Viral hepatitis and transplantation - VHPB News | Viral ... · Active immunoprophylaxis or...
Transcript of Viral hepatitis and transplantation - VHPB News | Viral ... · Active immunoprophylaxis or...
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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