Viral Hepatitis AndLiver Transplantation

Dr .Zeki KARASUEge University Medical School

Dep. Gastroenterology

Hepatitis B

HBV infection

in liver transplant recipients,

in western countries.

3-7 %10 %

0

20

40

60

80

100

120

94-95-96

97 98 99 2000 2001 2002 2003 2004 2005 2006 2007 2008

Ege University Experience

Total Live donor Cadaveric

020406080

100120140160180200220240260280300 HBV

HBV+D

HCV

Alcohol

PBC

PSC

Wilson

Budd-C

Fulminan

Autoimmun

Cryptogenic

Number

Ege University ExperienceEtiology (607 adult)

HBV Recurrence%

Time (years)

Survival (%)

Kim et al. Liver Transpl 2004; 10: 968–974

No prophylaxis

HBIG or LamivudinNon-HBV

HBIG+Lam

50

60

70

80

90

100

0 1 2 3 4 5

Post-Txprophylaxis

Treatment of recurrent

disease

Time

Pre-Tx treatments

Cirrhosis

Goals of Antiviral TherapyPre Transplant

To suppress the viral replication to undetectable HBV DNA levels. To avoid post transplant recurrence(Without acquiring resistance)

Control hepatic decompensation.

Avoid transplant.

Days Post-LTHBV DNA Patients at risk≥ 100,000 18 15 12 3< 100,000 159 86 28 9

100

60

20

P = .0003

HBV DNA> 100,000 copies/mL

HBV DNA < 100,000 copies/mL

0 1000 2000 3000

% H

BV

Rec

urre

nce

HBV DNA Level Pre-Transplant Predicts Risk of HBV Recurrence

Marzano et al. Liver Transpl 2005;11:402-409

In those patients with low HBV DNA levels recurrence rate was competible with patients undergoing LTX with undetectible serum HBV DNA.

HBV DNA < 400 copies/mL

%

Tenofovir(n = 45)

Tenofovir/ Emtricitabine

(n = 45)

Entecavir(n = 22)

Wk 12 51 47 50

Wk 24 66 74 68

Wk 48 71 88 73

Antiviral Therapy in Decompensated Cirrhosis

Schiff E, et al. AASLD 2009

Post-Txprophylaxis

Treatment of recurrent

disease

Time

Pre-Tx treatments

Cirrhosis

HBIG

+

Lamivudin(or other nucs)

HBIG Regimens used in US LT Centers

183 pts from NIH HBV-OLT study.All high dose HBIG perioperatively.

Degertekin et al AASLD 2008

Maintenance:A) iv 10,000IU/monthB) iv 1,000-5,000IU/monthC) im 1,000-5,000IU/monthD) discontinuation of HBIG

Recurrence (5 y)14%3%

10%10%

Karasu Z, et al. Antiviral Therapy 2004 Dec;9(6):921-7

Ege University ExperienceLow dose HBIG+Lamivudin:

80 cases

5% recurrence

median 18 (3-73) months follow up

Cadaveric100

209 HBV

Living donor109

HBV DNA (+):5 HDV :22

HBV DNA (+):5 HDV :40

HBV recurrence5

HBV recurrence6

follow-up 18 (6-48) months

11/2095 %

Reappearance of HBsAg after its initial disappearance post-OLT

Karasu Z. et al. J Gastroenterol Hepatol. 2007 Dec;22(12):2124-9.

Lam Plus Low-dose HBIG to Prevent Recurrent HBV Following LT

147 HBsAg-positive pts over 8 years.

LAM at transplant listing

HBIG IM 800 IU (7 days); 400-800 IU/month

Gane et al. Gastroenterology 2007;132(3):931-937

HBV recurrence 4% at 5 years.

Can we stop HBIG

2 types of approachs;

Active immunoprophylaxis or vaccination

Discontinuation of HBIG and continuing

prophylaxis with nucleoside analogues

HBV Vaccination: The first study from Spain reported encouriging results. However, these encouraging results were not confirmed in subsequent studies. To investigate the efficacy of HBV vaccination we conducted a study. We administered double course of double dose recombinant HBV vaccine, including pre-S antigens.

14 patients included into the study

Recombinant HBV vaccine (Genhavac B; containing HBV pre-S1, pre-S2, and S gene)

Vaccination started one month after HBIg discontinuation, and lamivudine (100 mg/day) was given throughout the study.

The first cycle 0, 1-, 6-month schedule

second cycle 0, 1-, 2-month scedule

Karasu Z, et al. J Viral Hepatitis 2004

Only 1 patient seroconverted

Post-Txprophylaxis

Treatment of recurrent

disease

Time

Pre-Tx treatments

Cirrhosis

0

20

40

60

80

Week48

Week96

Week144

HBV DNA (-)Hbe Ag (-)

ALT normalized

HBV DNA (-) Hbe Ag (-) ALT normalized

Schiff et al. Liver Transplantation 2007

Adefovir For LAM-Resistant HBV Recurrence

With continued treatment, an increasing proportion of patients who remained in the study had undetectable serum HBV DNA levels.

