Samuel hcv lt du hepatite 1-15

C.H.B.

Hepatitis C

in Liver Transplantation

Patterns of Recurrence and Therapy

Professor Didier Samuel

Centre Hépatobiliaire,

Inserm Unit 785, Paris XI University

Hopital Paul Brousse, Villejuif, France

C.H.B.

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

HCV

HBV

HDV

INDICATIONS

SURVIVAL

HDV

HBV

HCV

Current Situation of LT for Viral Hepatitis in Europe

C.H.B.

LT

Asymptomatic

hepatitis

Acute

Hepatitis

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

o Poor outcome, accounting for 2/3 of graft lost

o Five years post-LT, 30% of LT patients have a cirrhosis on the graft

o First cause of mortality

McCaughan

J Hepatol 2011

CHOLESTATIC HEPATITIS C

C.H.B.

Impact of Fibrosing Cholestatic Hepatitis on Survival

No FCH

FCH 19%

P=0.004

Antonini Am J Transplant 2011

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

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 Hepatology 2010

Liver Stiffness and Severity of HCV Recurrence

Piciotto J Hepatol 2007

Impact of SVR on Survival in Transplant HCV +ve Patients

Berenguer M AJT 2008

C.H.B.Feray J Hepatol 2011

HCV Recurrence: a Main Issue

Roche, Samuel Liver Int 2012

Antiviral Treatment Before Transplantation

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)

Antiviral Treatment in Patients Waiting

for Liver Transplantation, Risk of Sepsis Related to CPT

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

C.H.B.Hezode J Hepatol 2013

Risk Factors of Death and Severe infections in cirrhotics

on Triple therapy with Boceprevir or Telaprevir

The Cupic Study

Sofosbuvir + ribavirine in patients with cirrhosis and portal hypertension

• 50 patients with cirrhosis• Child-Pugh A and B, portal gradient > 6 mmHg, oesophagal/gastric varices

Afdhal N, Etats-Unis, EASL 2014, Abs. O68 actualisé

SOF 400 mg + RBV 1 000‒1 200 mgSVR 12

Observation SOF 400 mg + RBV 1 000‒1 200 mg

SVR 12

Arm 1n = 25

Arm 2n = 25

W0 W24 W48 W96W72

45


*1 patient non responder at w 8

Virologic Response during first 24 Weeks

According to Child Pugh Score

HC

V R

NA

< L

DQ

(%

)

Weeks

56

100 100 100 100

44

75

94 9394*

0

20

40

60

80

100

2 4 8 12 24

CP A

CP B

5/9 9/9 8/8 8/8 7/77/18 12/16 15/16 14/1515/16


47


Clinical Parameters of decompensation

Ascites Hepatic Encephalopathy

Patients , n SOF + RBV(n = 25)

Observation(n = 25)

SOF + RBV(n = 25)

Observation(n = 25)

Initial 6 9 5 2

W 12 5 8 3 3

W 24 0 7 0 4


49

Curry Gastro 2015

Sofosbuvir + Riba in Patients with HCC on the waiting List

Curry Gastro 2015

Sofosbuvir + Riba in Patients with HCC on the Waiting List

Post-Transplant SVR in those HCV RNA Negative at LT

Curry Gastro 2015

Sofosbuvir + Riba in Patients on the Waiting List

Recurrence Related to the Duration of HCV Indetectability Pre-LT

C.H.B.

DAA PK in Cirrhotics

Gamballi J Hepatol 2014

• 108 patients randomised 1:1 to 12 or 24 weeks of treatment

• GT 1 or 4 treatment-naïve or -experienced patients with decompensated

cirrhosis (CTP class B [7–9] or C [score 10–12]*)

• Broad inclusion criteria

– No history of major organ transplant, including liver

– No hepatocellular carcinoma (HCC)

– Total bilirubin ≤10 mg/dL, Hb ≥10 g/dL

– CrCl ≥40 mL/min, platelets >30,000/mm3

Flamm S, et al. AASLD 2014; Oral #239.

