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

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

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; 118:191-194 Baseline: 92 pts, HBsAg positive blood donors, normal ALT Follow-up: mean 130 mo., 68 pts; 21 with biopsy HBV-DNA: spot-dot hybridization

Characteristics at the baseline No Caption Found Characteristics 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

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

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

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

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

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.

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. 2003:37:1309-1319.

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

Survival in HBsAg carriers and controls patients= 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 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 1994. Martinot –Peignoux M et al. J.Hepatol 2002. Hsu et al Hepatology 2002. Mommeja-Marin H et al. Hepatology 2003; Manno,Gastroenterology 2004.

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 1991-1992 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

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

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

ALT flares in chronic hepatitis B ALT IU/l months

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

Classification of inactive carrier vs. chronic hepatitis Correct Sensitivity Specificity classification HBV DNA >vs < 30.000 cp >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 91.6 91.9 Manesis, Am J Gastro 2003

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 >1 log 6.6% ALT elevation 1 anti-HBs seroconversion Piccolo et al, EASL 2006, abs. # 469

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

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

Cofactors influencing the outcome of inactive HBV carriers HCV coinfection HDV coinfection HIV coinfection Alcohol abuse, steroids, immunosuppression

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

A new type of HBV carrier: The occult carrier

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

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