1. 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
C.H.B.

2. Evolution of Liver Transplantation
For Viral Cirrhosis without HCC in Europe
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Virus Delta Virus B Virus C
ELTR
fo
Be

3. Evolution of Liver Transplantation
For Viral Cirrhosis with HCC in Europe
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Virus Delta + HCC Virus B + HCC Virus C + HCC
fo
ELTR
Be

4. LIVER TRANSPLANTATION
IN VIRAL HEPATITIS B
Natural Course, Overview
C.H.B.

5. Liver Transplantation for Viral B Cirrhosis in USA
Kim WR Gastro 09

6. 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

7. Prophylaxis after
Liver Transplantation
C.H.B.

8. HBV Recurrence and Survival
According to Prophylaxis
D. Samuel et al. NEJM 1993;329:1842-7
C.H.B.

9. 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

10. Actuarial HBV Recurrence Rate in Relation
to Initial Liver Disease
Hôpital Paul Brousse: 19862000
100 284 Patients
Risk of Recurrence (%)
80
60 56.5
54.4
49.4 49.4 HBV-C
41.8
37.5
40
FHD
25.0 25.0 25.0 25.0
20 13.5 13.5 15.3 15.3
5.8 HDV-C
0 FHB
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Time (yr)
HBV-C = HBV cirrhosis; FHD = fulminant hepatitis B-Delta; HDV-C = HDV cirrhosis;
FHB = fulminant hepatitis B
Roche B et al. Hepatology. 2003;38:86

11. 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]

12. HBV Recurrence with Lam Monoprophylaxis
A Great Failure
Jiang WJG 2009

13. 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

14. HBsAg Clearance after LT on ETV Monoprophylaxis
Fung Gastro 2011 in Press

15. HBsAg Relapse after LT on ETV Monoprophylaxis
Fung Gastro 2011 in Press

16. Virology
HBV DNA and HBsAg Used 2 Distinct Pathways
Brunetto J Hepatol 2010
Nguyen J Hepatol 2010
Antiviral alone not able to block HBsAg

17. 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

18. HBV Recurrence
HBIG Monoprophylaxis vs Combined HBIG + Nucleos(t)ide
Paul Brousse 1995-2005
Factors independently associated
with HBV recurrence:
• HBV DNA at LT> 105 copies/ml
• HCC at LT
• HBIG monoprophylaxis
Faria Gastroenterology 2008

19. Low-Dose HBIG + Lamivudine
• 147 patients
• Pretransplant
• LAM if HBV DNA (+) (80% pts) 0.5 -
Proportion of Patients With
• Posttransplant
• LAM + HBIG IM 400–800 IU daily  7 0.4 -
HBV Recurrence
days
0.3 -
• LAM + HBIG IM 400/800 IU monthly
• HBV recurrence: 4% at 5 yr
0.2 -
• 5 pts with HBV recurrence
• All YMDD HBV
0.1 -
• ADV in all, 1 death from liver failure
• Factor independently associated with 0.0 - I I I I
HBV recurrence 2 4 6 8
• HBV DNA prior LAM Time Posttransplant (yr)
Number
147 124 89 56 14
at risk
Gane EJ et al. Gastroenterology. 2007;132:931

20. HBV Recurrence In Patients with and without HCC
Paul Brousse 1995-2005
Faria L. Gastroenterology 2008

21. HBV Recurrence Is Associated with HCC Recurrence
Paul Brousse 1995-2005
Faria L. Gastroenterology 2008

22. HBV Recurrence Is Associated with HBV DNA at LT
USA
Degertekin AJT 2010

23. 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

24. 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

25. 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

26. 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

27. 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

28. Discontinuation of HBIG after 12 Months HBIG + Lam
and Replacement by ADV/Lam
Positive HBsAg Detectable HBV DNA
ADV/Lam 1/15 (6%) 0/18 (0%)
HBIG/Lam 0/15 (0%) 0/18 (0%)
13 718 $ VS 8 289 $
Angus Hepatology 2008

29. 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

30. 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
Lenci I. J Hepatol 2011

