Società Italiana di Ematologia

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1 Società Italiana di Ematologia Sessione Educazionale 41 Congresso Nazionale Chemioterapia nel Portatore di Virus Epatitici Fisopatologia e diagnosi Sessione Educazionale Alfredo Marzano UODU Gastroepatologia Ospedale San Giovanni Battista di Torino

2 Società Italiana di Ematologia Sessione Educazionale 41 Congresso Nazionale Chemioterapia nel Portatore di Virus Epatitici Fisopatologia e diagnosi Sessione Educazionale Alfredo Marzano UODU Gastroepatologia Ospedale San Giovanni Battista di Torino

3 IDENTIFICATION OF VIRUS INDUCED LIVER DISEASE COINFECTIONS virus HEPATITIS LIVER DISEASE Other factors causing liver damage dismetabolisms, drugs, other hepatotropic viruses

4 Compagni di Viaggio! Autoimmunità Sindrome metabolica: diabete, dislipidemia etc Alcol Farmaci Disordini del metabolismo marziale Compartecipazione in malattie sistemiche Cause rare (Wilson, porphyria, A1AT etc)

5 Natural History of Chronic hepatitis Resolution Stabilisation Compensated Cirrhosis Acute Infection Chronic Hepatitis Cirrhosis Liver Cancer Death Fulminant Chronic Carrier Progression Decompensated Cirrhosis (Death) Years Adapted from Feitelson, Lab Invest 1994

6 PSE SBP Ascites Portal Hypertension (mmhg) 24 Bleeding Varices Subclinical portal hypertension 6 Portal hypertension = HVPG 6 mmhg Clinically significative portal hypertension >10 mmhg 0 Baveno III

7 Ipertensione portale coinvolgimento nelle malattie ematologiche Post-epatica postsinusoidale Intra-epatica sinusoidale presinusoidale Pre-epatica

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9 Spider nevi Splenomegaly Caput medusae Is it portal hypertension? Piastrinopenia Ipergammaglobulinemia What is the aetiology? Portal vein diameter >13 mm Portal venous flow velocity < 14 cm /sec Ombelical vein patency Esophageal varices

10 1. Definitions Clinical definitions A. 1. Baseline Liver disease? Virological categories (Update 2007: Fibroscan, role of liver biopsy) IDENTIFICATION OF HEPATITIS VIRUSES CARRIERS WITH LIVER DISEASE Latitude Longitude Time Date ALT HBV-DNA IgM anti-hbc N, O ; 8.15 a.m.,

11 The speed of propagation of the shear wave is proportional to the stiffness of the liver

12 Tecnica Cateterismo delle sovra-epatiche, HVPG e biopsia trans-giugulare Inserire scanner figure

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14 Hepatitis Virus Coinfection 63% HBV DNA+ 78% HBV DNA- Marzano, Liver Transplantation, April pts HBV+HCV (HBC) 30 pts HDV+HBV+HCV (HDC) Act HBV Act HCV 24 Inact HBV Inact HCV 15 Act HBV Inact HCV 15 Inact HBV Act HCV 49 Fluctuations 32/ 103 (31%) 15 active HDV; 15 HBV and HCV active, fluctuating in 8/15 (53%) Raimondo and AISF cooperative group, Hepatology 2006

15 Pathogenesis of viral hepatitis

16 HBV or HCV carrier Decreased immune recognition of virus-infected hepatocytes while chemotherapy immunosuppression Increased virus replication serum HBV DNA intrahepatic HBcAg number of productively HBV-infected hepatocytes* Rebound immune recognition of HBV-infected hepatocytes after restored T-cell function upon immunosuppression withdrawal (+++)

17 Fibrosant cholestatic hepatitis in immunocompromised +++ Immunosuppression +++ Viral load

18 HBV or HCV carrier Decreased immune recognition of HBV-infected hepatocytes while chemotherapy immunosuppression (-) Increased virus replication serum viremia intrahepatic viral antigenes number of productively viral-infected hepatocytes* Rebound immune recognition of viral-infected hepatocytes after restored T-cell function upon immunosuppression withdrawal (+++)

19 Lobular hepatitis

20 Prevalence of HBV and HCV in haematology HBV HCV HBsAg+ HBsAganti-HBc+ Europe China Europe China Range % 40% 80% Taiwan %*, ** Italy 8.8% 41.7% 17.5% Lymphoma in carriers 0R 2.6 (China)-2.8 (USA) in B-NHL Wang F et al, Cancer 2007; Ulcickas YM et al, Hepatology % (mean 12.4) Idiopathic 8-10% Cryoglob. type II *Mazzaro et al, DLD 2005, ** Zignego et al for the AISF, DLD 2007, Marcucci et al,haematologica 2006

21 Diagnosis HBV HCV HDV Diagnostic categories Anti-HBs Anti-HCV Anti-HDV immunity Anti-HBc exposure HBsAg infection HBV-DNA HBeAg HCV- RNA HDV- RNA replication IgM anti-hbc IgM anti-hcv IgM anti-hdv disease ALT inflammation

22 The dimension of HBV infection depends on its definition in Italy 2/100,000 HBsAg+ < 2% general population HBsAg+ Up to 20% HBsAgantiHBc+ Acute infection Chronic infection Inactive Infection Resolved infection ALT S-HBV DNA antihbc+/intra-hepatic HBV DNA

23 Natural course of chronic hepatitis B e-minus HBeAg HBeAg+ Chronic Hepatitis B anti-hbe anti-hbe+ Chronic Hepatitis B ALT wildtype e minus mutant

