HCV storia natural e cofattori

1
Paestum, 18 maggio 2006
Il portatore di HBV inattivo o malato ?
Giovanni Battista Gaeta Unità Epatiti Virali
Acute e Croniche Seconda Università di Napoli
2
Il progresso nella definizione della malattia da
HBV
Anni 50-60 60 70 90 2000
ALT (epatite post-trasfusionale a lunga
incubazione, evoluzione in cronicità)
HBsAg (Antigene Australia)
Istologia (Desmet, 1973)
Biologia Molecolare
Alta sensibilità
3
The healthy carrier the histology era
de Franchis et al. Ann Intern Med 1993
118191-194
Baseline 92 pts, HBsAg positive blood donors,
normal ALT
Follow-up mean 130 mo., 68 pts 21 with biopsy
HBV-DNA spot-dot hybridization
4
No Caption Found
Characteristics at the baseline
HBV-DNA 10/60
5
End of follow-up
6
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

7

Available HBV DNA Assays
Real Art HBV LC PCR
Artus Biotech
HBV Digene Hybrid-Capture I
HBV Digene Hybrid-Capture II

• Digene Corp.

Ultra-Sensitive Digene Hybrid-Capture II
Amplicor HBV Monitor
Roche MolecularSystems
Cobas Amplicor HBV Monitor
Cobas Taqman 48 HBV
Versant HBV DNA 1.0 NA
Bayer Corp.
Versant HBV DNA 3.0
Locarnini et al., Antiv.Therapy 2004
8

• The era of molecular biology
• Few copies of HBV-DNA can be detected
• (10 102)
• What the clinical significance ?

infection/disease
9
Standardisation of Nomenclature for Hepatitis B
(EASL consensus conference September 2002)

• Inactive HBsAg carrier
• Presence of HBsAg and anti-HBe in serum
• Serum HBV DNA lt 105 copies/ml
• Persistently normal serum ALT gt 6 months
• Liver histology (not essential) HAI grade lt 3

10

Available HBV DNA Assays
Real Art HBV LC PCR
Artus Biotech
HBV Digene Hybrid-Capture I
HBV Digene Hybrid-Capture II

• Digene Corp.

Ultra-Sensitive Digene Hybrid-Capture II
Amplicor HBV Monitor
Roche MolecularSystems
Cobas Amplicor HBV Monitor
Cobas Taqman 48 HBV
Versant HBV DNA 1.0 NA
Bayer Corp.
Versant HBV DNA 3.0
Locarnini et al., Antiv.Therapy 2004
11
Serum HBV DNA and Liver Inflammation in Chronic
Hepatitis B
Review of 26 prospective studies
Correlation between HAI and HBV DNA in untreated
patients (r0.78 P0.0001)
Mommeja-Marin H, et al. Hepatology.
2003371309-1319.
12
Correlation between change in HBV DNA and HAI
with treatment Review of 26 prospective studies
(r0.96 Plt0.0000)
Mommeja-Marin H, et al. Hepatology.
2003371309-1319.
13
Natural history of inactive HBsAg
carriersIncidence 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
14
Survival in HBsAg carriers and controls
patients 296 controls 157
Manno et al., Gastroenterology 2004127756-763
15
Percentage of patients who cleared HBsAg
Manno et al., Gastroenterology 2004127756-763
16
Chronic HBsAg carriers HBV DNA level
CHB HBeAg
CHB HBeAg
Serum HBV DNA (copies/mL)
Inactive Patients
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.
17
The R.E.V.E.A.L. HBV STUDY Risk Evaluation of
Viral Load Elevation and Associated Liver Disease
23,820 enrolled in 1991-1992
19,665 HBsAg negative
4,155 HBsAg positive
3,851 HBV-DNA tested
3,774 included in the analysis
395 with cirrhosis
Chen CJ, EASL Meeting 2005, Abs.476
18
Cumulative incidence of cirrhosis
N 3582
P lt0.001 Log rank test
Iloeje et al, Gastroenterology 2006 130678-686
19
Cumulative incidence of hepatocellular carcinoma
HBeAg negative with normal ALT at Baseline n
2925
Chen CJ, JAMA 2006 29565-73
20
ALT flares in chronic hepatitis B
ALT IU/l
21
HBV-DNA, ALT and IgM anti-HBc in 40 hepatitis
exacerbations in 23 HBV carriers

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
22
Classification of inactive carrier vs. chronic
hepatitis
Correct Sensitivity
Specificity classification

• HBV DNA
• gtvs lt 30.000 cp
• HBV DNA
• gtvs lt 100.000 cp
• anti-HBc IgM
• gtvs lt 0.200
• DNA IgM

• 80.0
• 68.0
• 56.0
• 92.0

• 100.0
• 100.0
• 91.6
• 91.9

• 94.3
• 90.8
• 81.6
• 92.0

Manesis, Am J Gastro 2003
23
Inactive HBV carriers in Central Italy
705 HBsAg positive subjects in 18 Centers 202
inactive carriers (29) 84 follow-up (6
mo.) 12 DNA increase gt1 log
6.6 ALT
elevation
1 anti-HBs seroconversion
Piccolo et al, EASL 2006, abs. 469
24
Outcome of anti-HBe pos chronic hepatitis B
102 Patients with chronic hepatitis at histology
Median follow-up 6 years (2-12)

• 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(?)

cirrhosis 49.2
cirrhosis 6.2
From Brunetto, 2002
25
Outcome of HBsAg/anti-HBe pos cirrhosis

• Hepatic decompensation
• 3/yr
• 47 with ascites
• 12 jaundice
• 9 variceal bleeding
• 30 more than one

no. 62
Median follow-up 6 years (2-12)
cirrhosis at baseline
Hepatocellular carcinoma without cirrhosis lt
0.2/yr (Western areas)
0.6 in Asia with cirrhosis gt
2.0/yr Predictors older age, male gender,
alcohol, environmental factors, coinfections,
genotype
10 HCC 9 terminal events
worsened 22
From Brunetto, 2002
26
Cofactors influencing the outcome of inactive HBV
carriers

• HCV coinfection
• HDV coinfection
• HIV coinfection
• Alcohol abuse,
• steroids,
• immunosuppression

27
The healthy carrier ( inactive with chronic
HBV PNAL with chronic HCV)
case-definition sensitive
28

• A new type of HBV carrier
• The occult carrier

29
Occult HBV infection
HBV-DNA detectable in liver tissue ( serum) by
PCR based methods following disappearance of
HBsAg in serum
30 in HCV chronic infections 60 in HBsAg
negative hepatocellular carcinoma
Torberson Thomas, Lancet Infect Dis,
2002 Pollicino et al, Gastroenterology, 2004
30
Il portatore di HBV inattivo o malato ?
Paziente HBsAg positivo con ALT normali

• HBV-DNAgt10,000 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