treatment of hepatitis c in liver transplantation ... · professor didier samuel centre...
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C.H.B.
Treatment of Hepatitis C in Liver Transplantation
Professor Didier Samuel
Centre Hépatobiliaire, Inserm Unit 785, Paris XI UniversityHopital Paul Brousse, Villejuif, France
Treatment of Hepatitis C in Liver Transplantation
Professor Didier Samuel
Centre Hépatobiliaire, Inserm Unit 785, Paris XI UniversityHopital Paul Brousse, Villejuif, France
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C.H.B.
With HCCWithout HCC
www.eltr.org
HCV
HBV
HDV
INDICATIONS
SURVIVAL
HDV
HBV
HCV
Current Situation of LT for Viral Hepatitis in Europe
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C.H.B.
LT
Asymptomatic hepatitis
AcuteHepatitis
FCH
Chronic Hepatitis
Chronic hepatitis
Death
RelT
Cirrhosis
Chronic Hepatitis
Patient
HCV RNA+
Adapted from Mc Caughan
20%
70%
10%
HCV Recurrence: a Main issue
• HCV recurrence
● Poor outcome, accounting for 2/3 of graft lost
● Five years post-LT, 30% of LT patients have a cirrhosis on the graf
● First cause of mortality
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C.H.B.
Impact of Fibrosing Cholestatic Hepatitis on Survival
No FCH
FCH 19%
P=0.004
Antonini Am J Transplant 2011
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Piciotto J Hepatol 2007
Impact of SVR on Survival in Transplant HCV +ve Patients
Berenguer M AJT 2008
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C.H.B. Feray J Hepatol 2011
HCV Recurrence: a Main Issue
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C.H.B.
PegIFN + RBV Before LTPegIFN + RBV Before LT
• Treatment PegIFN+RBV until LT
– 47 G1/4/6 patients
● 30 treated
● 17 not treated
• 32 G2/3 patients treated
● 29 treated
● 3 not treated
Everson Hepatology 2012
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C.H.B.
PegIFN + RBV Treatment Before LTPegIFN + RBV Treatment Before LT
Everson Hepatology 2012
Meld score: 12, CTP score : 7
Serious Infection rate: 7/59 (12) pts vs 0% control
Death pre-LT: 5/59 vs 2/20 (NS)
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9
Antiviral Treatment in Patients Waiting
for Liver Transplantation, Risk of Sepsis Related to CPT
Carrión JA et al. J Hepatol. 2009;50:719-28.
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C.H.B.Curry AASLD 2013. Washington, DC. Oral #213
Pre-Transplant Sofosbuvir + RBV Until LT
Patient Demographics
SOF + RBV (n=61)
Male, n (%) 49 (80)
Median age, y (range) 59 (46–73)
White, n (%) 55 (90)
BMI < 30 kg/m2, n (%) 43 (70)
HCV RNA > 6 log10 IU/mL, n (%) 41 (67)
Genotype, n (%)1a1b23a4
24 (39)21 (34) 8 (13)7 (12)1 (2)
Non-CC allele, n (%) 47/60 (78)
CTP score, n (%)5678
26 (43)18 (30)14 (23)3 (5)
Median MELD score, (range) 8 (6–14)
Prior HCV treatment, n (%) 46 (75)
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C.H.B.Curry AASLD 2013. Washington, DC. Oral #213
Post-Transplant Virologic Response
SOF + RBV was safe and effective in patients with well compensated cirrhosis,and prevented post-transplant HCV recurrence in 64% of patients who had
HCV RNA < 25 IU/mL prior to transplant
Pre-Transplant Sofosbuvir + RBV Until LT Pre-Transplant Virologic Response
Transplant PTVR 120
20
40
60
80
100 93
64
41/44*
25/39*†
Vir
al R
esp
on
se R
ate
(%)
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C.H.B.Curry MP, et al. AASLD 2013.
0 50 100 150 200 250 300 350
Days with HCV RNA Continuously TND Prior to Liver Transplant
No Recurrence (n=28) Recurrence (n=10)*
Median days TND
• No recurrence: 95
• Recurrence: 5.5
p
*3 patients with recurrent HCV had 0 consecutive days TND before transplant.
Pre-Transplant Sofosbuvir + RBV Until LT
Impact of Duration of Treatment on HCV Recurrence
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C.H.B.
● Antiviral treatment with Peg-IFN+RBV
● Treatment can be done at the stage of chronic hepatitis
● Peg-IFN +RBV = standard of care:
● Overall SVR: 30%;
● SVR G1: 25- 30%, SVR G3: 50% (Berenguer J Hepatol 2008,
Calmus J Hepatol 2012)
● EPO in 40% of patients
● Poor tolerance of treatment when F3-F4 (Carrion Gastro 2007,
Roche LT 2008): 30% of premature discontinuation
HCV Treatment after LTStandrad of Care Until 2012
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C.H.B.
Coilly AAC 2012
Coilly J Hepatol 2014
New Direct Acting Agent in HCV RecurrenceBoceprevir and Telaprevir
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C.H.B.
First Generation Protease inhibitorsTelaprevir, Boceprevir
First Generation Protease inhibitorsTelaprevir, Boceprevir
Coilly AASLD 2013
PegIFN/RBV PegIFN/RBV+BOC(800mg tid)
PegIFN/RBV PegIFN/RBV+TVR (750mg tid)
PegIFN/RBV+TVR (750mg tid)
Week -4 Week 0 Week 4 Week 12
n=35
n=19
n=25
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C.H.B.
