1. Il portatore di HBV: inattivo o malato ?
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. de Franchis et al. Ann Intern Med 1993; 118:191-194
The “healthy carrier”: the histology era
de Franchis et al. Ann Intern Med 1993; 118:
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. Characteristics at the baseline
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
102
104
103
105
106
107
108
1010
109 10 1
HBVDNA cp/mL
Artus Biotech
Real Art HBV LC PCR
HBV Digene Hybrid-Capture I
HBV Digene Hybrid-Capture II
Digene Corp.
Ultra-Sensitive Digene Hybrid-Capture II
Roche Molecular Systems
Amplicor HBV Monitor
Cobas Amplicor HBV Monitor
Cobas Taqman 48 HBV
Versant HBV DNA 1.0 NA
Bayer Corp.
Versant HBV DNA 3.0
102
104
103
105
106
107
108
1010
109 10 1
HBV DNA IU/mL
Locarnini et al., Antiv.Therapy 2004

8. infection/disease The era of molecular biology
Few copies of HBV-DNA can be detected
(10 –102)
What the clinical significance ?
infection/disease

9. Inactive HBsAg carrier
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 < 105 copies/ml
Persistently normal serum ALT > 6 months
Liver histology (not essential) HAI grade < 3

10. Available HBV DNA Assays
102
104
103
105
106
107
108
1010
109 10 1
HBVDNA cp/mL
Artus Biotech
Real Art HBV LC PCR
HBV Digene Hybrid-Capture I
HBV Digene Hybrid-Capture II
Digene Corp.
Ultra-Sensitive Digene Hybrid-Capture II
Roche Molecular Systems
Amplicor HBV Monitor
Cobas Amplicor HBV Monitor
Cobas Taqman 48 HBV
Versant HBV DNA 1.0 NA
Bayer Corp.
Versant HBV DNA 3.0
102
104
103
105
106
107
108
1010
109 10 1
HBV DNA IU/mL
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 (r=0.78; P=0.0001)
Mommeja-Marin H, et al. Hepatology. 2003:37:

12. Correlation between change in HBV DNA
and HAI with treatment Review of 26 prospective studies
(r=0.96; P<0.0000)
Mommeja-Marin H, et al. Hepatology. 2003:37:

13. Natural history of inactive HBsAg carriers Incidence per 100 person years of major events
De Franchis
1993
Bellentani
2002
Manno
2004
Hsu
area
Europe
Asia
N° patients 68 46
296
189
Median follow-up (yrs) 10 9 29 8
Histologic deterioration
0.15 NR
0.06
HCC
0.02
0.19
Liver-related death
0.01
HBsAg loss
1.0
0.9
0.6
NR = not reported

14. Survival in HBsAg carriers and controls
patients= 296
controls = 157
Manno et al., Gastroenterology 2004;127:

15. Percentage of patients who cleared HBsAg
Manno et al., Gastroenterology 2004;127:

16. Chronic HBsAg carriers: HBV DNA level
102
103
106
107
108
109
1010
104
105
CHB
HBeAg +
CHB
HBeAg –
Serum HBV DNA (copies/mL)
Inactive
Patients
Villeneuve JP et al. Gastroenterology Martinot –Peignoux M et al. J.Hepatol Hsu et al Hepatology Mommeja-Marin H et al. Hepatology 2003; Manno,Gastroenterology 2004.

17. 3,774 included in the analysis
The R.E.V.E.A.L. – HBV STUDY
Risk Evaluation of Viral Load Elevation and Associated Liver Disease
23,820 enrolled in
4,155 HBsAg positive
19,665 HBsAg negative
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
P <0.001
Log rank test
Iloeje et al, Gastroenterology 2006; 130:

19. Cumulative incidence of hepatocellular carcinoma
HBeAg negative with normal ALT at Baseline n= 2925
Chen CJ, JAMA 2006; 295:65-73

20. ALT flares in chronic hepatitis B
ALT IU/l
months

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
>vs < cp
>vs < 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
91.6
91.9
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.) % DNA increase >1 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 < 0.2%/yr (Western areas)
0.6% in Asia
with cirrhosis > 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. case-definition sensitive
The “healthy” carrier ( inactive with chronic HBV; PNAL with
chronic HCV)
viraemia
liver histology
outcome
HBV
<104 cp/ml
minimal,
inactive fibrosis
stable
HCV
wide range
20%
significant
20-30%
progression
case-definition sensitive

28. A new type of HBV carrier:
The occult carrier

29. Occult HBV infection 30% in HCV chronic infections
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. Paziente HBsAg positivo con ALT normali:
Il portatore di HBV: inattivo o malato ?
Paziente HBsAg positivo con ALT normali:
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