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C.H.B.
LIVER TRANSPLANTATION
IN VIRAL HEPATITIS
Natural Course, Overview
Didier SAMUEL, M.D.
Professor of Hepatology
CENTRE HEPATOBILIAIRE
INSERM PARIS XI UNIT 785
HOPITAL PAUL BROUSSE
VILLEJUIF, FRANCE
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Virus Delta Virus B Virus C
Evolution of Liver Transplantation
For Viral Cirrhosis without HCC in Europe
ELTR
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Virus Delta + HCC Virus B + HCC Virus C + HCC
Evolution of Liver Transplantation
For Viral Cirrhosis with HCC in Europe
ELTR
C.H.B.
LIVER TRANSPLANTATION
IN VIRAL HEPATITIS B
Natural Course, Overview
Liver Transplantation for Viral B Cirrhosis in USA
Kim WR Gastro 09
Prophylaxis of HBV Infection
Posttranplantation
Major improvements have been made in prevention of HBV infection in past 15 yrs
Before transplantation
– Lamivudine or adefovir
– Nucleos(t)ide analogues
After transplantation
– Anti-hepatitis B immunoglobulins (HBIG)
– Lamivudine or Adefovir, or ETV monoprophylaxis
– Combination HBIG + lamivudine/adefovir
– Combination HBIG + nucleos(t)ide analogue
C.H.B.
Prophylaxis after
Liver Transplantation
C.H.B.D. Samuel et al. NEJM 1993;329:1842-7
HBV Recurrence and Survival
According to Prophylaxis
Long-Term Use of IV HBIG Aim
High doses during anhepatic phase, then during
first wk
– Aim
Make serum HBsAg negative
Obtain protective anti-HBs titer
– Maintain protective anti-HBs titer
Effective in FHF, HDV-C
Less effective in nonreplicative HBV-C
- Possible low replication detected by PCR
Insufficient in replicative HBV-C
Actuarial HBV Recurrence Rate in Relation
to Initial Liver Disease
Hôpital Paul Brousse: 19862000
284 Patients
HDV-C
FHD
100
80
60
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20
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
41.8
25.0 25.0 25.0 25.0
5.8
13.5 13.5 15.3
Time (yr)
15.3
37.5
56.554.4
49.449.4 HBV-C
Ris
k o
f R
ecu
rren
ce (
%)
FHB
Roche B et al. Hepatology. 2003;38:86
HBV-C = HBV cirrhosis; FHD = fulminant hepatitis B-Delta; HDV-C = HDV cirrhosis;
FHB = fulminant hepatitis B
Lamivudine Monoprophylaxis
Patients remained HBsAg positive after liver transplant
Progressive decline of HBsAg1
Rate of HBV reinfection
– Related to HBV DNA level before liver transplant
– Related to treatment duration
– Increased with time posttransplant
HBV reinfection due to YMDD HBV mutant
Question of long-term compliance and risk of reinfection
1. Grellier L et al. Lancet. 1996;348:1212 [published correction in Lancet. 1997;349:364]
HBV Recurrence with Lam Monoprophylaxis
A Great Failure
Jiang WJG 2009
ETV Monoprophylaxis after LT
80 Patients
Mean follow up
Rate of HBsAg loss 86% and 91% at 1-2 years
10 patients had HBsAg reappearance
At end of FU :
– 18 Patients (22%) were HBsAg positive, one was HBV DNA
positive
Fung Gastro 2011 in Press
Fung Gastro 2011 in Press
HBsAg Clearance after LT on ETV Monoprophylaxis
Fung Gastro 2011 in Press
HBsAg Relapse after LT on ETV Monoprophylaxis
Virology
HBV DNA and HBsAg Used 2 Distinct Pathways
Nguyen J Hepatol 2010Brunetto J Hepatol 2010
Antiviral alone not able to block HBsAg
Posttransplant Combination
HBIG + Nucs: Rationale
Lower rate of escape mutation due to pressure on 2
different regions in HBV genome
– PreS/S region for HBIG
– YMDD region of polymerase gene for lNucs
Possible to reduce HBIG amount and overall cost
HBV Recurrence
HBIG Monoprophylaxis vs Combined HBIG + Nucleos(t)ide
Paul Brousse 1995-2005
Faria Gastroenterology 2008
Factors independently associated
with HBV recurrence:
• HBV DNA at LT> 105 copies/ml
• HCC at LT
• HBIG monoprophylaxis
Low-Dose HBIG + Lamivudine
• 147 patients
• Pretransplant
• LAM if HBV DNA (+) (80% pts)
• Posttransplant
• LAM + HBIG IM 400–800 IU daily 7
days
• LAM + HBIG IM 400/800 IU monthly
• HBV recurrence: 4% at 5 yr
• 5 pts with HBV recurrence
• All YMDD HBV
• ADV in all, 1 death from liver failure
• Factor independently associated with
HBV recurrence
• HBV DNA prior LAM
Gane EJ et al. Gastroenterology. 2007;132:931
0.5 -
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Number
at risk147 124 89 56 14
Time Posttransplant (yr)
HBV Recurrence In Patients with and without HCC
Paul Brousse 1995-2005
Faria L. Gastroenterology 2008
HBV Recurrence Is Associated with HCC Recurrence
Paul Brousse 1995-2005
Faria L. Gastroenterology 2008
HBV Recurrence Is Associated with HBV DNA at LT
USA
Degertekin AJT 2010
Prophylaxis Protocol
Place of HBIG in Combination?
