franchis et al. Ann Intern Med 1993; 118:191-194
Baseline: 92 pts, HBsAg positive blood donors,
normal ALT
Follow-up: mean 130 mo., 68 pts; 21 with biopsy
HBV-DNA: spot-dot hybridization
No Caption FoundCharacteristics at the baseline
HBV-DNA : 10/60
End of follow-up
Limits of a healthy carrier definition based on liver
histology and low sensitivity DNA testing
–Dependent upon:•Length of biopsy – 20mm optimal •Number of biopsies performed•Type of biopsy needle used•Pathologist experience
–HBV-DNA testing:•Spot-dot hybridizazion reveals pg of DNA•Subjective lecture
Digene Corp.
Roche MolecularSystems
Bayer Corp.
102 104103 105 106 107 108 1010109101HBV DNA IU/mL
HBV Digene Hybrid-Capture I
HBV Digene Hybrid-Capture II
Ultra-Sensitive Digene Hybrid-Capture II
Amplicor HBV Monitor
Cobas Amplicor HBV Monitor
Versant HBV DNA 1.0 NA
Versant HBV DNA 3.0
Cobas Taqman 48 HBV
Available HBV DNA Assays
Locarnini et al., Antiv.Therapy 2004
Artus Biotech Real Art HBV LC PCR
102 104103 105 106 107 108 1010109101HBVDNA cp/mL
The era of molecular biology
Few copies of HBV-DNA can be detected
(10 –102)
What the clinical significance ?
infection/disease
Inactive HBsAg carrier
Presence of HBsAg and anti-HBe in serum Serum HBV DNA < 105 copies/ml Persistently normal serum ALT > 6 months Liver histology (not essential) HAI grade < 3
Standardisation of Nomenclature for Hepatitis B Standardisation of Nomenclature for Hepatitis B (EASL consensus conference September 2002)(EASL consensus conference September 2002)
Digene Corp.
Roche MolecularSystems
Bayer Corp.
102 104103 105 106 107 108 1010109101HBV DNA IU/mL
HBV Digene Hybrid-Capture I
HBV Digene Hybrid-Capture II
Ultra-Sensitive Digene Hybrid-Capture II
Amplicor HBV Monitor
Cobas Amplicor HBV Monitor
Versant HBV DNA 1.0 NA
Versant HBV DNA 3.0
Cobas Taqman 48 HBV
Available HBV DNA Assays
Locarnini et al., Antiv.Therapy 2004
Artus Biotech Real Art HBV LC PCR
102 104103 105 106 107 108 1010109101HBVDNA cp/mL
Serum HBV DNA and Liver Inflammation in Chronic Serum HBV DNA and Liver Inflammation in Chronic Hepatitis BHepatitis B
His
tolo
gy
Act
ivit
y In
dex
(H
AI)
HBV DNA level (log10 c/mL)
His
tolo
gy
Act
ivit
y In
dex
(H
AI)
HBV DNA level (log10 c/mL)
Review of 26 prospective studies
Correlation between HAI and HBV DNAin untreated patients (r=0.78; P=0.0001)
Mommeja-Marin H, et al. Hepatology. 2003:37:1309-1319.
Median log10 HBV DNA decrease
Med
ian
imp
rove
men
t in
HA
I
Median log10 HBV DNA decrease
Med
ian
imp
rove
men
t in
HA
I
Correlation between change in HBV DNA and HAI with treatment Review of 26 prospective studies
Mommeja-Marin H, et al. Hepatology. 2003:37:1309-1319.
(r=0.96; P<0.0000)
Natural history of inactive HBsAg carriersNatural history of inactive HBsAg carriersIncidence per 100 person years of major eventsIncidence per 100 person years of major events
De Franchis
1993
Bellentani
2002
Manno
2004
Hsu
2002
● area Europe Europe Europe Asia
● N° patients 68 46 296 189
● Median follow-up (yrs) 10 9 29 8
● Histologic deterioration
0.15 NR NR 0.06
● HCC 0 0 0.02 0.19
● Liver-related death 0 0 0.01 0
● HBsAg loss 1.0 0.9 1.0 0.6
NR = not reported
Survival in HBsAg carriers and controlspatients= 296
controls = 157
Manno et al., Gastroenterology 2004;127:756-763
Percentage of patients who cleared HBsAg
Manno et al., Gastroenterology 2004;127:756-763
Chronic HBsAg carriers: HBV DNA level
Villeneuve JP et al. Gastroenterology 1994. Martinot –Peignoux M et al. J.Hepatol 2002. Hsu et al Hepatology 2002. Mommeja-Marin H et al. Hepatology 2003; Manno,Gastroenterology 2004.