31. Results
1 patient
30 patients stop HBIg HBs+
4 week after HBIg discontinuation
cccDNA 2nd biopsy
négative 29 patients
29 patients stop NUC
25 patients no HBV reactivation 4 patients became HBsAg +
after 24 months after 8-32 wks discontinuation NUCs
3 patients HBV DNA neg
1 patient HBV DNA > 50 in 4 weeks
seroconversion HBs
cccDNA pos on third biopsy
after 18 week. (16-24)
Lenci I. J Hepatol 2011

32. Discontinuation of HBV Prophylaxis after LT :
Patients with HBV recurrence
Lenci I. J Hepatol 2011

33. Strategies for Prevention
of HBV Recurrence
40%
36
36
Recurrence Rate
30% 33
33
Overall HBV
20%
18
18
10%
66
0%
Lamivudine Low-Dose High-Dose Lamivudine
(mono) HBIG HBIG + HBIG
Seehofer D, Berg T. Transplantation. 2005;80(1 suppl):S120

34. 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

35. HCV AND LIVER TRANSPLANTATION
C.H.B.

36. PATTERN OF HCV RECURRENCE POST OLTx
NO HEPATITIS CHRONIC HEPATITIS
20% 6 MTH
?
1 MTH
ACUTE HEPATITIS
OLT 70% 6 MTH
CHRONIC HEPATITIS CIRRHOSIS
1 MTH
1 MTH 
CHOLESTATIC
VIRAL
HEPATITIS
RECURRENCE
< 10 %
DEATH
Adapted From McCaughan 50%

37. CHOLESTATIC HEPATITIS C
McCaughan
J Hepatol 2011

38. Pathobiology of Chronic HCV Post LT
Immunosuppression - The immune
response
+
HCV load
- Inflammation +
IFN- related genes
IFN-
response Stimulation of the IMMUNE
RESPONSE by more HCV WINS
Proliferation
Acute Rejection
Apoptosis
Inflammation
Fibrosis
Stress Response
McCaughan and Zekry J.Hepatol 2004, Samuel Easl Hepatol 2006

39. HCV Entry in Hepatocyte
T Pietschmann Nature 2009

40. Streoids Increase HCV Entry in Liver Transplantation
Gc: Glucocorticoids
Gr: Glucocorticoid
Receptor
Ciesek Gastro 2010, Fafi Kremer J Hepatol 2010

41. Additive Effect of Anticlaudin, AntiE2 and HCVIg
on HCV Entry and Infection
Fofana Gastro 2010

42. EVALUATION OF THE SEVERITY OF HCV RECURRENCE
• 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
C.H.B.

43. HPVG, Fibrosis at 1 Year Post-Transplant and Outcome
Blasco Hepatology 2006; 43: 492-499

44. Fibrosis Stage at 12 months at Liver Biopsy and Survival
Gallegos-Orozco Liver Transplant 2009

45. Non Invasive Test (3-M-ALG) and HPVG at 6 and 12 Months
in Control and HCV Reinfected Patients
Carrion Gastro 2010

46. Non Invasive 3-MALG Test
and
Decompensation and Survival Post-Transplant
Carrion Gastro 2010

47. Liver Stiffness and Severity of HCV Recurrence
Carrion Hepatology 2010

48. Donor and Host Factors
of
HCV Recurrence
C.H.B.

49. EFFECT OF DONOR AGE
ON THE DEVELOPMENT OF HCV GRAFT FIBROSIS AND CIRRHOSIS
Cirrhosis and donor age Fibrosis and donor age
Wali et al. Gut 2002; 51: 248-252
C.H.B.
Berenguer Hepatology 2002; 36: 202-210

50. 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
Belli Liver Transplant 2007; 13: 733-740

51. 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)
C.H.B.

52. 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
Vivarelli J Hepatol 2007

53. 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
C.H.B.

54. Overall Role of IS
80
70
54
60 48
50
40 33
23 29
30
20 7
10
0
1999-2000 (n=52) 2001-2003 (n=90)
F3,4,FCH FCH AH
1999-2000 2001-2003 P
Duration Pred (d) 249 350 <.0001
Bolus MP 21 4.5 .002
Berenguer
> Is double (%) 25 10 .001
J Hepatol 2006
IFN preTH (%) 9 30 .006
Donor age (yr) 51 57 .07

55. 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.

56. 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.

57. ANTIVIRAL TREATMENT PRE-LT
Authors Patients Child Treatment Virologic SVR Tolerance
Response EOT Post-LT
Forns 30 A 50% INF 3M/d 9 (30%) 6/30 Decrease INF
(2003) (Time pre- B 43% +RBV (20%) 60%, RBV
LT 4 800mg 23%
C 7% Factors for
mths) Mean response : viral Stop 20%
G1:83% Duration : laod pre-LT, Sepsis: 2
12 wks Decrease viral Liver Failure:
(2-33 wks) load≥ 2 log Wk 4 4
Carrion 51 Meld Peg 2a 15 (29%) 10/51 infectious
(2008) G1:80% 11 180 g/wk (20%) risk
+RBV increased by
Factors response: Trt (NS)
51 0,8-1g/d G non 1,
controls Mean RVR Wk4
duration:
15 Wks
Forns J Hepatol 2003, Carrion J Hepatol 2008
C.H.B

58. Antiviral Treatment Before Transplantation
Roche, Samuel Liver Transplant 2010

59. Antiviral Treatment Immediately after Transplantation
Roche, Samuel Liver Transplant 2010

60. 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.

61. 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.

62. SVR and Snp near IL28 gene in Donor, Recipient,
Combined in Genotype 1 Transplant Patients
Fukuhara Gastro 2010 In Press
C.H.B.

63. SVR and IL28 mRNA expression in Transplant Liver
in Genotype 1 Transplant Patients
Fukuhara Gastro 2010 In Press
C.H.B.

64. 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%)
C.H.B.

65. Auto(Allo)immune Hepatitis and IFN
Sharma Liver Transplant 2007

66. Histological Outcome in Relation with
Virological Response to PEGIFN+ Ribavirine
Variables associated with Histological improvement: EVR, BR, SVR
Carrion Gastroenterology 2007
C.H.B.

67. Role of SVR After LT in HCV + Patients
Piciotto J Hepatol 2007; 46:459-465

68. Telaprevir In Naive HCV Non-Transplant Patients
McHutchison NEJM 09

69. Direct Antiviral Agents Before LT
A 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.

70. Direct Antiviral Agents After LT
A 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
C.H.B.

71. Interaction Telaprevir-Cyscloporine, Telaprevir-Tacrolimus
Dose normalised AUC X 4.5 Dose-normalised AUC X 70
Garg Hepatology 2011

72. Patient Survival after Liver Transplantation
For Viral Cirrhosis in Europe
From 13/11/1973 to 30/06/2009
Without HCC With HCC
1 92% 1
88% 87%
85%
82% 77%
Survie Cum.
,8 ,8 84% 71%
Survie Cum.
73%
81% 67% 82% 68%
,6 60%
,6 67%
59%
,4 55% ,4
Virus D (n=1148) 46%
Virus D (n=288)
Virus B (n=3398) Virus B (n=1810)
,2 ,2
Virus C (n=8545) Virus C (n=4882)
0 0
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Years Years

73. Evolution of Patient Survival after LT
For Viral Cirrhosis without HCC in Europe
From 13/11/1973 to 30/06/2009
After 2005
1 2000 to 2005
1995 to 2000
,8 1990 to 1995
Before 1990
Survie Cum.
,6
,4
,2
0
0 1 2 3 4 5 6 7 8 9 10
Years

74. Evolution of Patient Survival after LT
For Virus C Cirrhosis without HCC in Europe
From 13/11/1973 to 30/06/2009 2005
After
2000 to 2005
1
1995 to 2000
1990 to 1995
,8 Before 1990
Survie Cum.
,6
,4
,2
0
0 1 2 3 4 5 6 7 8 9 10
Years

75. Patient survival according to the year of LT
HBV Cirrhosis
ELTR update of December 2007 >= 2005 : 419
2000 to 2005 : 973
95 to 2000 : 831
100
91% 90% 90 to 95 : 653
85 to 90 : 175
80 <1985 : 12
60
% Survival
40
20
0
0 1 2 3 4 5 6 7 8 9 10
Years

76. 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.

77. 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
C.H.B.