HBIG at start is essential
– Immediately makes HBsAg negative
– Protects graft from immediate reinfection
High doses of HBIG
– Important at start
– Dose related to HBV DNA level at liver transplant3
– Lower doses can be used at medium term
1. Gane EJ et al. Gastroenterology. 2007;132:931; 2. Han SH et al. Liver Transpl. 2003;9:182; 3.
Dickson RC et al. Liver Transpl. 2006;12:124
Absence or Discontinuation of HBIG?
Cost?
Highly variable
– Depending countries, preparations ( ratio 1 to 4)
– High doses needed only at the start to control HBs Ag
– Medium term
Low doses in combination protocols
Decreased cost
Cost to be compared to combination new generation Nucs
Discontinuation of HBIG?
Few cases of HBV reinfection after 1-2 year
Yes but:
– Only if HBIG prophylaxis given
– On Lam, HBV reinfection cases increase with time
– Cases of long-term recurrence after discontinuation
– Residual HBV DNA in > 50% -70% of patients at 10 yr1,2
– Difficult to identify patients who have cleared virus
Roche Hepatology 2003, Hussain Liver Transplant 2007
Discontinuation of HBIG?
HBV Reinfection no more severe,
Nucs alone will give the same results?
HBV Reinfection no more severe?
– True if well monitored, but will be reinfected anyway
– Untrue if monitoring inaccurate, severe HBV reactivation
Nucs alone will give the same results?
– At best, it will be a non-inferiority comparison
– Will always be less good than combination HBIG +Nucs
Discontinuation of HBIG
Replacement by Lamivudine
21 pts stopped HBIG (Wong SN et al. Liver Transplant. 2007)
All on lamivudine
2 recurrence (actuarial rate of 3 year HBV recurrence 9% after HBIG withdrawal), both recurrence YMDD, 3 additional patients with transient HBV DNA
20 Pts stopped HBIG replaced by Lam: HBV reinfection 3/20 at 5 years (Buti Transplantation 2007)
HBV recurrence Increase with Follow-up
Discontinuation of HBIG after 12 Months HBIG + Lam
and Replacement by ADV/Lam
Angus Hepatology 2008
13 718 $ VS 8 289 $
Positive HBsAg Detectable HBV DNA
ADV/Lam 1/15 (6%) 0/18 (0%)
HBIG/Lam 0/15 (0%) 0/18 (0%)
Vaccine After Transplantation
Great discordance in results
– Good Results dependent of the adjuvant or Pre S vaccine
( none commercialised)
– Durability of response?
– Tolerance and reproducibility of results
– Response probably more frequent in FHB patients
(spontaneous seroconversion boosted by vaccine?)
How to identify patients susceptible to respond to vaccine?