24 Diagnostic significance of IgM anti-hbc Titer 188 1/10 5 1/ IMx Index 0.2 IMx Index 118 Chronic Acute Absent Hepatitis B Brunetto MR, 1988

25 Dynamic Ranges of HBV DNA Quantification HBV Digene Hybrid-Capture I Digene Corp HBV Digene Hybrid-Capture II Ultra-Sensitive Digene Hybrid-Capture II Bayer Corp. Versant HBV DNA 1.0 NA Versant HBV DNA 3.0 Roche Molecular Systems Amplicor HBV Monitor Cobas Amplicor HBV Monitor Cobas Taqman 48 HBV Artus Biotech Real Art HBV LC PCR HBV DNA IU/mL 10 10

26 Copy number ( log 10 ) Isotopic probe (full length) Nucleic acid amplification Sensitivity of nucleic acid (HBV DNA) and detection methods PCR PCR 10 5 copies/ml=100,000 copies/ml=20,000 UI/ml Nucleic acid amplification

27 1. Definitions A. Virological categories Update 2007: dynamic monitoring, specialistic evaluation

28 X Liver transplantation in HBsAg- recipients of antihbc+ donors Background Pooled data from 145 patients Recipient status antihbc+ antihbs± antihbcantihbs+ antihbc- antihbs- De-novo hepatitis B No prophylaxis NA 6/61 (9%) 74/99 (75%) De-novo hepatitis B prophylaxis 0 Prophylaxis No prophylaxis LAM* HBIG+LAM * + Perioperative HBIG adapted from Marzabeita, Liver Transplantation 2002

29 Anti-core positive patients: risk of sero-reversion in immunocompromised patients HBsAb HBsAg ALT days Wands 1975

30 1. Definitions A. Virological categories B. Virological events C. Clinical definitions A. Infection: HBV DNA and/or HBsAg+ in HBsAg+ or HBsAg- B. Disease (hepatitis): significant HBV DNA and ALT> UNV (+IgMHBc)

31 1. Definitions 2. Treatment strategies

32 Nucleos(t)ide analogues for HBV therapy Trade name Company Dosage * 2007 Nucleoside analogue - Lamivudine - Entecavir - Telbivudine - Emtricitabine ZEFFIX BARACLUDE TYZECA/SEBIVO* EMTRIVA ^ 100 mg/die 0.5mg/1mg/die 600 mg/die 200 mg/die Nucleotide analogue - Adefovir Dipivoxil HEPSERA 10 mg/die Tenofovir Disopr. Fum. VIREAD ^ 300 mg/die 415 Nucleoside+nucleotide analogue - Emtricitabine + * Tenofovir Disopr. Fum. ^ Drug approved for HIV TRUVADA ^ * Not available in Italy 200 mg mg/die *

33 HBV Therapeutic options log Adefovir log Lamivudine Telbivudine log Tenofovir log Nucleoside analogues Nucleotide analogues log log log Entecavir log log Adapted from van Bommel et al EASL 2005

34 LAM-resistance in immunocompromised active carriers YMDD emergence in patients treated with lamivudine before (immunocompetent) or after- LT (immunocompromised) (180, 204, 173) Patients (%) Rayes 2001 Nery 1998 Perrillo 1999 Fisher 2000 Malkan 2000 Ben-Ari % Fontana % 27% 60-65% 25 10% ) 0 Months of therapy: 6 m Reference: Rosenau Fontana Villeneuve Fontana Marzano Andreone Kapoor Perrillo Hadzyannis 2000 Lok 2003 Gaia 2004 AISF group 2004

35 Genetic barriers to antiviral drug resistance LVD 204 ± 180 Wild-type virus Lamivudine-resistant virus ADV 236 +/or or Adefovir-resistant virus Entecavir-resistant virus ADV in LVD-resistant patients ETV 236 +/or 181? 184 or 202 or 250 LVD then ETV 204 ± Adaptetd by Locarnini S, et al. J Hepatol 2006; 44:

36 Resistenze associate agli analoghi nucleos(t)idici L80I/V V84M; S85A V173L* L180M A181T/V A/S/T184A/G/I/S A194T S202G/I M204I/S M204V V214A; G215S N236T M250V nuclesidici nucleotidici LAM FTC LdT ETV ADV TDF *overlap S/P BASSA INTERMEDIA ALTA

37 Anti-HBV Drugs Potency LAM Telbivudine ETV in LAM-R ADF in LAM-R ETV in LAM naive ADF in naive TDF + Resistance Profile -

38 Response to nucleos(t)ide analogue therapy ALT HBV-DNA (log) LLQ ADV 10 mg/die Months

39 Virologic breakthrough ALT HBV-DNA (log) LLQ Clinical resistance Virologic breakthrough (genotypic resistance) Months

40 Clinical resistance (BR + VR) ALT HBV-DNA (log) LLQ Clinical resistance Months

41 Società Italiana di Ematologia 41 Congresso Nazionale Sessione Educazionale Take home messages 1. In tutti i pazienti Baseline Epatologico (virus + concause) Valutazione della condizione virologica 2. Pazienti HBV Monitoraggio Sessione Marcatori Educazionale ALT e HBV DNA PCR se profilassi o terapia; ALT e HBsAg in HBsAg-/anti-HBc+ 3. Pazienti HCV Monitoraggio ALT HCV RNA solo se influenza le scelte terapeutiche 4. Pazienti HDV Monitoraggio ALT HDV RNA solo se influenza le scelte terapeutiche