Trattamento con i nuovi farmaci nei pazienti sottoposti a trapianto di

Trattamento con i nuovi
farmaci nei pazienti
sottoposti a trapianto di
fegato
Maria Rosaria Piras
SSD Coordinamento Trapianto di Fegato
Azienda Ospedaliera Brotzu
Cagliari
19 dicembre 2015
Treatment Pre-LT with the Goal of Preventing HCV
Recurrence
Strategy 1: Treat to Cure
Antiviral
Antiviral Therapy
Therapy
LT
for 12-24 wks
100% HCV-free post-LT
SVR
No SVR
100% HCV- infected post-LT
Strategy 2: Treat to Achieve HCV RNA Undectability
Antiviral Therapy until
HCV RNA negative for ≥ 4 wks
On-Treatment Response
LT
Follow up
95% HCV-free post-LT if
HCV RNA negative at LT
Treatment Pre-LT with the Goal of Preventing HCV
Recurrence
Strategy 1: Treat to Cure
Antiviral
Antiviral Therapy
Therapy
LT
for 12-24 wks
100% HCV-free post-LT
SVR
No SVR
100% HCV- infected post-LT
Shorter duration
of therapy
Strategy 2: Treat to Achieve HCV RNA Undectability
Antiviral Therapy until
HCV
RNA
negative
for ≥TND
4 wks
High
% of
patients
achieve
LT
Follow up
HCV RNA on DAAs
On-Treatment Response
95% HCV-free post-LT if
HCV RNA negative at LT
Post-Transplant HCV Recurrence in patients in whom
HCV RNA was non detectable for 28 days prior to transplant
No Recurrence (n=29)
Recurrence (n=10)
Cirrhosis + HCC
CTP ≤ 7
MELD exception for HCC
48 wks or LT
No AEs due to SOF/RBV
No recurrence in 24/25 (96%) of
patients who maintained HCV RNA
TND >28 days
0
.
28
28
30
60
90
120
150
180
210
240
270
300
330
360
Days with HCV RNA Continuously TND Prior to Liver Transplant
Curry MP et al, Gastroenterology 2015
390
National program for early access to SOF therapy in Italy
for patients with chronic hepatitis C in liver LT waiting list
47
ITACOPS, AISF 2016
(227/243 pazienti, 93.5%)
N=227
HCC 47%
GT 1/2/3/4
TE 55%
HBsAg+ 5
HIV 10
MELD 13 (6-24)
CTP 8 (5-12)
SOF/RBV safe and
effective also in
decompensated
cirrhosis
227
PATIENTS
87
53 pts
pts
completed treatment
100 pts
OLT
47 patients
HCV RNA negative for > 4 wks
at OLT
3 pts
bridge therapy
44 pts
stop therapy
1 pt: medical decision
1 donor anti-HCV 1 donor HCV RNA
Negative:3 pts
SVR12:100%
Positive:5 pts
Negative:39 pts
SVR12: 87%
3030pts
pts
discontinued
therapy
10
10
pts died for
complications
of cirrhosis
53 pts
HCV RNA negative for < 4 wks
or still positive at OLT
34 pts
bridge therapy
2 deaths
(MOF)
Positive:1 pts
Negative:31 pts
SVR12: 97%
19 pts
stop therapy
3 deaths
Positive:6 pts
Negative:10 pts
SVR12:62.5%
Advanced cirrhosis N=60
Post-LT N=53
DCV 60 mg QD
Follow-up
SOF 400 mg QD
+RBV
Week 0
Week 12
Week 24
SVR 12
§ HCV GT 1-75% (GT1a 57%)
§ IL28B non CC 78%
§ Naive or experienced patients
§ DAA failures allowed except NS5A
§ HCC allowed
§ CTP B-C 80%
Advanced cirrhosis patients with treatment interrupted by LT could receive an
additional 12 wks of treatment immediately post-LT
Week 36
Cirrhotic Patients Transplanted During Treatment:
Ally-1 Study
*Discontinued RBV after 11 days due to hyperbilirubinemia resulting from post-LT biliary obstruction
Centro Trapianti di Fegato - Pancreas A.O. Brotzu
Direttore Dott. Fausto Zamboni
Cirrhotic Patients
Transplanted
During Treatment:
Cirrhotic
Patient Transplanted
During Treatment
Pre-transplant
SOF+LDV
PA
1b
TND (23 days)
Cirrhotic Patient
Transplanted
During Treatment
Post-transplant
HCV -
None
*Discontinued RBV after 11 days due to hyperbilirubinemia resulting from post-LT biliary obstruction
Post-Transplant Antiviral Therapy
Prevent graft
loss
Prevent extra-hepatic
complications
Reverse
complications of
decompensation
Timing of Post-LT Therapy
Early therapy better
How early is “early” ?
