Trapianto di fegato e organi solidi. Pierluigi Toniutto Sezione di Epatologia e Trapianto Epatico Università di Udine

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2 Trapianto di fegato e organi solidi Pierluigi Toniutto Sezione di Epatologia e Trapianto Epatico Università di Udine

3 Case 2 53-yr old white man PSC (CTP score 10, MELD 23, status UNOS 2B) HBsAb-, HBcAb- HCVAb- No signs of cholangiok Tense ascites OLT with female whole cadaveric liver (HBsAb+, HBcAb-) in 2004 Piggyback technique

4 Case 2 Bile duct reconstruction performed with end-to-end anastomoses with T-tube Discharged from the hospital 16 days after transplant TAC (blood levels between 10 to 15 ng/ml) + prednisone (25 mg/d) based immunosuppression Normal renal function

5 9 months later... The patient presented with anorexia and fatigue with fever (38 C) US examination revealed patent vascular anastomoses without dilation of the biliary three. Hepatic artery RI: No ascites ALT 1640 UI/L AST 1320 UI/L GGT 528 UI/L AF 498 UI/L BIL T/D 4.3/3.8 mg/dl HB 12.9 gr/dl WBC 4380/mm 3 PLT /mm 3

6 Discuss Diagnostic approach to acute hepatitis in the first year after LT

7 Potential causes of acute hepatitis in relation to the time elapsed from LT Rec of non HCV primary liver disease Lympho-proliferative disease Infective/toxic liver injury Viral related hepatitis Autoimmune hepatitis ACR Infections Biliary complications CMV HCV PNF EGD HAT PVT Ischemic/preservation injury months From: Zakim and Boyer: Taxbook of Hepatology; Saunders; 2006.

8 Case 2 CMV-DNA- EBV-DNA- HEV-RNA not available HCV-RNA- HBsAg+, HBeAg+, HBeAb+, HBcAb IgM+, HDVAg- HBV-DNA cp/ml Liver biopsy: acute hepatitis with ground glass cells, positive immune-reactivity to HBsAg. No rejection.

9 Discuss Clinical management Antiviral approach

10 Cumulative incidence of HBV resistance to LAM, ADV, ETV, LdT and TDF in pivot trials in nucleos(t)ide-naive patients with chronic HBV related hepatitis EASL Clinical guidelines of HBV. J Hepatol; 2012.

11 3 months later... LAM 100 mg + ADV 10 mg/day HBsAg-, HBsAb 59 UI/L, HBeAb+, HBeAg-, HBcAb T/IgM +/- HBV-DNA <200 cp/ml ALT 29 UI/L AST 21 UI/L GGT 31 UI/L AF 133 UI/L BIL T/D 0.8/0.5 mg/dl HB 14.2 gr/dl WBC 8890/mm 3 PLT /mm 3 Creatinin clearance 76 ml/min (Cockroft-Gault)

12 Discuss How to manage antiviral therapy

13 Discuss No clear indications to stop antivirals in HBsAb seroconversion in the early phase Maintenance of antivirals Lampertico et al. J Hepatol; 2015.

14 Further 3 months later... LAM 100 mg + ADV 10 mg/day HBsAg-, HBsAb 158 UI/L, HBeAb+, HBeAg-, HBcAb T/IgM +/- HBV-DNA <200 cp/ml Normal LFT Normal kidney function Stop LAM +ADV 12 month later: HBsAb 550 UI/L HBV-DNA undetectable Normal LFT

15 Discuss Factors associated to HBsAb seroconversion Role of HBV vaccination When For whom Transfer of HBV immunity from donors Monoclonal Ab to HBV

16 Vaccination against HBV Pre LT Post-LT Pre and post-lt

17 Vaccination against HBV Pre LT Pr e-ol T Disease Liver Cirrhosis Number of Success Reference Year M ethods Definition of Success Patients Rate (%) Number Published Novel adjuvant MPL/QS2 vaccine for 0, 4, 16, 18 weeks 16 HBsAb >500 IU/L without HBIG 80 [72] 2007 Experimental adjuvant vaccine for 0, 1, 2, 6, 12 months 8 HBsAb >500 IU/L 18 months without HBIG 25 [74] μg for 0, 1, 2, 6, 7, 8 months 18 HBsAb >500 IU/L 12 weeks after last vaccination 0 [70] 2009 Acute Liver Failure μg/month with minimal immune suppression 17 HBsAb >100 IU/L without HBIG 64 [78] μg/month 22 HBsAb >100 IU/L 6 months without HBIG 40 [77] μg/month 15 HBsAb >100 IU/L 3 months without HBIG 0 [68] μg 0, 1, 2, 3, months, 20 μg 4, 5, 6 months 50 HBsAb >60 IU/L 3 months without HBIG 24.6 [75] μg 0, 7, 14, 28 days, 20 μg 2, 3, 4 months 45 HBsAb >60 IU/L 3 months without HBIG 8.8 [75] μg 0, 1, 6 months 17 HBsAb >10 IU/L without HBIG 82 [69] μg for 0, 1, 2, 3, 4, 5 months 52 HBsAb >10 IU/L without HBIG 7.7 [73] μg/month 5 HBsAb >100 IU/L 6 months without HBIG 100 [77] μg/month with minimal immunosuppression 3 HBsAb >100 IU/L without HBIG 66 [78] 2009 Experimental adjuvant vaccine for 0, 1, 2, 6, 12 months 2 HBsAb >500 IU/L 18 months without HBIG 100 [74] 2005 HBIG, hepatitis B immunoglobulin; HBsAb, hepatitis B surface antibody. Takaki et al. Int J Mol Sci; 2015.

18 Algorithm for prophylaxis to prevent DNHB for recipients of HBcAb+ liver grafts Lin et al. WJG; 2015.

19 Vaccination against HBV Post LT * * *mainly related to HBsAg escape mutants Ishigami et al. Liver Transpl; 2014.

20 Vaccination against HBV Transfer of HBV immunity from donors Third generation vaccines (S protein, pres1 and pre S2 proteins) LDLT immunized for HBV transplanted in 14 recipients with chronic liver disease Cellular HBV immunity observed in 3 of 14 donor/recipient pairs. Schumann et al. Transplantation; 2009.

21 Vaccination against HBV Monoclonal Ab antibodies to S protein of HBV PBMC obtained from a vaccinated healthy donor (ADRI) and from person convalescing from acute HBV (PK) Cerino et al. PlosOne; 2015.

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