C.H.B.

HCV PRE AND POST-LIVER TRANSPLANTATION

Professor Didier SAMUEL

Centre Hépatobiliaire,

Inserm Unit 785, Paris XI University

Hopital Paul Brousse, Villejuif, France

C.H.B.

Evolution of Liver Transplantation for Viral Cirrhosis

in Europe.

With HCCWithout HCC

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800

1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Virus Delta Virus B Virus C

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1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Virus Delta Virus B Virus C

www.eltr.org

Trends in Waiting List for HCV Cirrhosis in USA

Kim Gastroenterology 2009

PATTERN OF HCV RECURRENCE POST OLTx

OLT

DEATH50%

NO HEPATITIS20%

CHRONIC HEPATITIS

ACUTE HEPATITIS70%

CHOLESTATIC HEPATITIS

< 10 %

VIRAL RECURRENCE

1 MTH

6 MTH

CHRONIC HEPATITIS CIRRHOSIS

?

6 MTH1 MTH

1 MTH

Adapted From McCaughan

McCaughanJ Hepatol 2011

CHOLESTATIC HEPATITIS C

FIBROSING CHOLESTATIC HEPATITIS C

Antonini AJT 2011

FCH in HCV-HIV Coinfected PatienstImpact on Survival

Antonini AJT 2011

Immunosuppression

Proliferation

Apoptosis

Fibrosis

HCV load Inflammation +

IFN- related genes IFN- 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

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 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

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)

No Impact of Steroid-Free IS on Graft HCV Fibrosis

Klintmalm Liver Transplant 2011

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 fibrosis stage, better survival with Tac?

Samonakis, J Hepatol 2012 in Press, Berenguer Nat Rev Gastroenterol 2011

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

SVRPost-LT

Tolerance

Forns(2003)

30(Time pre-

LT 4 mths)

G1:83%

A 50%B 43%C 7%

INF 3M/d+RBV 800mgMean

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)

51G1:80%

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

Antiviral Treatment in Patients Waiting

for Liver Transplantation, Risk of Sepsis Related to CPT

Carrión JA et al. J Hepatol. 2009;50:719-28.

Antiviral Treatment in Patients Waiting

for Liver Transplantation, Norfloxacin Prophylaxis

Carrión JA et al. J Hepatol. 2009;50:719-28.

C.H.B.

PegIFN + 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

C.H.B.

PegIFN + 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)

Roche, Samuel Liver Int 2012

Antiviral Treatment Before Transplantation

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.

Study ANRS HC29BOCEPRETRANSPLANT

Pilot study of Efficacy and Tolerablity of Boceprevir in combination with Peginterferon alpha-2b and Ribavirin in patients infected with HCV

genotype 1, naive or non responders with cirrhosis awaiting liver transplantation

Promoteur : ANRS

Coordinating investigator : Didier SamuelCo-investigators :

JC Duclos-Vallée, H Fontaine, B Roche

C.H.B.

Inclusion criteria

• Age > 18 years• Chronic HCV infection proved with a positive HCV PCR

during 6 months or more• Genotype 1• Patient with cirrhosis and registered for LT• MELD score ≤ 18• With or without hepatocellular carcinoma• Naïve or non responders

C.H.B.Curry AASLD 2013. Washington, DC. Oral #213

Pre-Transplant Sofosbuvir + RBV Until LT

Patient DemographicsSOF + 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)

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

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100 93

64

41/44* 25/39*†

Vir

al R

esp

on

se R

ate

(%)

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

Feray J Hepatol 2011

Strategies Before and After Transplantation

Zeisel J Hepatol 2011

Mechanism of HCV Entry

Roche, Samuel Liver Transplant 2010

Antiviral Treatment Immediately after Transplantation

C.H.B.

Antiviral Therapy PegINF+ RBV Post-TransplantationAuthors Studie

sPatients Years ETVR SVR Tolerance AR Factors

linked with SVR

Wang 21 (1RCT)

587 1980-05 42%(30-37)

27% (23-31)

Reduction 66% (61-70%)Stop: 26% ( 20-32)

5%(3-7)

No prior antiviral tt post-LTNon-1 G

Berenguer 19 (2RCT)

611 2004-07 42%(17-68)

30%G1: 28%G2: 71-100%G3:41% (30-77%)

Reduction:68%Stop 28%

6.4% EVRG2AdherenceBaseline viremia

Xirouchakis 6 RCT 264 2005-07 - 30%G1: 29%G2: 71-100%G3: 41% ( 30-77)

- 5%

Roche, Samuel Liver Int 2012, Wang AJT 2006, Berenguer J Hepatol 2008, Xirouchakis J Viral Hep 2008

Auto(Allo)immune Hepatitis and IFN

Sharma Liver Transplant 2007

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 IL28 in all Genotype Transplant Patients

Lange J Hepatol 11

C.H.B.

SVR According to IL 28

Charlton Hepatology 2011

C.H.B.

Survival (Death and Graft Loss) According to IL 28

Charlton Hepatology 2011

IL 28 Recipient IL 28 Donor

C.H.B.

IL 28 In the Donor should be determined on Graft Reperfusion Biopsy or PBMC, not on follow-up Biopsies

Coto-Llorena J Hepatol 2012

C.H.B.

