Viral Hepatitis And Liver Transplantation

Transcription

1 Viral Hepatitis And Liver Transplantation Dr.Zeki KARASU Ege University Medical School Dep. Gastroenterology

2 Hepatitis B

3 % HBV infection in liver transplant recipients, in western countries.

4 Ege University Experience Total Live donor Cadaveric

5 Ege University Experience Number Etiology (607 adult) HBV HBV+D HCV Alcohol PBC PSC Wilson Budd-C Fulminan Autoimmun Cryptogenic

6 HBV Recurrence %

7 Survival (%) HBIG+Lam Non-HBV HBIG or Lamivudin No prophylaxis Time (years) Kim et al. Liver Transpl 2004; 10:

8 Pre-Tx treatments Post-Tx prophylaxis Treatment of recurrent disease Cirrhosis Time

9 Goals of Antiviral Therapy Pre Transplant To suppress the viral replication to undetectable HBV DNA levels. To avoid post transplant recurrence (Without acquiring resistance) Control hepatic decompensation. Avoid transplant.

10 HBV DNA Level Pre-Transplant Predicts Risk of HBV Recurrence 100 P =.0003 % HBV Recurrence 60 HBV DNA > 100,000 copies/ml In those patients with low HBV DNA levels recurrence rate was competible with patients undergoing LTX with undetectible serum HBV DNA HBV DNA < 100,000 copies/ml Days Post-LT HBV DNA Patients at risk 100, < 100, Marzano et al. Liver Transpl 2005;11:

11 Antiviral Therapy in Decompensated Cirrhosis Schiff E, et al. AASLD 2009 HBV DNA < 400 copies/ml % Tenofovir (n = 45) Tenofovir/ Emtricitabine (n = 45) Entecavir (n = 22) Wk Wk Wk

12 Pre-Tx treatments Post-Tx prophylaxis Treatment of recurrent disease Cirrhosis Time

13 HBIG + Lamivudin (or other nucs)

14 HBIG Regimens used in US LT Centers 183 pts from NIH HBV-OLT study. All high dose HBIG perioperatively. Maintenance: Recurrence (5 y) A) iv 10,000IU/month 14% B) iv 1,000-5,000IU/month 3% C) im 1,000-5,000IU/month 10% D) discontinuation of HBIG 10% Degertekin et al AASLD 2008

15 Ege University Experience Low dose HBIG+Lamivudin: 80 cases 5% recurrence median 18 (3-73) months follow up Karasu Z, et al. Antiviral Therapy 2004 Dec;9(6):921-7

16 Karasu Z. et al. J Gastroenterol Hepatol Dec;22(12): HBV follow-up 18 (6-48) months Cadaveric 100 HBV DNA (+):5 HDV :22 Living donor 109 HBV DNA (+):5 HDV :40 Reappearance of HBsAg after its initial disappearance post-olt HBV recurrence 5 11/209 5 % HBV recurrence 6

17 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); IU/month HBV recurrence 4% at 5 years. Gane et al. Gastroenterology 2007;132(3):

18 Can we stop HBIG

19 2 types of approachs; Active immunoprophylaxis or vaccination Discontinuation of HBIG and continuing prophylaxis with nucleoside analogues

20 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.

21 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 Only 1 patient seroconverted Karasu Z, et al. J Viral Hepatitis 2004

22 Pre-Tx treatments Post-Tx prophylaxis Treatment of recurrent disease Cirrhosis Time

23 Adefovir For LAM-Resistant HBV Recurrence Week 48 Week 96 Week 144 With continued treatment, an increasing proportion of patients who remained in the ALT normalized study Hbe Ag had (-) HBV DNA (-) undetectable serum HBV DNA levels. HBV DNA (-) Hbe Ag (-) ALT normalized Schiff et al. Liver Transplantation 2007

24 209 HBV follow-up 18 (6-48) months Cadaveric 100 HBV DNA (+):5 HDV :22 Living donor 109 HBV DNA (+):5 HDV :40 HBV recurrence 5 11/209 5 % HBV recurrence 6

