8 Larissa International Congress of Internal Medicine

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1 8 Larissa International Congress of Internal Medicine Larissa, 18 th March 2016 IBD & Viral Hepatitis Alessio Aghemo, MD, PhD Division of Gastroenterology and Hepatology Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico University of Milan Milan, Italy

2 Epidemiology of HBV and HCV Infection in Europe HBV HCV Hahné et al. BMC Infectious Diseases 2013, 13:181

3 Age-Specific Prevalence of HBV and HCV Infection Immigrants 56 %HBeAg positive Several HDV/HCV coinfected Active/Early disease HBV Italian origin >90% HBeAg negative Few (HCV/HDV) coinfected Inactive/advanced disease AGE HCV 54 % % 9 % 7% 27 % Age-groups (years) Piovesan et al 2014 ; Bellentani et al. Gut 1999;44: ; Delcò F, et al AJG 1998;93:

4 Prevalence of Viral Hepatitis in IBD Patients (I) Study Year IBD Type Patients HBsAg % Anti-HBc % Anti-HCV % Biancone et al. Multicentre, Italy Esteve et al. Multicentre, Spain Tolentino et al. Single-center, Brazil Loras et al. REPENTINA-1 Spain Chevaux et al. Single-center, France 2001 CD / UC 332 / / / / CD CD + UC CD / UC 1128 / / / / CD / UC 252 / / / / 1.59 Weightened Prevalence % 8.1% 3.3% Gisbert JP et al. Aliment Pharmacol Ther 2011; 33:619-33

5 Prevalence of Viral Hepatitis in IBD Patients (II) 301 consecutive IBD patients Single-center, retrospective study Italy 25% 23.9% consecutive IBD patients Single-center, retrospective study Greece & Western Balkans 25% % % HBsAg Anti-HBc HBV Vaccination 1.3% 5 0.8% Anti-HCV 0 2.3% HBsAg Anti-HCV Papa A, et al. J Crohn s Colitis 2013;7:113-9 Katsanos KH, et al. J Crohn s Colitis 2010;4:450-65

6 HBV Virological Categories Active carrier Inactive carrier Anti-HBc pos HBsAg Pos Pos Neg Anti-HBs Neg Neg Pos/Neg Anti-HBc Pos Pos Pos HBeAg Pos/Neg Neg Neg HBV DNA serum IU/mL <2000 IU/mL Neg ALT Increased Normal Normal Liver damage Yes No No HBV DNA tissue Pos Pos Pos Marzano et al. DLD 2007:39;

7 HBV Reactivation During Immunosuppressive Treatment: Pathogenesis Immunosuppressors Cellular Response Hepatocyte HBV-cccDNA Humoral Response Lalazar G et al. Br J Hematol 2007

8 Virological Events Active carriers Progression of liver damage (REACTIVATION) Inactive carriers Increase of viremia and liver damage (REACTIVATION) Anti-HBc Re-emergence of HBsAg (SEROREVERSION) Marzano et al. DLD 2007:39;

9 HBV Reactivation after Infliximab Treatment in HBsAg+ patients with IBD: First Case Reports Study Year HBsAg status Drug Duration Treatment Outcome Esteve et al IFX + AZA 4 infusions No Recovered Esteve et al IFX + AZA 3 infusions LAM Died Colbert et al IFX + AZA + Steroids 24 months LAM Died Esteve et al IFX + AZA 24 months LAM Recovered Loras et al IFX + AZA - LAM Recovered / Died Loras et al IFX + AZA + Steroids - No Recovered IFX: Infliximab; AZA: Azathioprine; LAM: Lamivudine Gisbert JP et al. Aliment Pharmacol Ther 2011; 33:619-33

10 HBV-related Liver Dysfunction in IBD Patients Treated with Immunosuppressive Therapy REPENTINA-2 Trial (19 Spanish Centers) 104 IBD-HBV patients (25 HBsAg+ ; 79 antihbc+) treated with immunosuppressants (Corticosteroids, AZA, IFX, ADA, MTX) Liver Dysfunction: fold ALT increase + HBV-DNA increase > 2000 IU/ml (or HBV-DNA reappearance in previously negative) 50% % 6 hepatic failures /25 HBsAg+ 0% Anti-HBc All reactivations in patients receiving IFX ± AZA ± Steroids Loras C et al. Gut 2010;59:1340-6