SVR According to IL 28 in Recipient, Donor, and FU Biopsy

Coto-Llorena J Hepatol 2012

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

Impact of SVR on Suvival in Transplant HCV + Patients

Berenguer M AJT 2008

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

Garg Hepatology 2011

Telaprevir and Cyclosprine and Tacrolimus Interactions

Cmax increased by 1.4X

AUC Increased by 4.1-4.6X

T1/2 increased by 4 X

Cmax increased by 9.3X

AUC Increased by 70X

T1/2 increased by 5 X

Healthy volunteers Liver transplant patients

Alone Boce0

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Alone Boce0

2

4

6

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10

12

• Boceprevir in 5 transplant patients: the estimated oral clearance decreased

• Cyclosporine (n=3): 50% • Tacrolimus (n=2): up to 80%• Everolimus (n=1): 55%

Coilly, AAC, 2012

Cla

iranc

e or

ale

(L/h

)

Cyclosporine Tacrolimus

• CNI, cyclosporine or tacrolimus• PI: CYP 3A4 potent inhibitors• AUC increase

Garg, Hepatology, 2011Hulskotte, Hepatology, 2012

Boceprevir Telaprevir

Cyclosporine 2.7 4.6

Tacrolimus 9.9 70

Treatment After LT with Protease Inhibitors

One limitation: drug-drug interactions

• Cohort study, N=37• 5 transplant centers in France

Villejuif, Lyon, Grenoble, Marseille, Montpellier

• Inclusion criteria:• Active genotype 1 HCV chronic hepatitis• HCV recurrence, ≥ F2 or cholestatic hepatitis• Steady-state of immunosuppressive regimen• No contraindication for protease inhibitors, PEG-IFN/RBV

French Collaborative study

PEG-IFN/RBV PEG-IFN/RBV+Boceprevir (800mg tid)

PEG-IFN/RBV PEG-IFN/RBV+Telaprevir (750mg tid)

PEG-IFN/RBV+Telaprevir (750mg tid)

Week -4 Week 0 Week 4 Week 12

n=18

n=8

n=11

W48

Patients and Methods

C.H.B.

DAA Post-TransplantationPractical Issues

Coilly Liver Int 2013

ITT ITTPP PP

Bocéprévir (n=18) Télaprévir (n=19)

89%

63%

89%

75%

ITT ITTPP PP

Bocéprévir (n=13) tELA

64%

50%

67%

50%

ITT PP

p=ns p=ns

Virological response

EVR at Week 12 ETVR at Week 48

Boceprevirn=18

Telaprevirn=19

Boceprevirn=13

S-4 S2 S4 S8 S12 S16 S20 S24 S28 S32 S36 S40 S44 S480

1

2

3

4

5

6

7

8

9

Mean treatment duration: 42 ± 8.7 weeks

Treatment discontinuation Null response, n=1 Virological breakthrough , n=1 Adverse events, n=2

End of treatment with undetectable viral load, n=7

On going, n=7

HCV

vira

l loa

d (lo

g 10

IU/m

L)

Treatment duration

Boceprevir group, n=18

Mean treatment duration: 33 ± 10.2 weeks

S-4 S0 S4 S8 S12 S16 S20 S24 S28 S32 S36 S40 S44 S480

1

2

3

4

5

6

7

8

9

On going, n=10

HCV

vira

l loa

d (lo

g 10

IU/m

L)

Treatment duration

Telaprevir group, n=19

Treatment discontinuation Null response, n=4 Virological breakthrough , n=2 Adverse events, n=2

Boceprevir (n = 18)

Telaprevir (n = 19) p

Death – n°(%) 1 (5 %) 1 (5 %) ns

Infections – n° (%) 3 (17 %) 4 (21 %) ns

Hematotoxicity – n° (%)Anemia< 10 g/dL< 8 g/dLNeutropenia (<1 G/L)Thrombopenia (< 50 G/L)

18 (100 %)7 (39 %) 11 (61 %)5 (28 %)

16 (84 %)3 (15 %) 4 (21 %)3 (15 %)

ns

Dermatological toxicity –n° (%) 1 (5 %) 1 (5 %) ns

Renal failure – n° (%) 0 2 (9 %) ns

Diabetes mellitus – n° (%) 2 (10 %) 0 (26%) ns

Adverse events

Boceprevir Telaprevir

CNI dose reduction

Cyclosporine 1.8 3.4

Tacrolimus 5.2 23.8

CNI-PI interactions

• Dose reduction of CNI constantly required• No overdose• No biopsy-proven acute rejection

First Generation Protease inhibitorsTelaprevir, Boceprevir

Coilly AASLD 2013

EOT RVS 12 RVS 24

43%

41%

27%

60%

51%47%

Tela Boce

C.H.B.

The Advent of Second Generation DAAs

After Liver Transplantation

C.H.B.

PegIFN +RBV+Daclatasvir for FCH after LT

Fontana Liver Transpant 2012

C.H.B.

Sofosbuvir+Daclatasvir for FCH after LT

Fontana Am J Transplant 2013

C.H.B.

Sofosbuvir + 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

C.H.B.

Sofosbuvir + 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 fibrosis 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)

C.H.B.

Sofosbuvir + Ribavirin After Transplantation

Charlton AASLD 2013

Week 4 EOT* SVR 40

20

40

60

80

100100 100

77

39/39

C.H.B.

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

C.H.B.

Evolution of Liver Transplantation for Viral Cirrhosis

in Europe.

With HCCWithout HCC

www.eltr.org

C.H.B.

Evolution of Patient Survival after LT for Virus C

Cirrhosis without HCC in Europe (ELTR: 1988-2010)www.eltr.org

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

• Triple antiviral therapies with IFN in cirrhotics remains difficult

– Increase in SVR expected

– High rate of anemia , risk of sepsis and death

– Strategies to improve tolerance are necessary

– Treatment without IFN are strongly awaited

• First results of triple therapies after LT are encouraging

– Increased virologic response

– Acceptable tolerance and drug-drug interactions manageable

– Treatment without IFN awaited but IFN might remain

necessary in some patients