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HCV storia natural e cofattori
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 ALT (epatite post-trasfusionale a lunga incubazione, evoluzione in cronicità) HBsAg (Antigene Australia) Istologia (Desmet, 1973) Biologia Molecolare Alta sensibilità Anni ’50-’60 ’60 ’70 ‘90 2000 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 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 1 Artus Biotech 10 102 103 104 105 106 107 108 109 1010 HBVDNA cp/mL 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 Bayer Corp. Versant HBV DNA 1.0 NA Versant HBV DNA 3.0 1 10 102 103 104 105 106 107 108 109 1010 HBV DNA IU/mL Locarnini et al., Antiv.Therapy 2004 The era of molecular biology Few copies of HBV-DNA can be detected (10 –102) What the clinical significance ? infection/disease 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 1 Artus Biotech 10 102 103 104 105 106 107 108 109 1010 HBVDNA cp/mL 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 Bayer Corp. Versant HBV DNA 1.0 NA Versant HBV DNA 3.0 1 10 102 103 104 105 106 107 108 109 1010 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 Histology Activity Index (HAI) Correlation between HAI and HBV DNA in untreated patients (r=0.78; P=0.0001) HBV DNA level (log10 c/mL) Mommeja-Marin H, et al. Hepatology. 2003:37:1309-1319. Median improvement in HAI Correlation between change in HBV DNA and HAI with treatment Review of 26 prospective studies (r=0.96; P<0.0000) Median log10 HBV DNA decrease 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 2002 Europe Europe Europe Asia ● N° patients 68 46 296 189 ● Median follow-up (yrs) 10 9 29 8 0.15 NR NR 0.06 ● HCC 0 0 0.02 0.19 ● Liver-related death 0 0 0.01 0 1.0 0.9 1.0 0.6 ● area ● Histologic deterioration ● HBsAg loss 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 Serum HBV DNA (copies/mL) Chronic HBsAg carriers: HBV DNA level 1010 109 108 107 106 CHB HBeAg + CHB HBeAg – 105 104 103 102 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. 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 N = 3582 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 400 300 200 100 0 months HBV-DNA, ALT and IgM anti-HBc in 40 hepatitis exacerbations in 23 HBV carriers HBV-DNA ALT IgM 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 Correct Sensitivity classification Specificity HBV DNA >vs < 30.000 cp 94.3 80.0 100.0 HBV DNA >vs < 100.000 cp 90.8 68.0 100.0 >vs < 0.200 81.6 56.0 91.6 DNA + IgM 92.0 92.0 91.9 anti-HBc IgM 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 cirrhosis • 8-10% in HBeAg 6.2% neg •Predictors: older age, alcohol, coinfections, •recurrent flares, bridging necrosis, •fibrosis stage, genotype(?) cirrhosis 49.2% From: Brunetto, 2002 Outcome of HBsAg/anti-HBe pos cirrhosis no. = 62 Median follow-up 6 years (2-12) Hepatic decompensation • 3%/yr 47% with ascites 12% jaundice 9% variceal bleeding 30% more than one cirrhosis at Hepatocellular carcinoma baseline without cirrhosis < 0.2%/yr (Western areas) 0.6% in Asia worsened with cirrhosis > 2.0%/yr 22% Predictors: older age, male gender, alcohol, environmental factors, coinfections, genotype 10 HCC 9 terminal events From: Brunetto, 2002 Cofactors influencing the outcome of inactive HBV carriers • HCV coinfection • HDV coinfection • HIV coinfection • Alcohol abuse, steroids, immunosuppression The “healthy” carrier ( inactive with chronic HBV; PNAL with chronic HCV) viraemia liver histology outcome HBV HCV <104 cp/ml wide range minimal, inactive fibrosis 20% significant stable 20-30% progression case-definition sensitive A new type of HBV carrier: The occult carrier 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 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