NOT READY TO REPLACE HBIG
Lenci I. J Hepatol 2011
Discontinuation of all Prophylaxis after LT:
End of a Dogma ? • Inclusion criteria:
• > 5 years post-LT treated with HBIG ±Nuc
• Serum HBV DNA negative
• HBV DNA and cccDNA negative in liver biopsy 1
Results
30 patients stop HBIg
cccDNA 2nd biopsynégative 29 patients
29 patients stop NUC
1 patient HBs+
4 week after HBIg discontinuation
25 patients no HBV reactivationafter 24 months
4 patients became HBsAg +after 8-32 wks discontinuation NUCs
1 patient HBV DNA > 50 in 4 weekscccDNA pos on third biopsy
3 patients HBV DNA negseroconversion HBsafter 18 week. (16-24)
Lenci I. J Hepatol 2011
Lenci I. J Hepatol 2011
Discontinuation of HBV Prophylaxis after LT :
Patients with HBV recurrence
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30%
40%
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ate
Lamivudine
(mono)
Low-Dose
HBIG
High-Dose
HBIG
Lamivudine
+ HBIG
Strategies for Prevention
of HBV Recurrence
Seehofer D, Berg T. Transplantation. 2005;80(1 suppl):S120
3633
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Conclusion
HBIG + Nuc the Best combination at the start
At mid-term
– HBIG can be stopped in patients with low risk recurrence
Spontaneous HBV DNA negative patients at LT
FHF Patients
If Nuc are maintained
– In high risk Patients:
HBV DNA +ve at LT, HCC, HIV coinfection
Low dose HBIg + Nuc remain the best combination
C.H.B.
HCV AND LIVER TRANSPLANTATION
PATTERN OF HCV RECURRENCE POST OLTx
OLT
DEATH
50%
NO HEPATITIS
20%CHRONIC HEPATITIS
ACUTE HEPATITIS
70%
CHOLESTATIC
HEPATITIS
< 10 %
VIRAL
RECURRENCE
1 MTH
6 MTH
CHRONIC HEPATITIS CIRRHOSIS
?
6 MTH1 MTH
1 MTH
Adapted From McCaughan
McCaughan
J Hepatol 2011
CHOLESTATIC HEPATITIS C
Immunosuppression
Proliferation
Apoptosis
Fibrosis
HCV loadInflammation +
IFN- related genesIFN-response
-
Acute Rejection
Inflammation
Stress Response
The immune response
-
+
Pathobiology of Chronic HCV Post LT
McCaughan and Zekry J.Hepatol 2004, Samuel Easl Hepatol 2006
Stimulation of the IMMUNE
RESPONSE by more HCV WINS
T Pietschmann Nature 2009
HCV Entry in Hepatocyte
Ciesek Gastro 2010, Fafi Kremer J Hepatol 2010
Streoids Increase HCV Entry in Liver Transplantation
Gc: Glucocorticoids
Gr: Glucocorticoid
Receptor
Fofana Gastro 2010
Additive Effect of Anticlaudin, AntiE2 and HCVIg
on HCV Entry and Infection
C.H.B.
• Liver Biopsy
Gold Standard,
Bring additional information than fibrosis stage
. HPVG
Invasive, can be done with liver biopsy
Not routine for many Centres
. Non invasive tests
Biochemical
Elastometry (fibroscan)
. Time post-LT as an adding variable
EVALUATION OF THE SEVERITY OF HCV RECURRENCE
Blasco Hepatology 2006; 43: 492-499
HPVG, Fibrosis at 1 Year Post-Transplant and Outcome
Gallegos-Orozco Liver Transplant 2009
Fibrosis Stage at 12 months at Liver Biopsy and Survival
Carrion Gastro 2010
Non Invasive Test (3-M-ALG) and HPVG at 6 and 12 Months
in Control and HCV Reinfected Patients
Carrion Gastro 2010
Non Invasive 3-MALG Test
and
Decompensation and Survival Post-Transplant
Carrion Hepatology 2010
Liver Stiffness and Severity of HCV Recurrence
C.H.B.
Donor and Host Factorsof
HCV Recurrence
C.H.B.Berenguer Hepatology 2002; 36: 202-210
EFFECT OF DONOR AGE
ON THE DEVELOPMENT OF HCV GRAFT FIBROSIS AND CIRRHOSIS
Wali et al. Gut 2002; 51: 248-252
Cirrhosis and donor age Fibrosis and donor age
Belli Liver Transplant 2007; 13: 733-740
Fibrosis on the Graft In HCV+ve Liver Transplant Patients
According to Donor Age and Gender
Risk of Fibrosis: Stable over years, Higher in women receiving old donors
C.H.B.
