Samuel2 hcv lt du16

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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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

SURVIVALHDV

HBV

HCV

Current Situation of LT for Viral Hepatitis in Europe

C.H.B.

LT

Asymptomatic hepatitis

AcuteHepatitis

FCH

Chronic Hepatitis

Chronic hepatitis

DeathRelT

Cirrhosis

Chronic Hepatitis

PatientHCV RNA+

Adapted from Mc Caughan

20%

70%

10%

HCV Recurrence: a Main issue

• HCV recurrenceo Poor outcome, accounting for 2/3 of graft losto Five years post-LT, 30% of LT patients have a cirrhosis on the graft o First cause of mortality

McCaughanJ 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

ProliferationApoptosisFibrosis

HCV load Inflammation + IFN- related genes IFN-

response

-

Acute Rejection

InflammationStress 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 BiopsyGold Standard, Bring additional information than fibrosis stage

. HPVG Invasive, can be done with liver biopsyNot routine for many Centres

. Non invasive testsBiochemical

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 : 7Serious Infection rate: 7/59 (12) pts vs 0% controlDeath 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

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 ListPost-Transplant SVR in those HCV RNA Negative at LT

Curry Gastro 2015

Sofosbuvir + Riba in Patients on the Waiting ListRecurrence Related to the Duration of HCV Indetectability Pre-LT

• 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


LDV/SOF + RBV for 12 weeks is not an EMA-recommended treatment regimen; Error bars represent 90% confidence intervals;

TE: treatment-experienced; TN: treatment-naïve

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

0

20

40

60

80

100 87 8689 90

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 C12 wk (n=30)* 24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)*

Efficacy before LT Excellent results in compensated cirrhotic patients Lower efficacy in decompensated ones

Approved regimens

RBV RBVALLYRBV RBV Δ

SOF+LDV (1) SOF+DCV (2) 3D (3) SOF+SIM (4)

88%82%

94%

72%

Compensated

Child<11

(1) Charlton M. Gastroenterology 2015; (2) Poordad F, Etats-Unis, EASL 2015, Abs. L08; (3) Poordad F, Etats-Unis, EASL 2014, Oral late breaker LB O163 (4) Reddy R, Etats-Unis, EASL 2015, Abs. O007

Efficacy before LT SVR12 depends on severity of cirrhosis

o Using SOF+LDV or 3D, low platelets count and low albumin level are risk factors of relapse


SOF+LDV (1) SOF+DCV (2) 3D (3) SOF+SIM (4)

88%82%

94%

72%

Compensated

(1) Charlton M. Gastroenterology 2015; (2) Poordad F, Etats-Unis, EASL 2015, Abs. L08; (3) Poordad F, Etats-Unis, EASL 2014, Oral late breaker LB O163 (4) Reddy R, Etats-Unis, EASL 2015, Abs. O007

Efficacy before LT

SVR12 depends also on genotype


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8086

59

89

71

81

43

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7482

70

85

73

60

71

100

SVR1

2 %

(ITT

)

252 28 172 15 164 21 45 5 61 7 114 7 27 13 3

SOF + LDV + RBV SOF + LDV SOF + DCV + RBV SOF + DCV

Overall Genotype 1 Genotype 3 Others

p < 0,05

Foster G, UK, EASL 2015, Abs. O002

Combinaison SOF and NS5A inhibitor + RBV during 12 weeks 467 cirrhotic patients Child ≥ B7

Next Generation: Is this going to change?Astral 4: Sofobuvir + Velpatasvir

Ribavirin still required in most cirrhotic patients

Curry NEJM 2016

Safety before LT Good safety profile SAE rate of 20% (mainly due to RBV) Hepatic function is one issue

1. Ouwerkerk-Mahadeva S, et al. AASLD 2013. Oral #65; 2. Gilead Sciences Europe. SOVALDI (sofosbuvir), Summary of Product Characteristics, January 2014; 3. German P, et al. AASLD. 2013. Oral #52; 4. Khatri A, et al. AASLD. 2012. Oral #66; 5. Bifano M, et al. AASLD. 2011. Oral #78.

