Farmaci biologici e avventi avversi: Epatite B. Giammarco Mocci SC di Gastroenterologia Azienda Ospedaliera G. Brotzu - Cagliari

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1 Farmaci biologici e avventi avversi: Epatite B Giammarco Mocci SC di Gastroenterologia Azienda Ospedaliera G. Brotzu - Cagliari

2 Biologic agent for Rheumatoid Arthritis MTX- naive approval

3 OPPORTUNISTIC INFECTIONS

4 Global Impact Global Impact of of HBV Infection/Disease at the at turn the turn of of the new Millennium HBsAg-/antiHBc+ Imunocompromised HBsAg+ Imunocompetent 2 billion with evidence of HBV infection >100 million will die of cirrhosis or HCC 25-40% World population 6 billion 400 million with chronic HBV

5 HBV infection: prevalence 350 milioni di persone infette/mondo WHO Summit Conference October 2010 Locarnini S, Journall Hepatol, 2015

6 REUMATOLOGY IBD Inflammatory Disease DERMATOLOGY

7 Prevalence of HBV infection in ID patients ID PATIENTS ARE NOT A GREAT RISK POPULATION!! Lopez-Serrano P, WJH 2015

8 HBV Virological Categories HBsAg-positivi HBsAg-negativi Replicazione Attiva Inattiva OBI HBeAg Pos o Neg Neg Neg HBsAg-negative Anti-HBc Pos Pos Pos Anti-HBe Neg o Pos Pos Neg o Pos HBV DNA UI/mL < Neg* siero HBV DNA UI/mL fegato (qhbsag>1000) (qhbsag<1000) Pos Pos Pos Transaminasi Incrementate Normali Normali Persistenti o Intermittenti Persistentemente Persistentemente Epatite cronica^^ > 90% < 90% No^ Stato di Portatore Occulto Conclamato (OBI) anti-hbe pos. ; in 1/3 dei casi UI; * in più del 90% dei veri OBI; ^ in assenza di concause di epatopatia o storia di pregressa epatite B; ^^score necro-infiammatorio > 4 HAI Marzano A et al, DLD 2011

9 HBV reactivation in immunocompromised ALT 0 HBsAg + CH ++++ HBsAg OBI + Asia: ALT and/or DNA x 10 UNV Italy: ALT > UNV; DNA > pos or 2000 IU

10 Risk stratification for HBV reactivation Virological status HBsAg positive active carrier HBsAg positive inactive carrier Anti-HBc carrier

11 Risk stratification for HBV reactivation Disease Drugs Virus Haemat BMT Onc SOTs HIV Rheum RISK LOW MEDIUM HIGH Leflunomide Rituximab TNFa-inhibitors Other biological DMARDs Cyclophosfamide Combination therapies Medium/high-dose prednisone (>7.5 mg/die) Azathioprine Calcineurin inhibitors Methotrexate 6-mercaptopurine HBsAg+ anti-hbc+ HBsAg+ IBD NULL Low-dose prednisone (<7.5 mg/die) Sulfasalazine Hydroxychlorochine *

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13 HBVr in RA patients undergoing RTX De Nard F et al, WJH 2015

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15 Infliximab Indications ( ) Crohn s Disease US Crohn s Disease EU RA: joint damage Ankylosing Spondylitis Fistulizing CD maintenance Psoriatic Arthritis Moderate - Severe Psoriasis Ped CD RA: signs and symptoms RA: physical function Luminal CD maintenance Early Active RA Ulcerative Colitis CD: 3 rd to 2 nd line PsA: structural damage Indication US New indication Gastroenterology New indication Rheumatology New indication Dermatology

16 Cellular Immune Responses to HBV Ganem D, N Engl J Med 2004

17 HBV reactivation: - 35 (39%) HbsAg carriers - 9 (5%) anti-hbc+ 257 patients with positive HBV markers who received anti-tnf therapy - 89 HbsAg carriers - > in patients previously treated with immunosuppressive agents (96% vs 70%) - < in patients who received antiviral prophylaxis (23% vs 62%) Acute liver failure reported in 5 patients (4 died) anti-hbc+ IFX was associated with a higher rate of induced liver damage compared with ETA Perez Alvarez R et al, Medicine 2011

18 Prevalence of reactivation: 3.9% for treatment with ETA and 4.6% for ADA Cantini F, Intern J Rheumatol 2014

19 HBV reactivation after anti-tnfα in CD Gisbert JP et al, APT 2011

20 Screening: whom and what to check HBsAg HBeAg HBcAb HBVDNA HBeAb HBsAb Bessone F et al, WJH 2016

21 Prevention of HBVr in ID patients: Algorithm Lopez Serrano et al, WJH 2015 Inactive carrier: HBsAg+ ALT nn HBV DNA < 2000 UI OBI: HBsAg-/HBcAb+ ALT nn HBV DNA assente HBVDNA< 2000 UI/ml LAM until 12 mo after IT withdrawal HBVDNA > 2000 UI/ml or IT > 12 mo ETV/TDF Systematic Prophylaxis: RTX Regimi combinati se: HBsAb negative HBV DNA monitoring during follow-up not possible

22 VACCINATION An anti-hbs concentration of 10 miu ml measured 1 3 months after administration of the last dose of the vaccination is considered a reliable marker of protection against HBV infection Chevaux JB et al, IBD 2010 Loras C et al, Am J Gastroenterol 2009 Papa A et al, JCC 2013 Periodic (e.g. annual) testing to assess anti-hbs concentrations (and administering booster doses when anti- HBs levels decline to <10 miu ml) may be considered for IBD patients Rahier JF et al, JCC 2014

23 Hepatitis B Vaccination in IBD Gisbert J.P Gisbert J.P., AJG 2012

24 Hepatitis B Vaccination in IBD Loras C et al, JCC 2014

25 ABATACEPT & HBV Reativation APC MHC TCR T-cell CD28 Abatacept Kim PS et al, Arthritis Care Res 2012

26 TOCILIZUMAB & HBV Reativation «TCZ, if co-administred with pre-emptive NAs, produced favorable outcomes in RA patients and chronic HBV infection» «..Periodic monitoring of liver function tests and HBV-DNA: mandatory» De Nard F et al, WJH 2015

27 IgG1k monoclonal Ab against IL 12/23 Chiu HY et al British J Dermatol 2013

28 Wyant et al, Gut 2015 Vedolizumab did not affect the protective immunity to HBV In a placebo-controlled study of normal volunteers, a single 750 mg dose of vedolizumab did not lower rates of protective immunity to hepatitis B virus in volunteers who were vaccinated intramuscularly with 3 doses of recombinant hepatitis B surface antigen. Hepatitis B surface antibody (HBsAb) Mean HBsAb concentration, IU/L Serum IgA response to oral cholera vaccine Mean IgA titer, IU/L Normal visit day Normal visit day

29 CONCLUSIONS HBV reactivations are not uncommon in inactive HBV patients treated with immunosuppressive therapies for ID Current guidelines highly recommend prophylaxis in case of IS therapies ETV or TDF are recommended as the optimal agents against HBV reactivations Patients with occult or resolved HBV precise regularly HBV DNA monitoring during immunosuppressant therapy in order to detect reactivations There is a paucity of data concerning HBVr among new biological therapies