Pierluigi ToniuttoSezione di Epatologia e Trapianto EpaticoUniversità di Udine

Trapianto di fegato e organi solidi

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

Case 2

• Bile duct reconstruction performed with end-to-endanastomoses 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

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: 0.66. 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/mm3

• PLT 219000/mm3

Discuss

• Diagnostic approach to acute hepatitis in the first year after LT

0 1 2 3 4 5 6 7 months

PNFEGDHATPVT

Ischemic/preservation injury

ACRInfections

Biliary complicationsCMV

HCV

Rec of non HCV primary liver diseaseLympho-proliferative disease

Infective/toxic liver injuryViral related hepatitis

Autoimmune hepatitis

Potential causes of acute hepatitis in relation to the time elapsedfrom LT

From: Zakim and Boyer: Taxbook of Hepatology; Saunders; 2006.

Case 2

• CMV-DNA-• EBV-DNA-• HEV-RNA not available• HCV-RNA-• HBsAg+, HBeAg+, HBeAb+, HBcAb IgM+, HDVAg-• HBV-DNA 1280000 cp/ml• Liver biopsy: acute hepatitis with “ground glass cells”, positive

immune-reactivity to HBsAg. No rejection.

Discuss

• Clinical management• Antiviral approach

Cumulative incidence of HBV resistance to LAM, ADV, ETV, LdTand TDF in pivot trials in nucleos(t)ide-naive patients with chronicHBV related hepatitis

EASL Clinical guidelines of HBV. J Hepatol; 2012.

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/mm3

• PLT 242000/mm3

• Creatinin clearance 76 ml/min (Cockroft-Gault)

Discuss

• How to manage antiviral therapy

Discuss

• No clear indications to stop antivirals in HBsAbseroconversion in the early phase

• Maintenance of antivirals

Lampertico et al. J Hepatol; 2015.

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 + ADV12 month later:• HBsAb 550 UI/L• HBV-DNA undetectable• Normal LFT

Discuss

• Factors associated to HBsAb seroconversion• Role of HBV vaccination

– When– For whom

• Transfer of HBV immunity from donors• Monoclonal Ab to HBV

Vaccination against HBV

• Pre LT• Post-LT• Pre and post-LT

Vaccination against HBV

• Pre LT

Pre-OLT Disease Methods Number of Patients Definition of Success

Success Rate (%) Reference Number Year Published Liver Cirrhosis 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] 2005

40 μg for 0, 1, 2, 6, 7, 8 months 18

HBsAb >500 IU/L 12 weeks after last vaccination 0 [70] 2009

10–20 μg/month with minimal immune suppression 17 HBsAb >100 IU/L without HBIG

64 [78] 2009

20 μg/month 22

HBsAb >100 IU/L 6 months without HBIG 40 [77] 2012

20 μg/month 15

HBsAb >100 IU/L 3 months without HBIG 0

[68] 2011

40 μg 0, 1, 2, 3, months, 20 μg 4, 5, 6 months 50

HBsAb >60 IU/L 3 months without HBIG 24.6 [75] 2013

40 μg 0, 7, 14, 28 days, 20 μg 2, 3, 4 months 45

HBsAb >60 IU/L 3 months without HBIG 8.8 [75] 2013

40 μg 0, 1, 6 months 17

HBsAb >10 IU/L without HBIG 82 [69] 2000

40 μg for 0, 1, 2, 3, 4, 5 months 52

HBsAb >10 IU/L without HBIG 7.7 [73] 2005

Acute Liver Failure 20 μg/month 5

HBsAb >100 IU/L 6 months without HBIG 100 [77] 2012

10–20 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.

Algorithm for prophylaxis to prevent DNHB for recipients of HBcAb+ liver grafts

Lin et al. WJG; 2015.

Vaccination against HBV

• Post LT

Ishigami et al. Liver Transpl; 2014.

**

*mainly related to HBsAg escape mutants

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.

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.