Cadaveric100

209 HBV

Living donor109

HBV DNA (+):5 HDV :22

HBV DNA (+):5 HDV :40

HBV recurrence5

HBV recurrence6

follow-up 18 (6-48) months

11/2095 %

11 HBVrecurrence

HBV DNA (-)7

3 DiedHCC recurrence2 HBV DNA (-)

Lamivudin+AdefovirSTOPHBIG

18 (6-48) months

HBV DNA (+)1

Akyıldız M, et al. Journal of Gastroenterology and Hepatology2007

11 HBVrecurrence

HBV DNA (-)7

3 DiedHCC recurrence2 HBV DNA (-)

Lamivudin+AdefovirSTOPHBIG

18 (6-48) months

HBV DNA (+)1

Tenofovir

HBV DNA (-)1

Akyıldız M, et al. Journal of Gastroenterology and Hepatology2007

Hepatitis C

Western Countries

%25-50

Türkiye

%10-20

HCV in Liver Transplant Recipients

Number

Ege University ExperienceEtiology (607 adult)

020406080

100120140160180200220240260280300 HBV

HBV+D

HCV

Alcohol

PBC

PSC

Wilson

Budd-C

Fulminan

Autoimmun

Cryptogenic

HCV-RNA (+)

HCV-RNA (+)

75%

%

20%

Acute LobulerHepatitisFCH

Non-Hepatitic

HCV in Post-transplant Setting

75%

%

20%

Akut LobulerHepatitFCH

Non-Hepatitik

ChronicHepatitis

25 % 3-5 years25 % slower

Cirrhosis

HCV in Post-transplant Setting

75%

%

20%

Akut LobulerHepatitFCH

Non-Hepatitik

Chronic hepatitis

25 % 3-5 years25 % slower Cirrhosis

Decompansation4 years

75 %survival 20 %: 3years

HCV in Post-transplant Setting

Rowe IA et all. Transplant International 2008

Graft Loss Due To Recurrence Of PrimaryDisease After Liver Transplantation

Neuman UP et all. Transplantation 2007

Survival Of Patients AfterLiver Transplantation

>=2000 : 1410

<1985 : 10

95 to 2000 : 119690 to 95 : 915 85 to 90 : 287

0

.2

.4

.6

.8

1

Surv

ival

%

0 1 2 3 4 5 6 7 8 9 10Years

91% 86% 84%

ELTR

0

.2

.4

.6

.8

1

0 1 2 3 4 5 6 7 8 9 10Years

83% 72% 67%

HBV HCV

>=2000 : 3194

<1985 : 6

1995 to 2000 : 27051990 to 1995 : 13571985 to 1990 : 127

334667Liver Transplant 2006Berenguer (a/b)

335039Liver International 2006Mukherjee

193526Transplant International 2007Zimmermann

446755Am J Transplant. 2006Oton

335824J. Hepatology 2005Castells

122292Transplantation 2006Chadalavada

234647Liver Transplant 2006Fernandez

366824Transplantation 2006Neumann

455520J. Hepatology 2004Dumortier

193816Clin Transplant 2004Ross

263719Transplantation 2004Rodriguez-Luna

SVR(%)

EOT(%)Case (n)

Post-OLT treatment of Recurrent HCV PEGIFN + Ribavirin

Although, in post-transplant patients with recurrent chronic hepatitis C virus infection, end of treatment virologic responses are competible to those non-transplant patients, sustained virologic response rate is lower in the post-transplant setting.

Almost half of the patients with end of therapy response have experienced relapse; then SVR rate decreased significantly

Slow or late responders to PEG-IFN and ribavirin may benefit from an extended treatment course.

Berg Sanchez-Tapias Ferenci

33

16

31

46 44

77

0

20

40

60

80

100SV

R (%

)72 wk48 wk

Extending Therapyin Slow Responders

Berg T, et al. Gastroenterology. 2006.Sanchez-Tapias JM, et al. Gastroenterology. 2006Ferenci P et al AASLD 2006 Abstract 390

End of treatment virological response was competable in 48-72w groups, SVR was significantly higher among patients treated for 72 weeks

IFN alpha 2b 3MU TIW +

Ribavirin (800-1000 mg / day)PEG IFN 1,5 microgram / kg

+Ribavirin (800-1000 mg / day)

HCV RNA (+)

Stop therapy

HCV RNA (-)

HCVRNA

Week0 12 24 36 48

HCVRNA

HCVRNA

HCVRNA

HCVRNA

72 96 120 144

HCV HCV HCV HCVRNA RNA RNA RNA

Ege University Experience

Proper data on early or late virologic responders were not available while we were planning the study. We proposed that the interferon-induced immune response against hepatitis viruses might be slower in immunosuppressed patients and prolongation of treatment may increase the response rate. Although we had no reference regarding total duration, we chose three years of treatment.

13 Patients

IFN / PEG IFN + Ribavirin

2 Dropout1 RNA (-)

5 HCV RNA(+)

6 HCV RNA (-)

3 year tx

HCV RNA(-)

Ege University Experience

Karasu Z et al. APASL 2007Transplant Proceedings 2009

Since all six patients who could clear the virus after one year of treatment achieved sustained virologic response after three years of therapy, that duration may be enough or more than enough. Considering that none of the responders experienced a relapse, more than one year of therapy would be advisable for those who could clear the virus within one year.

21 patients

PEG-IFN + Ribavirin

3 HCV RNA (+)

4 HCV RNA(+)

14 HCV RNA (-)

66 (20-94) month therapy

13 HCV RNA(-)

Kornberg A. Journal of Gastroenterology and Hepatology 2007

49 (24-77) month therapy

Thank You

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