11 ECCO OI Consensus Guidelines. J Crohn s Colitis 2014;8:443-68; Marzano et al. DLD 2007:39; EASL HBV Clinical Practice Guidelines J Hepatol 2012;57: ECCO Consensus Guidelines for HBV Infection in IBD Patients receiving Immunomodulator Therapy All IBD patients should be tested for HBV Infection HBsAg, anti-hbs, anti-hbc In HBsAg+ test also HBeAg, antihbe, HBV-DNA HBsAg+ patients should receive potent antiviral agents (Nucleotide/side analogues) before, during and for at least 12 months after cessation of immunomodulator treatment AntiHBc+ patients should be monitored every 2-3 months by HBV- DNA assessment and treated if becoming HBV-DNA positive All HBV seronegative patients should receive HBV vaccination

12 ECCO OI Consensus Guidelines. J Crohn s Colitis 2014;8: Marzano et al. DLD 2007:39; Viganò et al. Epert Opin Biol Ther 2012;12: EASL HBV Clinical Practice Guidelines J Hepatol 2012;57: Prevention and/or Treatment of HBV Reactivation Active carrier Inactive carrier Anti-HBc+ Antiviral Treatment NUC Universal Prohpylaxis* (LAM) NUC** Monitoring NUC: nucleotide/nucleoside analogues; LAM: Lamivudine * Universal prophylaxis should be started 2-4 weeks before therapy and continued at least 6-12 months after immunosuppressive therapy has been suspended ** NUC should be preferred due to long-term immunosuppressive treatment Activate targeted prophylaxis in case of seroreversion

13 Reduced Efficacy of HBV Vaccination in IBD Patients under Immunosuppressive Treatment REPENTINA-3 Study Multicenter Prospective observational study 254 IBD patients receiving HBV vaccination (rhbag double dose months) Revaccination if antihbs<100 IU/ml following first vaccine course 50% First Vaccination Revaccination /254 45/144 Effective vaccination antihbs>100 U/L 110/254 63/144 Seroprotection antihbs IU/L Loras C, et al. J Crohn s Colitis 2014; 8:

14 TNF-alfa in HCV Virus Infection Triggers hepatocyte apoptosis Perpetuates liver inflammation Reduces IFN efficacy in clearing the virus Should we use TNF-alfa inhibitors in the treatment of HCV?

15 Safety of Immunosuppressive Treatments in HCV Patients REPENTINA-2 Trial 51 HCV-RNA positive IBD patients receiving immunosuppressants (Corticosteroids, AZA, IFX, ADA, MTX) Liver Dysfunction: fold ALT increase or significant HCV-RNA increase 50% % 6/8 receiving steroids All cases with MILD liver dysfunction /51 HCV+ Loras C et al. Gut 2010;59:1340-6

16 Safety of anti-tnf drugs in HCV-infected Patients Indication Patients Anti-TNF Tx Duration ALT increase HCV-RNA increase (> 2 Log) Rheumatology 83 IFX/ETA/A DA 3-44 mo 2 4 Crohn s Disease 4 IFX 1-12 mo 0 0 Psoriasis 6 ETA 6-12 mo 0 0 Various 15 ETA 3-14 mo 0 0 IFX: Infliximab; ETA: Etanercept; ADA: Adalimumab Viganò et al. Epert Opin Biol Ther 2012;12:

17 Natural History of HBV and HCV Infection in IBD Cirrhosis development rate in IBD patients: - 4/25 (16%) HBsAg+ patients after a mean of 13.5±4.2 years - 8/74 (10.8%) HCV+ patients after a mean time of 16.7±4.8 years Loras C et al. Gut 2010;59:1340-6

18 ECCO OI Consensus Guidelines. J Crohn s Colitis 2014;8: Viganò et al. Epert Opin Biol Ther 2012;12: Management of HCV Infection in IBD Patients Screening for HCV infection is recommended anti-hcv (+ HCV-RNA in anti-hcv+) Immunomodulators are not contraindicated in HCV+ patients, however the decision depends on the severity of IBD and liver disease. Regular Monitoring of liver tests is recommended (AST,ALT, ALP, GGT, bilirubin, albumin, platelets every 3 months) No data are available with anti-tnf drugs in hepatic dysfunction ( contraindicated in decompensated cirrhosis)

19 The HCV Life Cycle and Antiviral Therapy Targets CD81 Receptors Liver cell Transport and release Core of the virus released RNA uncoating Nucleocapsid assembly NS5A inhibitors New Therapies & Targets Life Cycle Step Translation & polyprotein processing Protease inhibitors NS5A inhibitors RNA replication NS5B polymerase inhibitors RNA synthesis

20 SVR Rates +/- RBV in Phase III Studies of Interferon Free Regimens Ferenci et al, Nat Rev Gastroenterol Hepatol 2015:12:284-92

21 IBD Drugs & HCV Treatment: Drug-drug Interactions with DAAs Azathioprine Mesalazine Steroids steroid effect if coadministered with OBV/PTV/r (2D-3D regimen) Simeprevir antiviral effect No data with anti-tnf agents