Basic requirements
• Prevent histological injury/fibrosis
• Reduce likelihood of cholestatic hepatitis
• Simplify evaluation of abnormal liver tests
Safety and efficacy studies used ≥ 6 months
post-LTà interpret as “clinically stable”
• Stable renal function, resolved anemia, low
dose PPI,stable immunosuppression
• Dose interruption very unlikely
European DCV Compassionate Use Program
• N=80
• Male 70%
• White 93%
• Median age 58 yr
• TE 69%
• HCV RNA 6.2 log IU/ml
• GT1 87% (a=32%)
• HBV coinfection 6%
• ≥ post LT 3.3 yrs(0.3-21)
• Cirrhosis 43%
• CTP B/C 43%
• MELD > 15 22%
• FCH 11%
• RBV 30%
• TAC 74%
• CsA 21%
• Everolimus11%
• Sirolimus 2%
• MMF 51%
• Steroids 16%
24 wks
Well tolerated
No significant DDI
No Rejection
Herzer K et al. AASLD 2015
SVR (mITT) by Liver Disease Status
Herzer K et al. AASLD 2015
U.S. DCV Expanded Access: Post-transplant Cohort
100
97
100
80
SVR12 (%)
N=62 (treatment
available N=42)
Age 59 yrs
HCV RNA ≥5 log IU/ml
GT 1/2/3 n% 49/12/57
F3/F4 69%
Decompensated
cirrhosis 31%
MELD n%
<9 (37)
10-15 (61)
>16 (42)
HCC 26%
FCH 16%
Dual kidney/LT 7%
TAC 47%
CSA 12%
Everolimus/sirolimus
15%
MMF 75%
Steroids 18%
Well tolerated
No significant DDI
No rejection
60
40
20
32
0 33
• 
• 
• 
32
33
GT 1
8
8
8
8
GT 3
1 GT 1 patient experienced post-treatment relapse
Additionally, 1 GT 2 patient in the post-transplant
cohort achieved SVR12
NS5A sequencing (population based) in relapse
patient identified Y93H RAV
Brown RS et al. EASL 2016, poster SAT-251 (modified)
Patients With Fibrosing Cholestatic Hepatitis
Patient
1
2
3
4
5
HCV
GT
1
3
1a
3
3
Treatment
Weeks of
Treatment
Reason for
Discontinuation
Bilirubin
Normalized
at EOT
DCV+SOF
DCV+SOF
DCV+SOF
DCV+SOF
DCV+SOF
24
17
12
10
24
Headachea
Insurance denial
Pruritusa
-
Yes
Yes
Yes
No
Yes
SVR12
Yes
Yes
Yes
Yes
Yes
•  Among the 62 enrolled patients, 8 had FCH, of whom 5 had data
at
post-treatment Week 12
•  All 5 showed rapid viral decline and achieved SVR12
•  General improvements from baseline in MELD score and total bilirubin
levels were observed
Brown RS et al. EASL 2016, poster SAT-251
Treatment after LT: Solar-1 and Solar-2
SOF
+ LDV
± RBV
N=667
Pre-Post LT
CTP B/C N=323
Post-LT
CTP B/C N=112
Safe and well
tolerated irrespective
of the degree of
decompensation or
whether patients
were pre- or-post LT
Analysis excluded 13 patients transplanted prior to posttreatment Week (FU) 12 with HCV RNA <LLOQ at last
measurement prior to transplant, and 3 pretransplant patients who were CTP A at baseline. Error bars represent 95%
confidence intervals (CIs).