STEROIDS AND HCV
• Controversial role
– Increase viral load (Fong Gastro 1994, Gane Gastro 1996)
– Increase viral hepatocyte entry (Gastro 2010)
– Boluses of steroids deleterious (Berenguer J Hepatol 2000)
– Rapid withdrawal deleterious (Berenguer Hepatology 2003,
McCaughan J Hepatol 2004, Vivarelli J Hepatol 2007)
» Immune rebound?
– Immunosuppression without steroids: not yet proven beneficial
(Klintmaln Liver Transplant 2007)
Vivarelli J Hepatol 2007
Rapid Steroid Withdrawal Deleterious for Hep C Recurrence
Group A: Rapid Steroid Withdrawal D91
Group B: Slow Decrease in steroids,
Stop at M25
% patients without severe Fibrosis
C.H.B.
HCV Recurrence , Cyclosporine vs Tacrolimus
• There is currently no proof of superiority of one vs another
– Antiviral effect of Cyclosporine only in vitro
– Better efficacy of IFN in Ciclosporine patients not confirmed
– Randomized studies showed earlier reinfection with Tac but no
difference in survival and fibrosis stage
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29
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80
1999-2000 (n=52) 2001-2003 (n=90)
F3,4,FCH FCH AH
Overall Role of IS
1999-2000 2001-2003 P
Duration Pred (d)
Bolus MP
249
21
350
4.5
<.0001
.002
> Is double (%) 25 10 .001
IFN preTH (%)
Donor age (yr)
9
51
30
57
.006
.07
Berenguer
J Hepatol 2006
C.H.B.
ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION
– Difficult to manage in decompensated cirrhotic patients
– Risk of deterioration of liver function
– Risk of sepsis, severe neutropenia, and anemia
– Poor antiviral effect at this stage
– However, some patients candidates to LT:
» Have preserved liver function (those with HCC)
» Have a long expected waiting time for LT
» Have never been treated or are ”false” non responders
C.H.B.
ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION
» 124 patients
• 56 Child A, 45 Child B, 23 Child C
• 86 Genotype 1, 16 Genotype 2, 17 Genotype 3
» SVR:
• 50% in genotype non-1,
• 13% in genotype 1
» 22 complications in 15 patients ( 21 in Child B and C), 4 died
» No HCV recurrence in sustained responders.
Everson Hepatology 2005
C.H.B
Authors Patients Child Treatment Virologic Response EOT
SVR
Post-LT
Tolerance
Forns
(2003)
30
(Time pre-LT 4
mths)
G1:83%
A 50%
B 43%
C 7%
INF 3M/d
+RBV 800mg
Mean Duration :
12 wks
(2-33 wks)
9 (30%)
Factors for response : viral
laod pre-LT,
Decrease viral load≥ 2 log Wk 4
6/30
(20%)
Decrease INF 60%, RBV
23%
Stop 20%
Sepsis: 2
Liver Failure: 4
Carrion
(2008)
51
G1:80%
51 controls
Meld 11
Peg2a 180g/wk
+RBV
0,8-1g/d
Mean duration: 15 Wks
15 (29%)
Factors response: G non 1,
RVR Wk4
10/51
(20%)
infectious risk
increased by Trt (NS)
ANTIVIRAL TREATMENT PRE-LT
Forns J Hepatol 2003, Carrion J Hepatol 2008
Roche, Samuel Liver Transplant 2010
Antiviral Treatment Before Transplantation
Roche, Samuel Liver Transplant 2010
Antiviral Treatment Immediately after Transplantation
C.H.B.
PegIFN+RBV for Established Infection after Transplantation
• SVR: 25-45%
– Genotype 1: 30-35%
– Genotype 2-3: 60-70%
• Variables associated with SVR:
– Non-1 Genotype
– EVR, RVR
– Adherence to therapy
– Low pretreatment viral load
Berenguer J Hepatol 2008, Roche Liver Transplant 2010
C.H.B.
Treatment with PEG IFN + RBV After LT
SVR Dependent of Fibrosis stage
• 27 Pts mild Hepatitis C (F1-F2): SVR 48%
• 27 Pts severe hepatitis C (F3-F4), Cholestatic Hepatitis: SVR 18%
• F3-4: 4/15
• Cholestatic hepatitis, 1/12 ( Carrion Gastro 2007)
• 20% F3-F4 vs 1% F1 Patients died or were retransplanted ( Roche
Liver transplant 2008)
C.H.B.
SVR and Snp near IL28 gene in Donor, Recipient, Combined in Genotype 1 Transplant Patients
Fukuhara Gastro 2010 In Press
C.H.B.