Pharmacokinetic changes according to liver function

Hepatic function impairment AvoidMild Moderate Severe

Simeprevir1 + 2.44 + 5.22 Child CSofosbuvir2 + 1.26 + 1.43Ledipasvir3 No adjustementParitaprevir/r4 - 0.71 + 1.62 + 10.23 Child COmbitasvir4 + 0.92 + 0.70 + 0.45Dasabuvir4 + 1.17 + 0.84 + 4.19 Child C?Asunaprevir5 - 0.79 + 9.8 + 32 Child B/CDaclatasvir5 - 0.57 - 0.62 - 0.64

Decompensated CirrhosisIs Delisting Possible?

BaselineMELD < 15(n = 199)

Patie

nts (

%)

0

10

20

-16

0

-11 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 7 8 9 12 13

Deterioration : 26 %

0 0

Improvement: 56 %

<1 2 3 3

8 8

1517 18

13

7

2 1 <1 1<1 <1<1

BaselineMELD ≥ 15

(n = 72)

Patie

nts (

%)

0

10

20

-16 -11 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 7 8 9 12 13

Deterioration : 11 %Improvement : 76 %

52

3

1110

16

8

1413

5

03 3

0 00 00

522

Gane EJ, New Zealand, AASLD 2015, Abs. 1049

Variations of MELD score Baseline/EOT in SOLAR I and II studies among Child>B cirrhotics

Association Between Improvement and SVR

Munoz J, USA, AASLD 2015, Abs. 202

Only 28% had an improvement in the MELD score ≥ 3 points

Delta

MEL

D

+10

+15

56 %+50

-5-10-15-20

20 % 23 %

020

All MELDimprovement

No change MELD

deterioration

406080

100

SVR1

2 (%

) Some patients improve without achieving SVR Although achieving SVR, some patients worsen

(comorbidities?)

Meta-analyses of 5 studies

Is there a Point of no Return?

National cohort study in patients waiting for LT in France

SVR12 = 88 %

183 patients

ESLD without HCC

N=77

LT31%

Delisting for improvement

16%

HCCN=106

LT54%

Drop-out6%

Coilly A, France, AASLD 2015, Abs. 95

7.5

AUC: 0.814

Child-Pugh score

MELD score

CHC, n=70Complete improvement

No response

Partial improvement

Is there a Point of no return?

National cohort study in patients waiting for LT in France: SVR12 = 88 %

Coilly A, France, AASLD 2015, Abs. 95

36%

28%

36%

Cirrhosis, n=53

21% Child B

25% Child C

72% Child A

MELD score could not be the good marker

Taking into account the System of Organs

AllocationDeaceased donor

Male 61 yo, G1bESLD without HCCMELD 23 after SBPListed for LT

National allocation system

Taking into account the system of organs allocationDeaceased donor

Male 61 yo, G1bESLD without HCCMELD 23 after SBPListed for LT

AscitesCovert HE

LT still indicates but no more access…

National allocation system

HCV treatment

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 LTStandard of Care Until 2012

C.H.B.

Coilly AAC 2012

Coilly J Hepatol 2014

First Generation Protease inhibitors in HCV RecurrenceBoceprevir and Telaprevir

C.H.B.Coilly Plos One 2015


C.H.B.Coilly Plos One 2015


C.H.B.

Triple Therapy with Telaprevir or BoceprevirThe Crush Study

Burton J Hepatol 2014

ToleranceAnemia < 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 (%)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.


Charlton Gastro 2015

C.H.B.

Sofosbuvir + Ribavirin After TransplantationTolerance

Charlton AASLD 2013 and Gastro 2015

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

Hb Creatinin

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 2015

C.H.B.