25 STOP HBIG 11 HBV recurrence Lamivudin+Adefovir HBV DNA (+) 1 18 (6-48) months HBV DNA (-) 7 3 Died HCC recurrence 2 HBV DNA (-) Akyıldız M, et al. Journal of Gastroenterology and Hepatology2007

26 STOP HBIG 11 HBV recurrence Lamivudin+Adefovir HBV DNA (+) 1 Tenofovir 18 (6-48) months HBV DNA (-) 7 3 Died HCC recurrence 2 HBV DNA (-) HBV DNA (-) 1 Akyıldız M, et al. Journal of Gastroenterology and Hepatology2007

27 Hepatitis C

28 HCV in Liver Transplant Recipients Western Countries Türkiye %10-20 %25-50

29 Ege University Experience Number Etiology (607 adult) HBV HBV+D HCV Alcohol PBC PSC Wilson Budd-C Fulminan Autoimmun Cryptogenic

30 HCV-RNA (+) HCV-RNA (+)

31 HCV in Post-transplant Setting % 20% Acute Lobuler Hepatitis FCH 75% Non-Hepatitic

32 HCV in Post-transplant Setting % 20% Akut Lobuler Hepatit FCH 75% Non-Hepatitik Chronic Hepatitis 25 % 3-5 years 25 % slower Cirrhosis

33 HCV in Post-transplant Setting % 20% Akut Lobuler Hepatit FCH 75% Non-Hepatitik Chronic hepatitis 25 % 3-5 years 25 % slower Cirrhosis survival 20 %: 3years Decompansation 4 years 75 %

34 Graft Loss Due To Recurrence Of Primary Disease After Liver Transplantation Rowe IA et all. Transplant International 2008

35 Survival Of Patients After Liver Transplantation Neuman UP et all. Transplantation 2007

36 >=2000 : to 2000 : to 95 : to 90 : 287 <1985 : 10 ELTR >=2000 : to 2000 : to 1995 : to 1990 : 127 <1985 : 6 Survival % % 86% 84% % 72% 67% Years HBV Years HCV

37 Post-OLT treatment of Recurrent HCV PEGIFN + Ribavirin Case (n) Rodriguez-Luna Transplantation EOT (%) 37 SVR (%) 26 Ross Clin Transplant Dumortier J. Hepatology Castells J. Hepatology Neumann Transplantation Mukherjee Liver International Berenguer (a/b) Liver Transplant Fernandez Liver Transplant Chadalavada Transplantation Oton Am J Transplant Zimmermann Transplant International Although, in post-transplant patients with recurrent chronic hepatitis C virus infection, end Almost of treatment half of the virologic patients responses with end are of competible therapy response to those have non-transplant experienced patients, relapse; then SVR rate decreased significantly

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

39 Extending Therapy in Slow Responders wk 72 wk SVR (%) Berg T, et al. Gastroenterology Sanchez-Tapias JM, et al. Gastroenterology Berg Sanchez-Tapias Ferenci End of treatment virological response was competable in 48-72w groups, SVR was significantly higher among patients treated for 72 weeks

40 Ege University Experience HCV RNA HCV RNA HCV RNA HCV RNA Week IFN alpha 2b 3MU TIW + Ribavirin ( mg / day) HCV RNA HCV RNA (-) HCV HCV HCV HCV RNA RNA RNA RNA PEG IFN 1,5 microgram / kg + Ribavirin ( mg / day) HCV RNA (+) Stop therapy 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.

41 Ege University Experience 13 Patients IFN / PEG IFN + Ribavirin 2 Dropout 1 RNA (-) 5 HCV RNA (+) 6 HCV RNA (-) 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. 3 year tx HCV RNA (-) Karasu Z et al. APASL 2007

42 21 patients PEG-IFN + Ribavirin 3 HCV RNA (+) 4 HCV RNA (+) 14 HCV RNA (-) 49 (24-77) month therapy 66 (20-94) month therapy 13 HCV RNA (-) Kornberg A. Journal of Gastroenterology and Hepatology 2007

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