SVR and IL28 mRNA expression in Transplant Liver in Genotype 1 Transplant Patients
Fukuhara Gastro 2010 In Press
C.H.B.
Tolerance to Treatment
• The tolerance is poor
• 40-80% rate of doses reduction
• 40-50% discontinuation rate
• Anaemia++ is the first cause of discontinuation
• EPO is required in many cases ( > 30%)
• Risk of rejection and alloimmune hepatitis ( 2-15%)
Auto(Allo)immune Hepatitis and IFN
Sharma Liver Transplant 2007
C.H.B.
Histological Outcome in Relation with Virological Response to PEGIFN+ Ribavirine
Carrion Gastroenterology 2007
Variables associated with Histological improvement: EVR, BR, SVR
Piciotto J Hepatol 2007; 46:459-465
Role of SVR After LT in HCV + Patients
McHutchison NEJM 09
Telaprevir In Naive HCV Non-Transplant Patients
C.H.B.
Direct Antiviral Agents Before LTA New Challenge
• Data In cirrhotic patients are lacking
• Therapies with IFN will remain poorly tolerated
• Increase possibility to achieve SVR or on treatment
virologic response
• Increase risk of virologic breakthrough
• Duration, safety issues to be analysed
• Therapies without IFN awaited
C.H.B.
Direct Antiviral Agents After LTA New Challenge
• Increase possibility to achieve SVR or on treatment virologic
response
• Interaction between anti NS3 protease and calcineurin
inhibitors
• Duration, safety issues to be analysed
• Therapies without IFN awaited
Interaction Telaprevir-Cyscloporine, Telaprevir-Tacrolimus
Garg Hepatology 2011
Dose normalised AUC X 4.5 Dose-normalised AUC X 70
Virus D (n=1148)
Virus C (n=8545)
Virus B (n=3398)
0
,2
,4
,6
,8
1
Surv
ie C
um
.
0 1 2 3 4 5 6 7 8 9 10
Years
82%73%
67%81%
67%
55%
92%88%
85%
0
,2
,4
,6
,8
1
Surv
ie C
um
.
0 1 2 3 4 5 6 7 8 9 10
Years
Virus D (n=288)
Virus C (n=4882)
Virus B (n=1810)
84%68%
60%82%
59%
46%
87%
77%71%
Patient Survival after Liver Transplantation
For Viral Cirrhosis in Europe
From 13/11/1973 to 30/06/2009
With HCCWithout HCC
Before 1990
After 2005
1995 to 2000
1990 to 1995
2000 to 2005
0
,2
,4
,6
,8
1Surv
ie C
um
.
0 1 2 3 4 5 6 7 8 9 10
Years
Evolution of Patient Survival after LT
For Viral Cirrhosis without HCC in Europe
From 13/11/1973 to 30/06/2009
0
,2
,4
,6
,8
1Surv
ie C
um
.
0 1 2 3 4 5 6 7 8 9 10
Years
Before 1990
After 2005
1995 to 2000
1990 to 1995
2000 to 2005
Evolution of Patient Survival after LT
For Virus C Cirrhosis without HCC in Europe
From 13/11/1973 to 30/06/2009
Patient survival according to the year of LT
HBV CirrhosisELTR update of December 2007
2000 to 2005 : 973
<1985 : 12
95 to 2000 : 831
90 to 95 : 653
85 to 90 : 175
>= 2005 : 419
0 1 2 3 4 5 6 7 8 9 10
Years
0
20
40
60
80
100
% S
urv
ival
91% 90%
C.H.B.
CONCLUSION
• Survival still affected by HCV recurrence
• Monitoring combining liver biopsy and non invasive methods
• Treatment before Transplantation poorly effective
– SVR before LT , no recurrence post-LT
– HCVRNA negativity at LT, Risk of post transplant recurrence
reduced by 70%
• Treatment after transplantation :
– Effective at time of Chronic hepatitis before the F3 stage
» 30-40% SVR in G1 Patients
» 70% SVR in G2-G3 Patients
C.H.B.
CONCLUSION
• Advent of Direct antiviral agents will open a new era
• Before LT: Presence of IFN in the treatment arm will remain a
limitating factor
• After LT: new strategies will arise
• Viral breakthrough, tolerance, interaction with calcineurin
inhibitors, treatment duration:
– Open questions for the close future