Compassionate Use Sofosbuvir + Ribavirin ± PegIFN in Liver Transplant Patients

X Forns Hepatology

in press 2015

C.H.B.

Compassionate Use Sofosbuvir + Ribavirin ± PegIFN in Transplant Patients: Virologic Response

X Forns Hepatology In Press 2015

C.H.B.

Compassionate Use Sofosbuvir + Ribavirin ± PegIFN in Transplant Patients: Virologic Response: Clinical Outcome

X Forns Hepatology 2015

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

12 or 24 weeks LDV/SOF + RBV after LT: Solar 1 studyExcellent results in F0-F3 Patients

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 Charlton et al, Gastroenterology 2015

Sofosbuvir + Daclatasvir After LT-The Cupilt Study

• Decision of investigator

Week 0 Week 12 Week 24 Week FU12

SOF=400mg/day; DCV=60mg/day; RBV=decision of physician according to renal function

SOF+DCV

SOF+DCV+RBV

SOF+DCV+RBV

SOF+DCV

n=11

n=3

n=52*

n=64*

Coilly et al, EASL 2015

Sofosbuvir + Daclatasvir After LT-The Cupilt StudyVirological Kinetics

Coilly et al, EASL 2015 Mean time to achieve undetectability: 5.7±3.3 weeks [1-20]

0 4 8 12 16 20 2401234567

SOF+DCV (n=75)SOF+DCV+RBV (n=55)

Week

HCV

RN

A (

log

IU/m

L)

p=ns

Sofosbuvir + Daclatasvir After LT-The Cupilt StudySVR according to Treatment Duration


SOF+DCV (n=11) SOF+DCV+RBV (n=3) SOF+DCV (n=64) SOF+DCV+RBV (n=52)Week 12 Week 24

100%

67%

100% 98%100%

67%

97% 96%

EOT SVR12

Virological breakthrough n=1

Lost of FU n=1Relapse n=1

Death n=2Wk1 & FU Wk6

p=ns

Sofosbuvir + Daclatasvir After LT-The Cupilt StudyOverall Tolerability


• One death at week 1: hyperosmolar coma in a patients with a previous history of diabetes mellitus

• One death at week 6 post-treatment: HCC recurrence (HCV RNA negative)• 4 cardiac disorders: 2 High Blood Pressure, 2 cardiac decompensations in patients

with past history of cardiomyopathy

Overall (n=130) SOF+DCV (n=75) SOF+DCV+RBV (n=55) p

Serious adverse events 30 (23.1) 15 (20.0) 15 (27.3) ns

Death 2 (1.5) 0 (0) 2 (3.6) ns

Cardiac disorders 4 (3.0) 1 (1.3) 3 (5.5) ns

Biopsy proven acute rejection 2 (1.5) 1 (1.3) 1 (1.8) ns

Infections (G3/4) 9 (6.9) 3 (4) 6 (10.9) ns

Sofosbuvir + Daclatasvir After LT-The Cupilt StudyHematological Adverse Events


Overall (n=130) SOF+DCV (n=75) SOF+DCV+RBV (n=55)

Anaemia 49 (37.7) 17 (22.6) 32 (58.2) Grade 0 (but EPO) 7 (5.3) 1 (1.3) 6 (11.0) Grade 3/4 (<8 g/dL) 18 (13.8) 6 (8.0) 12 (21.8) Erythropoietin use 30 (23.1) 9 (12.0) 21 (38.2) Blood transfusion 13 (10.0) 5 (6.7) 8 (6.2) RBV reduction for AE 25 (19.2) - 25 (45.5) Neutropenia 35 (27) 13 (17.3) 22 (40) Grade 3/4 (<0.75G/L) 8 (6.2) 1 (1.3) 7 (12.8) G-CSF use 2 (1.6) 1 (1.3) 1 (1.8) Thrombocytopenia 37 (28.5) 20 (26.7) 17 (30.1) Grade 3/4 (<50G/L) 7 (5.4) 3 (4.0) 4 (7.3)

