Recurrent HCV after a Pre-LTx Course of SOF/DAC:

Didier Samuel, Teresa Antonini

Centre Hépato-Biliaire, Inserm –Paris Sud Research Unit 1193 Hôpital Paul Brousse, Villejuif, France

3rd Optimize Workshop, Using DAAs in Patients with Cirrhosis and Liver Recipients, Wien

Case presentation: M. D, 56 y

History of HCV: Transfusional contamination

Genotype 1a

IL-28B polymorphism CT

Peg IFN/RBV 2005

Non responder

Case presentation

Liver function: Albumin: 37 g/L

Total Bilirubin: 22 μmol/L

Prothrombin: 75%, INR 1.2

Creatinine: 80 μmol/L

Platelet count: 120x109/L

Mild ascites

No hepatic encephalopathy

Case presentation

Liver function: Albumin: 37 g/L

Total Bilirubin: 22 μmol/L

Prothrombin: 75%, INR 1.2

Creatinine: 80 μmol/L

Platelet count: 120x109/L

Mild ascites

No hepatic encephalopathy

Child-Pugh Score A 6

MELD 9

Case presentation

Hepatocellular carcinoma: 1 Nodule

3 cm, segm VI-VII

Successfully treated by microwave ablation in 2012

Strategy?

Strategy?

Anti HCV therapy?

Strategy?

Anti HCV therapy?

Liver Transplantation

Strategy?

Anti HCV therapy?

After Liver Transplantation

Before Liver Transplantation

Hill AM, AASLD 2015

Impact of SVR: Risk of death

HCV

-90

-80

-30

-20

-10

Réd

uctio

n of

dea

th %

-70

-60

-50

-40

-71 -62

HCV/F4

-73

-84

HCV/HIV

-75 -73

Univariate Multivariate

0 Meta-analysis 15 studies N= 34 563 patients

Hill AM, AASLD 2015

Impact of SVR: Risk of HCC

HCV 0

2

4

14

16

18

20

% p

ts a

fter

5 y

6

8

10

12

HCV/F4 HCV/HIV

2,9

9,3

5,3

13,9

0,9

10

HCV n = 12 496 Follow-up

6,1 y

HCV/F4 n = 4 987 Follow-up

6,6 y

Co-infected HCV/HIV n = 2 085 Follow-up

4,7 y

SVR Non SVR

Meta-analysis 15 studies N= 34 563 patients

Hill AM, AASLD 2015

Impact of SVR: Risk of LT

Meta-analysis 15 studies N= 34 563 patients

HCV 0

2

4

14

16

18

20

Patie

nts

afte

r 5

y (%

)

6

8

10

12

HCV/F4 HIV/HCV

0

2,2 0,2

7,3

0,6 2,7

HCV n = 108

Follow-up 4,2 y

HCV/F4 n = 1 046

Follow-up 7,7 y

VIH VHC n = 2 039

Follow-up 4,9 y

SVR Non SVR

Sofosbuvir/Ledipasvir/RBV in Decompensated Cirrhotics

Flamm SL et al, AASLD, 2014

12

11

10

9

8

7

6

5

Improvement (n = 33) Worsening

(n = 4)

(n = 2)

(n = 3)

(n = 5)

Stability (n = 10)

Chi

ld- P

ugh

Scor

e

•HCV recurrence is universal

• Natural history of HCV is accelerated compared to non-transplant setting

• 30% of patients develop cirrhosis at 5 years post-LT

Forman, Gastroenterology 2002

High risk of recurrence

What Type of Treatment ( France 2012)?