First Generation Protease inhibitorsTelaprevir, Boceprevir
First Generation Protease inhibitorsTelaprevir, Boceprevir
Coilly AASLD 2013
0,48
0,4
0,26
0,64
0,510,47
Tela Boce
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C.H.B.
First Generation Protease inhibitorsTelaprevir, Boceprevir
First Generation Protease inhibitorsTelaprevir, Boceprevir
Coilly AASLD 2013
0,54
0,35 0,33 0,33
SVR 12 According to FibrosisP= NS
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C.H.B.
First Generation Protease inhibitorsTelaprevir, BoceprevirHematological Safety
First Generation Protease inhibitorsTelaprevir, BoceprevirHematological Safety
Coilly AASLD 2013
BOCEPREVIR (n=35)
TELAPREVIR (n=44) p
Anemia (Hb<10g/dL) 95% 96% ns
Anemia (Hb<8g/dL) 63% 45% ns
RBV dose reduction + EPO use 94% ns
Red blood cell transfusion 49% ns
Neutropenia (NC<1G/L) 73% 45% 0.011
Thrombopenia (Plat<50G/L) 48% 28% ns
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C.H.B.
The Advent of Second Generation DAAs
After Liver Transplantation
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C.H.B.
PegIFN +RBV+Daclatasvir for FCH after LTPegIFN +RBV+Daclatasvir for FCH after LT
Fontana Liver Transpant 2012
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C.H.B.
Sofosbuvir+Daclatasvir for FCH after LTSofosbuvir+Daclatasvir for FCH after LT
Fontana Am J Transplant 2013
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C.H.B.
Sofosbuvir + Ribavirin After TransplantationSofosbuvir + Ribavirin After Transplantation
Charlton AASLD 2013
SOF 400 mg + RBV 400‒1200 mg (N=40) SVR12
• Patients with recurrent HCV post-liver transplant
– Liver transplant ≥6 and ≤150 months prior to enrollment
– Any HCV genotype
– Naïve or treatment-experienced
– CTP ≤7 and MELD ≤17
• Low, ascending-dose RBV regimen starting at 400 mg/day,
escalated based on hemoglobin levels
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C.H.B.
Sofosbuvir + Ribavirin After TransplantationSofosbuvir + Ribavirin After Transplantation
Charlton AASLD 2013
SOF + RBV (N=40)
Male, n (%) 31 (78)
Median age, y (range) 59 (49-75)
White, n (%) 34 (85)
BMI <30 kg/m2, n (%) 30 (75)
Mean HCV RNA log10 IU/mL (range) 6.55 (4.49-7.59)
Genotype, n (%)1a1b234
22 (55)11( 28)
06 (15)1 (3)
IL28B, n (%)CCCTTT
13 (33)16 (40)11 (28)
Metavir-equivalent fi brosis stage, n (%)None or minimal (F0)Portal Fibrosis (F1-F2) Bridging Fibrosis (F3)Cirrhosis (F4)
1 (3)14 (35)9 (23)16 (40)
Prior HCV Treatment, n (%) Yes 35 (88)
Median years since liver transplantation (range) 4.3 (1.02-10.6)
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C.H.B.
Sofosbuvir + Ribavirin After TransplantationSofosbuvir + Ribavirin After Transplantation
Charlton AASLD 2013
Week 4 EOT* SVR 40
20
40
60
80
100100 100
77
39/39
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C.H.B.
Sofosbuvir + Ribavirin After TransplantationTolerance
Sofosbuvir + Ribavirin After TransplantationTolerance
Charlton AASLD 2013
0 1 2 3 4 8 12 16 20 24 FU-2 FU-410
11
12
13
14
15
0,8
0,9
1,0
1,1
1,2
HbCreatinin
20% Received EPO
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C.H.B.
CONCLUSIONCONCLUSION
• Before Liver Transplantation
– Triple antiviral therapies with IFN in cirrhotics is diffi cult
– Treatment without IFN will be necessary
– Strategies of on treatment virological response to be priorized
– Questions:
● Duration of treatment, Timing in relation to LT?
● Virological resistance?
● Improvement of liver function on DAAs?
● Relapse and risk of liver failure?
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C.H.B.
CONCLUSIONCONCLUSION
• First results of triple therapies after LT are encouraging
– Increased virologic response
– Drug-drug interactions manageable
– However tolerance is a limiting factor
• Treatment without IFN awaited but IFN might remain necessary in some patients:
– Transplant HCV infected patients diffi cult to treat
• Keep in mind the objective:
– Not to treat without IFN
– The eradication of HCV after Transplantation
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SL Friedman Journal of Hepatology 2014 In press
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C.H.B.
AknowledgementsAknowledgements
VirologistsS Haïm-BoukobzaAM Roque-Afonso
PathologistsM SebaghC Guettier Pharmacologists
L Bonhomme-FaivreV Furlan
AM Taburet
Audrey CoillyBruno Roche
Teresa AntoniniRodolphe Sobesky
Jean-Charles Duclos-ValléeCentres
• J Dumortier• S Radenne• D Botta-Fridlund• GP Pageaux• V Leroy• SN Si-Ahmed
Centre Hépato-Biliaire
AFEF prospective groupof liver transplantation