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Giovanni Battista Gaeta Unità Epatiti Virali Acute e Croniche Seconda Università di Napoli Paestum, 18 maggio 2006 Il portatore di HBV: inattivo o malato.

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Presentation on theme: "Giovanni Battista Gaeta Unità Epatiti Virali Acute e Croniche Seconda Università di Napoli Paestum, 18 maggio 2006 Il portatore di HBV: inattivo o malato."— Presentation transcript:

1 Giovanni Battista Gaeta Unità Epatiti Virali Acute e Croniche Seconda Università di Napoli Paestum, 18 maggio 2006 Il portatore di HBV: inattivo o malato ?

2 Il progresso nella definizione della 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 2000 Alta sensibilità

3 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

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 Digene Corp. Roche Molecular Systems Bayer Corp. 10 2 10 4 10 3 10 5 10 6 10 7 10 810 10 9 101 HBV 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 10 2 10 4 10 3 10 5 10 6 10 7 10 810 10 9 101 HBVDNA cp/mL

8 The era of molecular biology Few copies of HBV-DNA can be detected (10 –10 2 ) What the clinical significance ? infection/disease

9 Inactive HBsAg carrier Presence of HBsAg and anti-HBe in serum Serum HBV DNA < 10 5 copies/ml Persistently normal serum ALT > 6 months Liver histology (not essential) HAI grade < 3 Standardisation of Nomenclature for Hepatitis B (EASL consensus conference September 2002)

10 Digene Corp. Roche Molecular Systems Bayer Corp. 10 2 10 4 10 3 10 5 10 6 10 7 10 810 10 9 101 HBV 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 10 2 10 4 10 3 10 5 10 6 10 7 10 810 10 9 101 HBVDNA cp/mL

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. 2003:37:1309-1319.

12 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)

13 Natural history of inactive HBsAg carriers Incidence per 100 person years of major events De Franchis 1993 Bellentani 2002 Manno 2004 Hsu 2002 areaEurope Asia N° patients6846296189 Median follow-up (yrs)109298 Histologic deterioration 0.15NR 0.06 HCC000.020.19 Liver-related death000.010 HBsAg loss1.00.91.00.6 NR = not reported

14 Survival in HBsAg carriers and controls patients= 296 controls = 157 Manno et al., Gastroenterology 2004;127:756-763

15 Percentage of patients who cleared HBsAg Manno et al., Gastroenterology 2004;127:756-763

16 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. Inactive Patients CHB HBeAg + Serum HBV DNA (copies/mL) CHB HBeAg – 10 2 10 3 10 6 10 7 10 8 10 910 10 4 10 5

17 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 STUDY Risk Evaluation of Viral Load Elevation and Associated Liver Disease Chen CJ, EASL Meeting 2005, Abs.#476

18 Cumulative incidence of cirrhosis Iloeje et al, Gastroenterology 2006; 130:678-686 N = 3582 P <0.001 Log rank test P <0.001 Log rank test

19 HBeAg negative with normal ALT at Baseline n= 2925 Cumulative incidence of hepatocellular carcinoma 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 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

23 705 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

24 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(?)

25 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 terminal events Hepatic decompensation 3%/yr 47% with ascites 12% jaundice 9% variceal bleeding 30% more than one 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

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) viraemia liver histology outcome HBV <10 4 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 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 60% in HBsAg negative hepatocellular carcinoma Torberson & Thomas, Lancet Infect Dis, 2002 Pollicino et al, Gastroenterology, 2004

30 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:


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