Peg IFN/RBV/Tela

Peg α2a: 180 μg/w RBV: 1000 mg/d (15mg/Kg) Telaprevir: 750 mg/Tid

2nd Treatment

2nd Treatment

Peg IFN/RBV/Tela

Peg α2a: 180 μg/w RBV: 1000 mg/d (15mg/Kg) Telaprevir: 750 mg/Tid

0

1

2

3

4

5

6

7

8

W4 W8 W12

log

log

2nd treatment

Peg IFN/RBV/Tela

Peg α2a: 180 μg/w RBV: 1000 mg/d (15mg/Kg) Telaprevir: 750 mg/Tid

0

1

2

3

4

5

6

7

8

W4 W8 W12

log

log

STOP

2nd Treatment

Peg IFN/RBV/Tela

0

1

2

3

4

5

6

7

8

W4 W8 W12

log STOP

Mutation R155K

Peg α2a: 180 μg/w RBV: 1000 mg/d (15mg/Kg) Telaprevir: 750 mg/Tid

2nd Treatment

Peg IFN/RBV/Tela

Peg α2a: 180 μg/w RBV: 1000 mg/d (15mg/Kg) Telaprevir: 750 mg/Tid

Case presentation

Deteriorating Liver function : Albumin: 24 g/L

Total Bilirubin: 27 μmol/L

Prothrombin: 58%, INR 1.56

Creatinine: 100 μmol/L

Mild ascites

No hepatic encephalopathy

Child-Pugh Score B7

MELD 14

REFERRED FOR OLT

3rd Treatment before LT?

2005 Non responder

Peg IFN/RBV Peg IFN/RBV/Tela

2012 Non responder

R155K

?

3rd Treatment before LT?

SOF/RBV?

SOF/SIM? SOF/DCV?

SOF/LDV? Omb-ABT450/r Dasa+RBV?

3rd treatment before LT?

SOF/RBV?

Osinusi A et al. Jama 2013

3rd treatment before LT?

SOF/RBV?

SOF/SIM?

SOF/DCV?

SOF/LDV?

Omb-ABT450/r Dasa+ RBV?

3rd Treatment before LT?

SOF/SIM?

www.hcvforum.org

3rd treatment before LT?

SOF/RBV?

SOF/SIM?

SOF/DCV?

SOF/LDV?

Omb-ABT450/r Dasa+ RBV?

SOF/DCV SVR12%

Sukowski M et al.NEJM 2014

3rd Treatment before LT?

SOF/RBV?

SOF/SIM?

SOF/DCV?

SOF/LDV?

Omb-ABT450/r Dasa+ RBV?

3rd treatment before LT?

SOF/RBV?

SOF/SIM?

SOF/DCV?

SOF/LDV?

Omb-ABT450/r Dasa+ RBV?

NOT AVAILABLE AT THAT

TIME IN FRANCE

3rd Treatment before LT?

2005 Non responder

Peg IFN/RBV Peg IFN/RBV/Tela

2012 Non responder

R155K

SOF/ DCV

3rd Treatment

Sofosbuvir Daclatasvir

SOF= 400mg/d DCV= 60mg/d

3rd Treatment

Sofosbuvir Daclatasvir

SOF= 400mg/d DCV= 60mg/d

STOP

3rd Treatment

Sofosbuvir Daclatasvir

SOF= 400mg/d DCV= 60mg/d

STOP

Mutation 31M,58P

3rd treatment

Sofosbuvir Daclatasvir

Mutation 31M,58P

http://www.genafor.org

3rd treatment

Sofosbuvir Daclatasvir Mutation

31M,58P

Finally..

SOF/RBV?

SOF/SIM?

SOF/DCV?

SOF/LDV?

Omb-ABT450/r Dasa+ RBV?

Finally..

SOF/RBV?

SOF/SIM?

SOF/DCV?

SOF/LDV?

Omb-ABT450/r Dasa+ RBV?

Finally..

SOF/RBV?

SOF/SIM?

SOF/DCV?

SOF/LDV?

Omb-ABT450/r Dasa+ RBV?

Virological Resistance

Finally..

SOF/RBV?

SOF/SIM?

SOF/DCV?

SOF/LDV?

Omb-ABT450/r Dasa+ RBV?

Virological Resistance

Virological Resistance

And Now?

Resistant variants

Potent antiviral therapy eliminates sensitive variants

Resistant variants can expand

Resistant variants

Potent antiviral therapy eliminates sensitive variants

Persistance of resistant virus

Return to pre-treatment status

Finally..

- HCV population and clonal amino acid analyses in patient treated by PI, suggest that PI resistant population may return to pre-treatment levels over time

Sullivan et al, CID 2013

For telaprevir, 60-89% of patients no longer had detectable resistant variants after a median FU of 10,6 months for G1a

DISCUSSION

-This patient developed NS5A resistance in addition to PI’s

resistance.

-No clear identified Strategy

- Retreat before LT? Whith what drug?

- Treat after LT?

- Add IFN to decrease resistance?

- Add RBV ?

- Assess mutation before retreatment?