recurrent hcv after a pre-ltx course of...
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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?