Download - Samuel virus lt du 2012
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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
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C.H.B.
LIVER TRANSPLANTATION
IN VIRAL HEPATITIS B
Natural Course, Overview
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Liver Transplantation for Viral B Cirrhosis in USA
Kim WR Gastro 09
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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
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C.H.B.
Prophylaxis after
Liver Transplantation
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C.H.B.D. Samuel et al. NEJM 1993;329:1842-7
HBV Recurrence and Survival
According to Prophylaxis
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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
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Actuarial HBV Recurrence Rate in Relation
to Initial Liver Disease
Hôpital Paul Brousse: 19862000
284 Patients
HDV-C
FHD
100
80
60
40
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
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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]
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HBV Recurrence with Lam Monoprophylaxis
A Great Failure
Jiang WJG 2009
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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
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Fung Gastro 2011 in Press
HBsAg Clearance after LT on ETV Monoprophylaxis
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Fung Gastro 2011 in Press
HBsAg Relapse after LT on ETV Monoprophylaxis
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Virology
HBV DNA and HBsAg Used 2 Distinct Pathways
Nguyen J Hepatol 2010Brunetto J Hepatol 2010
Antiviral alone not able to block HBsAg
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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
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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
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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 -
0.4 -
0.3 -
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2
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I
8P
rop
ort
ion
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nts
Wit
h
HB
V R
ec
urr
en
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Number
at risk147 124 89 56 14
Time Posttransplant (yr)
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HBV Recurrence In Patients with and without HCC
Paul Brousse 1995-2005
Faria L. Gastroenterology 2008
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HBV Recurrence Is Associated with HCC Recurrence
Paul Brousse 1995-2005
Faria L. Gastroenterology 2008
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HBV Recurrence Is Associated with HBV DNA at LT
USA
Degertekin AJT 2010
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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
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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
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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
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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
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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
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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%)
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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
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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
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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
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Lenci I. J Hepatol 2011
Discontinuation of HBV Prophylaxis after LT :
Patients with HBV recurrence
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36
33
18
6
0%
10%
20%
30%
40%
Ove
rall
HB
V
Recu
rren
ce R
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
18
6
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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
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C.H.B.
HCV AND LIVER TRANSPLANTATION
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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
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McCaughan
J Hepatol 2011
CHOLESTATIC HEPATITIS C
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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
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T Pietschmann Nature 2009
HCV Entry in Hepatocyte
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Ciesek Gastro 2010, Fafi Kremer J Hepatol 2010
Streoids Increase HCV Entry in Liver Transplantation
Gc: Glucocorticoids
Gr: Glucocorticoid
Receptor
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Fofana Gastro 2010
Additive Effect of Anticlaudin, AntiE2 and HCVIg
on HCV Entry and Infection
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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
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Blasco Hepatology 2006; 43: 492-499
HPVG, Fibrosis at 1 Year Post-Transplant and Outcome
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Gallegos-Orozco Liver Transplant 2009
Fibrosis Stage at 12 months at Liver Biopsy and Survival
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Carrion Gastro 2010
Non Invasive Test (3-M-ALG) and HPVG at 6 and 12 Months
in Control and HCV Reinfected Patients
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Carrion Gastro 2010
Non Invasive 3-MALG Test
and
Decompensation and Survival Post-Transplant
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Carrion Hepatology 2010
Liver Stiffness and Severity of HCV Recurrence
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C.H.B.
Donor and Host Factorsof
HCV Recurrence
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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
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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
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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)
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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
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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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48
23
54
29
7
33
0
10
20
30
40
50
60
70
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
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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
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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
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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
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Roche, Samuel Liver Transplant 2010
Antiviral Treatment Before Transplantation
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Roche, Samuel Liver Transplant 2010
Antiviral Treatment Immediately after Transplantation
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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
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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)
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C.H.B.
SVR and Snp near IL28 gene in Donor, Recipient, Combined in Genotype 1 Transplant Patients
Fukuhara Gastro 2010 In Press
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C.H.B.
SVR and IL28 mRNA expression in Transplant Liver in Genotype 1 Transplant Patients
Fukuhara Gastro 2010 In Press
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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%)
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Auto(Allo)immune Hepatitis and IFN
Sharma Liver Transplant 2007
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C.H.B.
Histological Outcome in Relation with Virological Response to PEGIFN+ Ribavirine
Carrion Gastroenterology 2007
Variables associated with Histological improvement: EVR, BR, SVR
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Piciotto J Hepatol 2007; 46:459-465
Role of SVR After LT in HCV + Patients
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McHutchison NEJM 09
Telaprevir In Naive HCV Non-Transplant Patients
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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
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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
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Interaction Telaprevir-Cyscloporine, Telaprevir-Tacrolimus
Garg Hepatology 2011
Dose normalised AUC X 4.5 Dose-normalised AUC X 70
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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
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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
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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
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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%
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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
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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