Efficacy after LT Most regimens allow to achieve a SVR12 rate of >90%

Approved regimens

SOF+RBV (1) SOF+LDV (2) SOF+DCV (3,4) 3D (5) SOF+SIM (6,7)

70%

95% 94% 95%90%


(1) Charlton M, Gastroenterology, 2015; (2) Charlton M, Gastroenterology, 2015; (3) Coilly A, EASL G15, 2015; (4) Poordad F, Etats-Unis, EASL 2015, Abs. L08; (5) Kwo py, NEJM, 2014; (6) Pungpapong S, Hepatology 2015. (7) Reddy R, Etats-Unis, EASL 2015, Abs. O007

Leroy et al, Clin Gastroenterol Hepatol 2015

Impressive Efficacy in FCH Transplant Patients

Sofosbuvir + Daclatasvir or Sofosbuvir + Ribavirine in 23 Patients with FCH-The Cupilt Cohort

Leroy et al, Clin Gastroenterol Hepatol 2015

Sofosbuvir + Daclatasvir or Sofosbuvir + Ribavirine in 23 Patients with FCH-The Cupilt Cohort

Impressive Efficacy in FCH Transplant Patients

Compassionate use of Sofosbuvir + Ribavirine +- Peg IFN After LT- Clinical outcome

Forns et al, Hepatology 2015

Efficacy Lower in Transplant Patients with Advanced Cirrhosis

Ciclosporine Tacrolimus

Sofosbuvir

Sofosbuvir/Ledipasvir

Ciclosporine AUC - 2% Tacrolimus AUC + 13%

Daclastavir

Simeprevir

Ciclosporine AUC +4.74 Tacrolimus AUC +79%

Ombitasvir, paritaprevir, ritonavir, dasabuvir

Ciclosporine AUC +5.82Dosage ÷5

Tacrolimus AUC +57.10.5mg/wk ou 0.2mg/2days

Safety after LT Good safety profile SAE rate of 20% (mainly due to RBV) Issue: drug-drug interactions

Coilly, A. Liver Int. 2015

Safety after LT Good safety profile SAE rate of 20% (mainly due to RBV) Issue: drug-drug interactions

Coilly, A. France, G15, EASL 2015.

ANRS C023 CUPILT cohort: SOF+DCV

Tacrolimus Ciclosporine Everolimus MMF

Number of patients 78 37 13 71

Number who changed dosage –

n (%)44 (56 %) 18 (49 %) 5 (38 %) 9 (13 %)

Most changes occurred after 4 weeks of treatment, reflecting improvement in liver function more than clinically relevant drug-drug interactions

To monitor immunosuppressive drugs is still mandatory

C.H.B.

SVR with DAA in LT Patients

Gamballi J Hepatol 2014

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

Conclusion 3: Management ProposalTreatment with DAA Before or After LT

Patients on waiting list

HCC

Child A/B

Treat before LT

Child C

Consider benefits

To control HCC: Treat

Reduced access to LT:

Delay

ESLD – No HCC

Child B

Consider MELD score

Low: Treat High: Delay

Child C

Treat after LT

Take Home Messages

Treat hepatitis C using DAA before or after LT? Both strategies are feasible with excellent efficacy results and good safety profiles

Regarding efficacy, better results are achieved after LT than before in decompensated cirrhotic patients

Regarding safety, drug-drug interactions and degree of hepatic impairment are still issues, and favor the use of NS5A inhibitors

Withdraw patients of waiting list is feasible and should concern about 30% of patients.

Centre Hépato-BiliaireA Coilly

E De MartinF Chiappini

B RocheR Sobesky

F SalibaT Antonini

JC Duclos-ValléeAnd all the Team at The CHB

Health & Medicine

Samuel2 hcv lt du16