InactivePatients
CHBHBeAg +
Se
rum
HB
V D
NA
(c
op
ies
/mL
)
CHBHBeAg –
102
103
106
107
108
109
1010
104
105
23,820 enrolled
in 1991-1992
4,155 HBsAg positive 19,665 HBsAg negative
3,851 HBV-DNA tested
3,774 included in the analysis
395 with cirrhosis
The R.E.V.E.A.L. – HBV STUDYRisk Evaluation of Viral Load Elevation and Associated Liver Disease
Chen CJ, EASL Meeting 2005, Abs.#476
Cumulative incidence of cirrhosis
Iloeje et al, Gastroenterology 2006; 130:678-686
N = 3582N = 3582
P <0.001
Log rank test
P <0.001
Log rank test
HBeAg negative with normal ALT at Baseline n= 2925
Cumulative incidence of hepatocellular carcinoma
Chen CJ, JAMA 2006; 295:65-73
ALT flares in chronic hepatitis BALT flares in chronic hepatitis B
0
100
200
300
400
AL
T I
U/l
months
HBV-DNA, ALT and IgM anti-HBcHBV-DNA, ALT and IgM anti-HBcin 40 hepatitis exacerbations in 23 HBV carriersin 40 hepatitis exacerbations in 23 HBV carriers
HBV-DNAALTIgM anti-HBc
HBV-DNA increments preceded or were simultaneous to ALT elevations in 96.2% of cases. The ALT flares preceded or
were simultaneous to IgM anti-HBc increments in 96.2% of cases
Colloredo Mels G., 1994
Classification of inactive carrier vs. chronic hepatitis
HBV DNA
>vs < 30.000 cp
HBV DNA
>vs < 100.000 cp
anti-HBc IgM
>vs < 0.200
DNA + IgM
94.3
90.8
81.6
92.0
80.0
68.0
56.0
92.0
100.0
100.0
91.6
91.9
Correct Sensitivity Specificity
classification
Manesis, Am J Gastro 2003
705 HBsAg positive subjects in 18 Centers
202 inactive carriers (29%)
84 follow-up (6 mo.) 12% DNA increase >1 log
6.6% ALT elevation
1 anti-HBs seroconversion
Piccolo et al, EASL 2006, abs. # 469
Inactive HBV carriers in Central Italy
Outcome of anti-HBe pos chronic hepatitis B Outcome of anti-HBe pos chronic hepatitis B
102 Patients with chronic hepatitis at histology
From: Brunetto, 2002
cirrhosis
49.2%
Median follow-up
6 years (2-12)
cirrhosis
6.2%
Progression to cirrhosis
•2-5%/yr in HBeAg positive patients• 8-10% in HBeAg neg•Predictors: older age, alcohol, coinfections,•recurrent flares, bridging necrosis, •fibrosis stage, genotype(?)
Outcome of HBsAg/anti-HBe pos cirrhosis Outcome of HBsAg/anti-HBe pos cirrhosis
From: Brunetto, 2002
worsened
22%
Median follow-up
6 years (2-12)
cirrhosis
at
baseline
no. = 62
10 HCC
9 terminalevents
Hepatic decompensation• 3%/yr 47% with ascites 12% jaundice 9% variceal bleeding 30% more than one
Hepatocellular carcinomawithout cirrhosis < 0.2%/yr (Western areas) 0.6% in Asiawith cirrhosis > 2.0%/yrPredictors: older age, male gender, alcohol, environmental factors, coinfections, genotype
Cofactors influencing the outcomeof inactive HBV carriers
• HCV coinfection
• HDV coinfection
• HIV coinfection
• Alcohol abuse, steroids, immunosuppression
The “healthy” carrier ( inactive with chronic HBV; PNAL withchronic HCV)
viraemia
liver histology
outcome
HBV
<104 cp/ml
minimal,inactive fibrosis
stable
HCV
wide range
20%significant
20-30%progression
case-definition sensitive
A new type of HBV carrier:
The occult carrier
Occult HBV infectionHBV-DNA detectable in liver tissue (± serum) by PCR based methods following disappearance of HBsAg in
serum
30% in HCV chronic infections30% in HCV chronic infections
60% in HBsAg negative hepatocellular carcinoma60% in HBsAg negative hepatocellular carcinoma
Torberson & Thomas, Lancet Infect Dis, 2002Pollicino et al, Gastroenterology, 2004
HBV-DNA>10,000 cp/ml = area rischio
(2000 IU/ml)Seguire per un anno ad intervalli di
3 mesi ALT, anti-HBc IgM, HBV-DNA Biopsia epatica nei casi dubbi
Il portatore di HBV: inattivo o malato ?
Paziente HBsAg positivo con ALT normali: