1. LIVER TRANSPLANTATION
IN VIRAL HEPATITIS B
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 Survival After Liver Transplant for
HBV-Related Liver Disease
100 ERA 1 (1987–1991)
P<0.01
90
Survival (%)
80 Other
70
HBV
60
50
0 1 2 3 4 5
Time (yr)
100 ERA 2 (1992–1996) 100 ERA 3 (1997–2002)
P=0.19 P=0.14
90 90
HBV
Other
Survival (%)
Survival (%)
80 80
Other
70 HBV 70
60 60
50 50
0 1 2 3 4 5
0 1 2 3 4 5
Time (yr) Time (yr)
Kim WR et al. Liver Transpl. 2004;10:968
3. Prophylaxis of HBV Infection
Posttranplantation
Major improvements have been made in prevention of
HBV infection in past 15 yr
Before transplantation
– Lamivudine or adefovir
After transplantation
– Anti-hepatitis B immunoglobulins (HBIG)
– Lamivudine monoprophylaxis
– Combination HBIG + lamivudine
4. Long-Term Prophylaxis of
HBV Infection Posttransplantation
Questions
• Is prophylaxis still necessary at long term?
• What is optimal dosage of HBIG?
• What is optimal route of HBIG and for what duration?
• Is it possible to stop HBIG administration and
in whom?
• Which antiviral to be used after transplantation?
5. 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
11. Lamivudine Monoprophylaxis
Posttransplantation
HBV Reactivation Due to YMDD Variant
100
80 No Immunoprophylaxis (n=67)
% HBsAg (+)
60
Lamivudine (n=42)
40
Long-term HBIG (n=209)
20
N=28
N=39
N=34
N=40
0 12 24 36 48 60
Time (mo)
Perrillo RP et al. Hepatology. 2001;33:424
12. 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]
13. Adefovir Monoprophylaxis
Recurrence of HbsAg or Serum HBV DNA Following On-Study Liver Transplantation
Marker Concomitant HBIG No HBIG
(n=34) (n=23)
HBsAg
Confirmed* 0 (0%) 0 (0%)
First test was only positive† 2 (6%) 2 (9%)
Serum HBV DNA >1000 copies/mL
Confirmed*‡ 2 (6%) 0 (0%)
Single positive test§ 4 (12%) 3 (13%)
No short-term recurrence, no long-term data available
*2 consecutive positive tests
†HBsAg was detected on only first test between days 4 and 67 posttransplantation. 2 patients had no further follow-up,
and 2 patients had subsequent negative tests over 2 (to day 239) and 2 visits (to day 667)
‡In these 2 patients, the first 2 tests posttransplantation detected serum HBV DNA (maximum 32,084 and 29,672
copies/mL), and subsequently, serum HBV DNA was undetectable on 3 (to day 309) and 7 (to day 528) measurements
§Maximum titer among 7 tests was 3055 copies/mL. 4 patients subsequently had undetectable serum HBV DNA
(measured over next 25–211 days); 3 patients did not have further laboratory follow-up
Schiff E et al. Liver Transpl. 2007;13:349
14. Posttransplant Combination
HBIG + Lamivudine: 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 lamivudine
Possible to reduce HBIG amount and overall cost
15. 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
16. Long-Term Anti-HBs Titers in Patients
Receiving Low-Dose HBIG + Lamivudine
Plasma (anti-HBs) Titers at 1, 3, and 12 mo Posttransplant
(Horizontal Bars Demonstrate Median Values)
10000 –
1 mo
Plasma [anti-HBs] Titer
1000 – 3 mo
12 mo
100 –
10 –
1–
1 mo 3 mo 12 mo
Timepoint Posttransplant
Gane EJ et al. Gastroenterology. 2007;132:931
17. HBIG + Lamivudine vs Lamivudine
LAM + HBIG: 114 pts
LAM: 51 pts
HBV DNA >105 at LT: Recurrence 88% in the LAM group vs 28% in combined group
HBV DNA <105 at LT: Recurrence 18% in the LAM group vs 8% in combined group
Zheng S et al. Liver Transplant. 2006;12:253
18. HBV Recurrence in Relation to
Pretransplant PCR HBV DNA Level
Lamivudine Monoprophylaxis Lamivudine + HBIG
Prophylaxis
Marzano A et al. Liver Transpl. 2005;11:402
19. HBV Recurrence In Patients Receiving HBIG Monoprophylaxis vs
Combined HBIG + Antiviral
Paul Brousse 1995-2005
Factors independently associated with
HBV recurrence:
HBV DNA at LT> 100 000 copies/ml
HCC at LT
HBIG monprophylaxis
Faria Gastroenterology 2008 in press
20. HBV Recurrence In Patients with and without HCC
Paul Brousse 1995-2005
Faria Gastroenterology 2008 In press
21. HBV Recurrence Is Associated with HCC Recurrence
Paul Brousse 1995-2005
Faria Gastroenterology 2008 In press
22. Prophylaxis Protocol
Place of HBIG in Combination?
HBIG at start is essential
– Immediately makes HBsAg negative
– Protects graft from immediate reinfection
IV administration important at start
– Good results also with IM immediately1
– Can be replaced safely by IM administration at medium term2
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
23. Prophylaxis Protocol:
Which Antiviral in Combination?
Almost all studies have used lamivudine
In cases of pretransplant, HBV strain resistant to lamivudine
– Cases of severe recurrence despite HBIG + LAM1,2
– Adefovir should be added to HBIG
Adefovir can be used in first line3
– Risk of escape mutation lower
– Doses to be adapted in case of impaired renal clearance
No reported experience with entecavir
1. Rosenau J et al. J Hepatol. 2001;34:895; 2. Roche B et al. Hepatology. 2003;38:86;
3. Schiff E et al. Liver Transpl. 2007;13:349
24. Discontinuation of HBIG?
Arguments for discontinuation
– High cost
– Constraining, high degree of compliance
– Few cases of HBV reinfection after 3 yr posttransplant
Arguments against discontinuation
– Cases of long-term recurrence after discontinuation
– Residual HBV DNA in >50% of patients at 10 yr1,2
– Difficult to identify patients who have cleared virus
Open questions
– Who to select?
– When to stop?
Probable consensus
– Maintain prophylaxis (antiviral, vaccine)
Roche B et al. Hepatology. 2003;38:86; Hussain M et al. Liver Transpl. 2007;13:1137
25. Discontinuation of HBIG
Replacement by Lamivudine
LT Recipients
29 Patients Total
HBIG + LAM for 1 month
Randomization
HBIG + LAM LAM
N=15 N=14
18 mos
N=6
HBIG + LAM LAM
N=15 N=14
83 mos 83 mos 83 mos
HBIG + LAM (N=9) LAM (N=6) LAM (N=14 )
HBV Recurrent (N=1) HBV Recurrence (N=2) HBV Recurrence (N=1)
Buti M et al. Transplantation. 2007;84;650
26. Discontinuation of HBIG
Replacement by Lamivudine
21 patients stopped HBIG
– 18 patients stopped after 11 months
– 3 patients stopped after 15 days
All on lamivudine
2 recurrence (actuarial rate of 3 year HBV recurrence 9% after HBIG
withdrawal), one following lamivudine discontinuation
Both recurrence YMDD
3 additional patients with transient HBV DNA
Wong SN et al. Liver Transplant. 2007;13:374
27. HBV Vaccination After Discontinuation of HBIG or LAM
62% Ab response 80% Ab response
Sanchez-Fueyo A et al. Hepatology. 2000;31:496 Bienzle U et al. Hepatology. 2003;38:811
17% Ab response
Angelico M et al. Hepatology. 2002;35:176 4/50 Responders
Lo CM et al. J Hepatol. 2005;43:283
29. Vaccine After Transplantation
Great discordance in results
– Results of Berlin not confirmed by others and in
larger series
– Poor tolerance to Berlin vaccine
– Durability of response?
– Response probably more frequent in FHB patients (spontaneous
seroconversion boosted by vaccine?)
How to identify patients susceptible to respond to vaccine?
31. Future Strategies for Prevention
of HBV Recurrence
HBIG + LAM/ADV
HBIG IM + LAM/ADV
HBIG + LAM/ADV HBIG + LAM Vaccination
Nucleoside monoprophylaxis
Nucleotide monoprophylaxis
Nucleoside + nucleotide
HBIG
Induction
Nucleoside ± nucleotide
Liver Transplant 0.5–2 yr
Seehofer D, Berg T. Transplantation. 2005;80(1 suppl):S120
32. Conclusion
Major improvement with Combination HBIG + antiviral
Questions :
– Dose of HBIG taking into account viral parameters
– Ideal antiviral:Good tolerance, low resistance profiles
– Antiviral combination alone?
– Long-term prophylaxis mandatory
Possibibility to stop HBIG ?
Yes in selected groups but not mandatory; best long-term concept: low
dose HBIG + antiviral
33. NEW STRATEGIES
IN PREVENTION AND TREATMENT
TO MINIMIZE
POST-TRANSPLANT HCV RECURRENCE
Professor Didier SAMUEL
Centre Hépatobiliaire,
Inserm Unit 785, Paris XI University
Hopital Paul Brousse, Villejuif, France
C.H.B.
34. 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
RECURRENCE
HEPATITIS
< 10 %
DEATH
Adapted From McCaughan
Adapted From McCaughan 50%
35. Cumulative probability of developing
HCV-graft cirrhosis
50%
Berenguer,2002
Sanchez-Fueyo,2002
Prevalence of Cirrhosis
40%
Prieto,1999
Gane,1996
30%
Feray,1999
Neumann,2002
20%
Neumann, 2004
10% IC patient
Poynard,1997
0%
0 1 2 3 4 5
Years Posttransplant
Adapted from Gane , Berenguer
36. Late-onset severe
Early exponential increase
HCV-liver disease
followed by stabilization
N=57 with initial benign
(n=183)
evolution (F0-1 in first bx)
Late onset F: 20/57 (34%)
3
4
2,5
Fibrosis Stage
2 3
0.08
1,5
0.25 2
1
1.2
0,5 1
0
1 3 5 7 10 0
1 3 5 7
Duration of infection (years) Duration of infection (years)
Neumann, J hepatol 2004
Berenguer et al, Liver transpl 2003
37. PATIENT SURVIVAL IN LIVER TRANSPLANT PATIENTS
WITH HCV CIRRHOSIS ON THE GRAFT
Patients Survival After Cirrhosis Patient Survival After Graft Cirrhosis
on the Graft First Decompensation
M Berenguer et al. Hepatology 2000; 32:852 C.H.B.
38. PATHOBIOLOGY of CHOLESTATIC HCV
Immune response
Immunosuppression •Absent CD4 responses
•Stable quasispecies
(High level)
TH-2 like cytokine
HCV load response (IL-10 & IL-4)
Cytopathic allograft
damage IMMUNOSUPPRESSION MARKEDLY
INHIBITING THE IMMUNE RESPONSE
WINS
McCaughan and Zekry J Hepatol 2004; Samuel EASL
report J Hepatol 2006
39. Pathobiology of Chronic HCV Post LT
Immunosuppression - The immune
response
+
- HCV load Inflammation +
γ
IFN-γ related genes
α
IFN-α
response Stimulation of the IMMUNE
RESPONSE by more HCV WINS
Proliferation
Acute Rejection
Apoptosis
Inflammation
Fibrosis Stress Response
McCaughan and Zekry J.Hepatol 2004, EASL Report J Hepatol 2006
40. DYNAMIC OF HCV REPLICATION IN THE FIRST HOURS AFTER LT
Garcia-Retortillo Hepatology 2002: 35: 680 C.H.B.
41. Cholestatic HCV :
Intrahepatic Viral Load
( X106 m-RNA copies / ug RNA)
Intrahepatic viral load
1.4
* * P = 0.005 Chol vs AR, CHI & CHC
1.2
1.0
0.8
0.6
0.4
0.2
0
Chol AR CHI CHC
Chol = Cholestatic HCV post transplant
AR = Acute rejection + HCV
CHI = HCV post transplant
CHC = HCV pre transplant
Zekry et al. Liver Transplant 2002;8:292
42. Relation Between Histology and Liver HCV RNA
HCV RNA Log (CU)
CU) p < 0.03
HCV RNA (CU)
CU) ** p=0.01
1000
220 •
**
200 •
180 100 •
• •
•
• •
160 • •
140 • •
•
• •
120 2 7 10 •
•
15 • •
100 8 • •
•
•
80 •
60 34 1 •
40
•
20
0 .1
lobular CAH cholestasis Normal Acute hepatitis CAH
hepatitis
Decrease of HCV RNA with progression to CAH
High HCV RNA at time of acute hepatitis High initial HCV RNA related with more severe CAH
Di Martino et al. Hepatology 1997
C.H.B.
43. Prediction of survival based on
first year fibrosis
Survival (%)
100
50
F at one year:
0 (n=68)
0 1-2 (n=76)
3-4 (n=39)
0 1 2 3 4 5 6 7 8 9 10 11
Neumann et al, J Hepatol 04
44. HPVG, Fibrosis Stage 1 Year in HCV +ve Transplant Patients and 0utcome
Blasco Hepatology 2006; 43: 492-499
45. HPVG and Fibrosis Stage (Ishak) in HCV +ve Transplant Patients
Samonakis Liver Transplant 2007; 13: 1305-1311
47. 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
49. 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
50. Graft Survival According to Donor Age in HCV and ALD Patients
Mutimer Transplantation 2006; 81: 7-14
51. HCV RECURRENCE IN LIVING DONOR TRANSPLANTATION
Donor Age: 47 ( 13-86) in CDLT vs 31 ( 19-58) LDLT p<0.01
Cya : 59% in CDLT vs 14% LDLT p<0.01
Biliary Complications: 22% in CDLT vs 72% in LDLT p<0.01
Garcia Retortillo Hepatology 2004; 40: 699-707 C.H.B.
52. HCV Recurrence in Split, CDLT and LDLT
Histologic recurrence
LDLT Grade and stage of hepatitis C
LDLT
Humar AJT 2005; 5: 399-405
55. STEROIDS AND HCV
• Controversial role
– Increase viral load (Fong Gastro 1994, Gane Gastro 1996)
– Boluses of steroids deleterious (Berenguer J Hepatol 2000)
– But rapid withdrawal deleterious (Berenguer Hepatology 2003,
McCaughan J Hepatol 2004)
» Immune rebound?
– Immunosuppression without steroids: not yet proven beneficial
C.H.B.
56. HCV Recurrence in Patients Without Steroids
No différence in Patient and graft survival at 1 year
Waiting for histological analysis long-term
Klintmalm Liver Transplant 2007
57. 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
58. HCV Recurrence , Cyclosporine, Tacrolimus
• Controversial Role of Tacrolimus and Cyclosporine
• Tacrolimus Deleterious? Not proven:
– Absence of CyA independently associated with severe fibrosis (Berenguer
Hepatology 2003)
– More rapid reinfection with tacrolimus (Levy Transplantation 2004, Samuel
ATC 2005, Berenguer 2006)
– Better efficacy of IFN in patients treated with CyA ( Calmus AASLD 2007)
– Antiviral effect of de la CyA in replicon system (Watashi Hepatology 2003; 38:
1282-1288).
C.H.B.
60. MMF and HEPC
• Induction with MMF associated with more severe recurrence?
(Berenguer J Hepatol 2000, M Berenguer Hepatology 2003; 38:34 - 41)
• What is sure
– No antiviral action
– Deleterious or favourable impact unknown
C.H.B.
61. MMF And Hep C
Decrease of CNI
And introduction of MMF:
• Increase viral load
• Decrease fibrosis
• Decrease ALT
Bahra AJT 2005; 5: 406-411
62. Overall Role of IS
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
63. 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.
65. Antiviral Treatment In HCV+ve Cirrhotic Patients
Before Liver Transplantation
Kuo, Terrault AJT 2006; 6: 449-458
66. 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
» Low increase therapy
• IFN (1.5MU X3/wk to 3MU after wk 2) + ribavirin (600 mg/d
to 800mg/d after wk 4)
» 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.
67. ANTIVIRAL TREATMENT BEFORE TRANSPLANTATION
• Interferon + Ribavirin before LT
– 30 HCV Cirrhotic pts; Child A: 15, Child BC: 15; Genotype 1b: 25
» IFN 3MU/day + Ribavirin 800 mg/day until LT
» 9 (30%) virologic response
» 11 patients required filgrastim and 8 required EPO
» No change in LFTs
» Factors of response: low viral load, low ALT, non-1 genotype
» After LT:
• 6/9 responders remained HCV RNA Neg after LT,
• 3 relapsed
Forns et al J Hepatol 2003 C.H.B.
68. TREATMENT PRE-LT
auteurs Patients Child treatment Virologic Response SVR Tolérance
during trt Post-LT
Forns 30 A 50% INF 3M/j 9 (30%) 6/30 Baisse INF
(2003) (Délai pré- B 43% +RBV 800 (20%) 60%, riba
TH 4 mois) 23%
C 7% Durée Facteurs réponse:
G1:83% moyenne: charge virale pré- Arrêt 20%
Pts exclus 12 sem trt, Sepsis: 2
40% (2-33 sem) Diminution charge Insuf
virale de 2 log sem 4 hépatique: 4
Carrion 51 Meld α
Pegα2a 15 (29%) 10/51 Risque
(2008) G1:80% 11 µ
180µg/sem (20%) infectieux
+RBV augmenté par
Factors response: G trt (NS)
51 0,8-1g/j non 1,
contrôles Durée response virologic at
moyenne: wk4
15 sem
C.H.B
69. ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION
• Treatment in Child A patients waiting for LT
– Group of patients with HCC on Child A cirrhosis
– Child B patients
• There is place for treatment with the increased waiting time
• However:
– Is it possible to delay LT to achieve SVR?
– Balance between the aim to achieve SVR and the risk of hepatic
deterioration or HCC growth
– Treatment until LT with virologic response without waiting for
SVR?
C.H.B.
70. ANTIVIRAL TREATMENT DURING TRANSPLANTATION
HYPERIMMUNE ANTI-HCV INMUNOGLOBULINS (HCIG)
• Polyclonal HCIG (Davis Liver Transplant 2005)
– RCT:
» HCIG 75 mg/kg 17 infusions on 14 weeks
» HCIG 200 mg/Kg 17 Infusions on 14 weeks
» Placebo
• Decrease of ALT, No effect on HCV RNA
– Monoclonal HCV AbXTL 68 (Schiano Liver Transplant 2006)
» - 2.4 log HCV RNA decrease in 240 mg group vs - 1.5 log in
placebo at d 2, no difference at d 7
» Significant increase of anti-E2 at d 7 in 240 mg group
C.H.B.
71. PRE-EMPTIVE TREATMENT OF HCV RECURENCE AFTER TRANSPLANTATION
– In the first post-transplant weeks:
» Low viral load
» Risk of rejection high
• Frequent presence of acute rejection and hepatitis on the
same liver biopsy during the first month
» High level of Immunosuppressive treatment
» Risk of poor hematological tolerance +++:
• Severe anemia, leucopenia and thrombocytopenia
• Patients are anemic before treatment
» Septic and surgical complications frequent
C.H.B.
73. MEAN HCV VIRAL LOAD IN LIVER TRANSPLANT PATIENTS
TREATED PREEMPTIVELY WITH PEGIFN ALPHA 2A
SVR: 8%
Chalasani Hepatology 2005; 41: 289-298
74. PREEMPTIVE TREATMENT IN
IN HCV LIVER TRANSPLANT PATIENTS
51/124 Patients eligible, 44 Received one dose of treatment
6/124 (5%) achieved SVR
Adherence to Treatment ETVR and SVR
Shergill AJT 2005; 5: 118-124
75. MEAN HCV VIRAL LOAD IN LIVER TRANSPLANT PATIENTS
TREATED WITH PEGIFN ALPHA 2A
SVR : 8%
Chalasani Hepatology 2005; 41: 289-298
76. TREATMENT INTERFERON-RIBAVIRINE AFTER TRANSPLANTATION
Pts Bioch HCV
Authors Treatment response RNA SVR
(N) (%) Neg
IFN 3MU x 3 / week + 48 %
Bizollon Ribavirine(6 M) 21 100% ND
Hepatology 1997
then Rbv(6 M) 24%
Samuel INF 3MU x 3 / wks +
Ribavirine(12 M) 28 ND 32% 21.4%
Gastro 2003
Gopal INF 3MU x 3 / wks +
Ribavirine(1-17 M) 12 75% 50% 8.3%
Liver Transp 01
Lavezzo IFN 3MUX3/wks + Rbv 33% 22% (6M)
(6 vs 12 Mths) 57 ND
J Hepatol 02 23% 17%(12M
Menon IFN 3MUX3/weeks +
rbv (1 year) 26 42% 35% 30%
Liver Transp 02
Shakil IFN 3MUX3/weeks+
RBV ( 1 year) 38 18% NA 5%
Hepatol 02
77. KINETIC OF HCV RNA ACCORDING TO VIROLOGIC RESPONSE IN
HCV POSITIVE TRANSPLANT PATIENTS
Castells J Hepatol 2005; 43: 53-59
78. Treatment with PEG Interferon + Ribavirine
• 20 patients treated With Peg IFN (0.5µg/Kg to 1 µg/Kg) +
Ribavirin 400 to 800 mg/d)
• 80% infected with genotype 1
• 4 withdrawn
• 13 required doses reduction of ribavirin due to anemia
• End of treatment virologic response 65%
• SVR: 9/20: 45%
Dumortier J Hepatol 2004
C.H.B.
79. Treatment with PEG Interferon + Ribavirine
27 patients mild Hepatitis C (F1-F2):
SVR: 48%
27 Patients with severe hepatitis C
(F3-F4) , cholestatic hepatitis C:
SVR: 18%
(1/12 Cholestatic hepatitis, 4/15 F3-4
Carrion Gastroenterology 2007
C.H.B.
80. Histological Outcome in Relation with
Virological Response to PEGIFN+ Ribavirine
Variables associated with Histological improvement: EVR, BR, SVR
Carrion Gastroenterology 2007
C.H.B.
83. Treatment with PEG Interferon + Ribavirine
• Transpeg Study:
– 100 patients
– Peg IFN alpha 90 µg/wk + Ribavirin 600 mg/d then increased to
PegIFN 180 µg/wk + Ribavirin 100 mg/d for one year
– Randomisation at M12 placebo vs RBV maintainance
• At Week 52, 60/97 (62%) patients had a virologic response by
ITT;75 % by per-protocol (PP).
• At week 78, SVR: 34% Genotype 1- 4, 75% Genotype 2-3
• 37% Use of EPO
Calmus, Samuel AASLD 2006 C.H.B.
84. FACTEURS PREDICTIFS DE REPONSE AU TRAITEMENT
Facteurs significatifs en analyse univariée, non significatifs
En analyse multivariée. Sharma P, et al. liver Transpl 2007;13:1100-1108 C.H.B
85. 1 Year and Long Term Histological Outcome after
Treatment In Relation With Initial Stage of Fibrosis
20% of F3-F4 patients died or were retransplanted after treatment vs 1% of F1-F2
Roche Liver Transplantation 2008 In Press C.H.B
86. Predictive Factors for Response To IFN
in Genotype 1 Transplant Patients
• 67 Patients
• EOT virological response: 45 %
• SVR: 33%
• Predictive factors of response:
– At baseline and on treatment:
» Peg IFN vs standard IFN
» Early virological response
» EPO use
Berenguer Liver Transplant 2006
C.H.B.
87. 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
C.H.B.
88. Tolerance to Treatment: Risk of Rejection
• Risk of Rejection controversial: 0-35% after IFN alone (Gane
Hepatology 98, Wright Hepatology 94, Feray Hepatology 95)
• 5% in 2 randomized studies(4%) (Samuel Gastro 03, Chalasani Hepatol 05 )
• 25-35% in non randomized studie, in patients treated with IFN, PEG
IFN alone or with Ribavirine (Saab Liver Transpl04, Stravitz Liver
Transplant 04, Dumortier J Hepatol 04)
• Risk of rejection not dependent of HCV RNA persistence
• Differences may be due to:
– Underdiagnosed in NR patients with high LFTs
– Different type and level of immunosuppression
– Different risk by using IFN, Peg IFN ± Ribavirin
C.H.B.
91. Telaprevir (VX-950) + pegIFN: antiviral effect in
treatment-naïve patients with HCV G1
HCV RNA 1
median
change from 0 Baseline
baseline
(log10 IU/mL) -1 PegIFN
+ placebo
-2
-3
-4 Telaprevir
-5
Telaprevir
+ pegIFN
-6
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Treatment day
Reesink HW et al. EASL 2006
92. FUTURE TREATMENT OF HCV RECURENCE
AFTER TRANSPLANTATION ?
Antiprotease BILN 2061
Hinrichsen Gastroenterology 2004; 127:1347-1355 C.H.B.
93. Histological Outcome in SVR Transplant Patients
Necroinflammatory score reduction, Fibrosis Score Stability
Bizollon Gut 2003, 52, 283-287
C.H.B.
94. Graft Histology In HCV+ve Liver Transplant Patients
With or Without SVR
Median Follow-up : 57 Months in NR and 52 months in SVR
Bizollon AJT 2005; 6: 449-458
95. Survival Without Cirrhosis In HCV+ve Liver Transplant Patients With
or Without SVR
Bizollon AJT 2005; 6: 449-458
100. Role of SVR After LT in HCV + Patients
Piciotto J Hepatol 2007; 46:459-465
101. Improved Survival In HCV+ve Liver Transplant Patients
Italian Multicenter Study
Belli Liver Transplant 2007; 13: 733-740
102. Patient (A) and Graft (B) Survival of HCV+ve vs HCV Neg
Liver Transplant Patients
Tuluvath Liver Transplant 2007;
103. HCV Recurrence After LT Deceased vs living donors
Schmeding Liver Transplant 2007;
104. Survival of Liver Transplant Patients
Over Years in USA
Tuluvath Liver Transplant 2007;
105. Survival of Liver Transplant Patients Over Years in USA
Lower graft Survival and no Improvement in HCV +ve Patients
HCV Positive
HCV Negative
Tuluvath Liver Transplant 2007;
106. Survival of HCV+ve Liver Transplant Patients in USA
Donor HCV- vs HCV +
Deceased vs LDLT
Tuluvath Liver Transplant 2007;