LDV/SOF + RBV for 12 weeks is not an EMA-recommended treatment regimen;

*Patients with CTP scores 13–15 excluded; CrCl: creatinine clearance;

EMA: European Medicines Agency

SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhosis

Wk 0 Wk 12 Wk 36Wk 24

SVR12N=53

SVR12N=55 LDV/SOF + RBV

LDV/SOF + RBV



Error bars represent 90% confidence intervals;

TE: treatment-experienced; TN: treatment-naïve

SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhosis

87 8689 90

0

20

40

60

80

100

CTP B CTP C

SV

R12 (

%)

26/30 19/22 18/2024/27

LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks

SVR rates were similar with 12 or 24 weeks of LDV/SOF + RBVVirological response was associated with improvements in bilirubin, albumin, MELD and CTP

scores in both CTP class B and C patients

Prospective, multicentre study of 12 or 24 weeks of LDV/SOF + RBV in TN and TE HCV GT 1 and 4 patients with CTP B (N=59) or CTP C (N=49) clinically decompensated cirrhosis


LDV/SOF + RBV for 12 weeks is not an EMA-recommended treatment regimen

*Missing FU-4: n=2 CTP B 12 wk; n=4 CTP B 24 wk; n=2 CTP C 12 wk;

n=7 CTP C 24 wk; BL: baseline; FU: follow-up

SOLAR-1: LDV/SOF + RBV in decompensated cirrhosis:

Change in MELD from BL to Week 4

(-8)

-6

-4

-2

0

2

4

-6

-4

-2

0

2

4

n=5 n=5 n=2 n=3

(+10)

CTP B CTP C

12 wk (n=30)* 24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)*

C.H.B.

o Antiviral treatment with Peg-IFN+RBV

Treatment 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 LT

Standard of Care Until 2012

C.H.B.

Coilly AAC 2012

Coilly J Hepatol 2014

First Generation Protease inhibitors in HCV Recurrence

Boceprevir and Telaprevir

C.H.B.

Triple Therapy with Telaprevir or Boceprevir

The Crush Study

Burton J Hepatol 2014

Tolerance

Anemia < 10 : 78%

Blood Transfusion: 57%

EPO: 81%

GCSF: 41%

Creat 0.5 mg/l : 38%

Rash: 11%

Hospitalizations for infection: 11%

Discontinuation: 15%

Deaths : 9%

C.H.B.

Triple Antiviral Therapy with Telaprevir in HIV-HCV Liver Transplant Recipients

Antonini et al. AIDS 2013

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 Gastro 2015

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.


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 (%)

1a

1b

2

3

4

22 (55)

11( 28)

0

6 (15)

1 (3)

IL28B, n (%)

CC

CT

TT

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.


Charlton Gastro 2015

C.H.B.

Sofosbuvir + Ribavirin in Liver Transplant Patients

Difficulty to identify Relapsers

M Charlton Gastro 2015

GS 33107 AUC

Sofosbuvir AUC

RBV mean daily dose

RBV AUC

C.H.B.


Tolerance

Charlton AASLD 2013 and Gastro 2015

0.8

0.9

1.0

1.1

1.2

10

11

12

13

14

15

0 1 2 3 4 8 12 16 20 24 FU-2 FU-4

HbCreatinin

SAE: 15%, SAE leading to discontinuation: 5%, fatique 30%,

Hb< 10g:/dl: 33%; Hb< 8g: 3%, 20% Received EPO

C.H.B.

Compassionate Use Sofosbuvir + Ribavirin± PegIFN

in Liver Transplant Patients

X Forns Hepatology In Press 2015

C.H.B.


in Liver Transplant Patients

X Forns

Hepatology

in press 2015

C.H.B.


in Transplant Patients: Virologic Response


C.H.B.


in Transplant Patients: Virologic Response: Clinical Outcome


C.H.B.


in Transplant Patients: outcome


ABT450/Ritonavir/Ombitasvir + Dasabuvir + RBV in LT

Recipients with Recurrent HCV GT 1

• Phase II Study on efficacy and tolerance of ABT-450/r/ombitasvir

150 mg/100m g/25 mg/d + dasabuvir 250 mg x 2/d in patients

with HCV reinfection post-LT

• Patients G1, fibrosis ≤ F2 at Liver biopsy, no prior PEG/RBV after LT

• Dosing RBV free for the investigator

• CNI adaptation

– Tacrolimus 0.5 mg/week or 0.2 mg/3 days

– Ciclosporine 1/5 of initial daily dosing once a day

3D + RBV(n = 34)

SVR12

D0 W24 W72

Kwo P, Etats-Unis, EASL 2014, Abs. O114 actualisé

C.H.B.

ABT450/Ritonavir/Ombitasvir + Dasabuvir + RBV in LT Recipients

with Recurrent HCV GT 1

P Kwo NEJM 2015

• 1 premature discontinuation for Rash (rash, anxiety)• No rejection• 4 patients Tac though level > 15 mg/ml (15,7-34)→ réversible of créatinin in 2 patients

Anemia

n (%)3D + RBV(n = 34)

8-10 g/dl 8 (23,5)

6,5-8 g/dl 1 (2,9)

EPO 5 (14,7)

n (%)J0

(n = 34)Fin TTT(n = 34)

400 mg/d 3 (9) 4 (12)

600-800 mg/d 19 (56) 25 (73)

1 000-1 200 mg/d 12 (35) 5 (15)

Dosing of RBV

Kwo P, Etats-Unis, EASL 2014, Abs. O114 actualisé

ABT450/Ritonavir/Ombitasvir + Dasabuvir + RBV in LT Recipients with Recurrent HCV GT 1

Sofosbuvir/Simeprévir + RBV 12 weeks for HCV RecurrencePost-Transplantation

• Multicenter study, 109 transplant patients with histologically proven recurrent HCV. • Delay post-LT : 29 months (median). Median FU : 23 weeks• Cholestatic recurrence: 11 % ; METAVIR F3-F4 : 29 %

Pungpapong S, Etats-Unis, AASLD 2014, Abs. 9 actualisé

Virologic Response ITT

Tau

x d

e r

ép

on

se (

%)

EOT SVR4 SVR12

99101

2323

7678

8390

2022

6368

8390

2022

6368

Sofosbuvir/Simeprévir + RBV 12 weeks for HCV RecurrencePost-Transplantation(G1)

• 1 case of acute pancreatitis. Interruption of treatment for 2 weeks. No recurrenceafter retreatment 12wks : response.

• 1 case of drug induced pneumopathyleading to death due to MOF

Pungpapong S, Etats-Unis, AASLD 2014, Abs. 9 actualisé

Tolerance (AE)

Adverse Events %

Asthenia 9

Hyperbilirubinemia 5

Nausea 4

Headaches 4

Prurit 3

Anaemia (group non RBV) 2

Anaemia (group RBV) 42

Reduction RBV dosing 100

EPO 50

Tolerance (SAE)

Sofosbuvir/Daclatasvir for Fibrosing Cholestasis after LT(CUPILT Study)

• Prospective multicenter French cohort Study

Leroy V, France, AASLD 2014, Abs. 21 actualisé

No FCHHCV recurrence

Recurrent HCV(n = 2)

Biliary stenosisArtérial thrombosisAcute rejection

Treatment FU

Groups pooled

(n = 2)

(n = 6)

(n = 15)* Ribavirine était administrée à 13 patients

Decompensated Cirrhosis (n = 2)

Cohort CUPILT (10/2013 - 04/2014)(n = 131)

Clinical Criteria FCH(n = 27)

Histological HFC(n = 23)

PEG-INFα + SOF + RBV

SOF + RBV

SOF + DCV + RBV*

W0 W12 W24 FU 12


Clinical response 24*

*Survival without retransplantation, total bilirubine < 34 mmol/l, absence of ascites and no encephalopathy

Evolution of Bilirubin at 24 weeks

0 4 8 12 16 20 24

SOF + RBV + PEG

SOF + DCV + RBV

0

20

40

60

80

100

Time (weeks)

Inci

de

nce

de

ré

po

nse

clin

iqu

e (

%)

0 4 8 12 16 20 24

Time (weeks)

0

50

100

150

200

Mé

dia

ne

de

bili

rub

ine

to

tale

(µ

mo

l/)L

n =

20

(8

7 %

)



• Tolerance – SAE : 12 (52 %)– Anaemia grade 3-4 : 6/26 %)– Infection : 7 (30 %) – Neutropenia grade 3-4 : 3 (13 %)– Renal failure : 1

Virologic Response According to TreatmentA

RN

VH

C <

15

UI/

mL

(%)

*1 patient HIV-HCV , génotype 1b, F4 relapsed

SOF + RBV + PEG

SOF + DCV + RBV

8 15 8 15 8 15 8 13 8 11


• 223 patients randomised 1:1 to 12 or 24 weeks of treatment

– ≥3 months from liver transplant

– No hepatocellular carcinoma

• Stratified at screening: F0–F3, CTP A, B, C

• Broad inclusion criteria:

– Total bilirubin ≤10 mg/dL, Hb ≥10 g/dL

– CrCl ≥40 mL/min, platelets > 30,000

• RBV dosing

– F0–F3 and CTP A cirrhosis: weight-based (<75 kg = 1000 mg; ≥75 kg = 1200 mg)

– CTP B and C cirrhosis: dose escalation, 600–1200 mg/d

Reddy KR, et al. AASLD 2014; Oral #8.

LDV/SOF + RBV for treatment of HCV in patients

with post-transplant recurrence

LDV/SOF + RBV for 12 weeks is not an EMA-recommended treatment regimen

Prospective, multicentre study in TN and TE GT 1 and 4 patients, who were post-liver transplantation and received 12 or 24 weeks of LDV/SOF + RBV

Wk 0 Wk 12 Wk 36Wk 24

SVR12N=112

SVR12N=111 LDV/SOF + RBV

LDV/SOF + RBV

Reddy KR, et al. AASLD 2014; Oral #8.

LDV/SOF + RBV in Post-Transplant Recurrence


Error bars represent 2-sided 90% exact confidence intervals

96 9685 60

98 9683 67

0

20

40

60

80

100

F0–F3

SV

R12

(%)

53/55 22/26 15/18

CTP B

55/56 25/26 24/25 2/3

CTP A

LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks

3/5

CTP C

SVR rates were similar with 12 or 24 weeks of LDV/SOF + RBV

C.H.B.

DAA Interactions with CNI (Tacrolimus and Cyclosporine)


C.H.B.

SVR with DAA in LT Patients


HCV patients awaiting LT

Compensated cirrhosis

GT 1–4

SOF + DCV ± RBV

SOF + SMV ± RBV

LDV/SOF ± RBV

ABT Quad therapy (GT 1)

GT 2–3

SOF + RBV

SOF + DCV ± RBV (GT 3)

Decompensatedcirrhosis

GT 1–4

SOF + DCV ± RBV

LDV/SOF ± RBV

GT 2–3

SOF + RBV

SOF + DCV ± RBV(GT 3)

Figure 1: Alternative strategies to treat HCV infection in patients on a waiting list in 2014-2015

A Coilly Liver Int 2015

HCV recurrence

GT 1–4

No CNI adjustment

SOF + SMV ± RBV

SOF + DCV ± RBV

LDV/SOF ± RBV*

SMV + DCV ± RBV*

CNI adjustment

GT 1

ABT-450/r + ombitasvir + dasabuvir + RBV

GT 3

SOF + DCV ± RBV

GT 2

SOF + RBV

Figure 2: Alternative strategies to treat HCV recurrence after liver transplantation in 2014-2015

A Coilly Liver Int 2015

C.H.B.

Management of Cirrhotic and Transplant Patients

with DAA


C.H.B.

CONCLUSION

• The Field of Liver Transplantation In HCV Patients is moving

dramatically with IFN-free regimen

• Some questions are open:

– Treat before or after Transplantation?

–Remove patients from the waiting list?

–Which combination?

–Duration of treatment ? Use of RBV?

–How to avoid relapse? Risk of liver failure in case of relapse?

• The survival after transplantation for HCV infection will improve

C.H.B.

Aknowledgements

Virologists

S Haïm-Boukobza

AM Roque-Afonso

PathologistsM Sebagh

C Guettier PharmacologistsL Bonhomme-Faivre

E Rudant

AM Taburet

Audrey Coilly

Bruno Roche

Teresa Antonini

Rodolphe Sobesky

Eleonora de Martin

Jean-Charles Duclos-Vallée

Centres•J Dumortier

•S Radenne

•D Botta-Fridlund

•GP Pageaux

•V Leroy

•SN Si-Ahmed

Centre Hépato-Biliaire

AFEF prospective group

of liver transplantation

Date post:	14-Jul-2015
Category:	Health & Medicine
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Samuel hcv lt du hepatite 1-15

Health & Medicine