Gane, AASLD, 2015, 1049
Centro Trapianti di Fegato - Pancreas A.O. Brotzu
Direttore Dott. Fausto Zamboni
Patient Disposition:
Post-transplant
Cohort
Startedtreatment
treatmentn=49
n=49(+(+6 6retreated)
retreated)
Started
SOF+RBV
n=34/
SOF+RBV
n=1
SOF+RBV(compassionate
(compassionateuse)
use)=20/
=20/SOF+NS5A
SOF+NS5Ai
n=34/
SOF+RBV
n=1
Completed treatment
N = 48 (87%)
Ongoing treatment
N =7
Discontinued prematurely
N=0
Adverse events
anemia N =1 5 (27%)
Treatment outcome available
N = 47
Treatment outcome pending
N=1
Demographic and Baseline DiseaseCharacteristics
SOF/RBV
N=21
SOF/NS5Ai±RBV
N=34
Male 84%
80%
88%
Median age 50 yr (34-67)
56 (46-67)
50(34-67)
TE 68%(P-INF+RBV/SOF+RBV)
14 (67%)
24 (70%)
HCV RNA ≥6 log IU/ml (4-8)
≥6 (4-8)
≥6 log (3-8)
GT1-54%(GT1a 22%)/GT2(6%)GT3(18%)GT4(22%)
43/9/24/24%
65/3/12/20%
HBV-HDV coinfection N=1
1
0
HCC 52%
12 (57%)
16 (47%)
Months from LT ≥ 6 (6-144)
6-134
6-144
F3-F4 = 54%
18 (90%)
6 (18%)
Cirrhosis 34% CTP A 90%/B 10%
10
6
FCH N=2 (4%)
1
1
RBV 82%
21
32
TAC/CSA/Everolimus/MMF/Steroids %(73-5-22-69-16) 12/2/7/11/4
28/1/5/27/5
Centro Trapianti di Fegato - Pancreas A.O. Brotzu
Direttore Dott. Fausto Zamboni
12
Week 0
24
36
48
SVR 24
N=21
SOF + RBV
67%
N=27
SOF/LDV ± RBV
SVR12
100%
N=8
SOF/ DAC + RBV
SVR12
100%
SVR24
N=6
Centro Trapianti di Fegato e Rene-Pancreas A.O. Brotzu
Direttore Dott. Fausto Zamboni
24
12
Week 0
36
48
SVR 24
N=21
SOF + RBV
67%
N=27
SOF/LDV + RBV
SVR12
N=8
SOF/ DAC + RBV
SVR12
Well tolerated
No significant DDI
No rejection
FCH N=1
GT3
SOF + RBV
NR= 7
100%
100%
SVR
100%
SVR24
N=6
GT1b=3 (F3=1/cirrhosis=2)
GT 3 =2 (F3=1/cirrhosis=1)
GT4 =1 (cirrhosis=1)
Centro Trapianti di Fegato - Pancreas A.O. Brotzu
Direttore Dott. Fausto Zamboni
DAAs Failure: Retreatment with NS5Ai
SVR 24 = 100% (N=6/6)
SOF+LDV+RBV (n=4)
SOF+DAC+RBV (n=2)
0
24
weeks
4/4
2/2
SOF/LDV
+ RBV
SOF/DAC
+RBV
1-Conclusions
•  Treatment of HCV infection in patients awaiting LT is a good strategy
to prevent HCV graft infection: it will increase survival an simplify
post-LT follow-up
•  Viral clearance may be associated with improvement in liver function,
leading to delisting in some cases
•  Treatment is not recommended in patients with very advanced liver
disease
•  All patients with HCV infection after LT are candidates for IFN-free
antiviral therapy
•  Treatment is recommended at an early stage of hepatitis C
recurrence, preferably when patients are in stable condition
•  In those cases of early recurrence (cholestatic forms) treatment
shoud be administered as soon as the diagnosis is made
Complicanze pre e post Trapianto di fegato
SSD Coordinamento Trapianto di Fegato
A.O. Brotzu - Cagliari
fpost-OLT à NAFLD Insufficienza renale acuta più frequente nel post operatorio
Dott.ssa Laura Mameli Dott.Francesco Sanna
Direttore: Dott.ssa Maria Rosaria Piras
Patogenesi multifatoriale
e fattori in parte comuni a iperlipemia e diabete
Stile di vita, modifiche immunosoppressione Osteopenia e fratture spontanee frequenti
soprattutto I° semestre post-OLT
Centro Trapianti Fegato - Pancreas
Patogenesià m. colestatica, deficit
e sintesi ed
assorbimento vit.D,
A.O.Brotzu
- Cagliari
Malnutrizione, ipogonadismo, immobilità, diuretici,
rapida perdita massa, recente
Direttore: Dott.Cise
Fausto Zamboni
Osteopenia e fratture spontanee frequenti ° semestre post-OLT
Patogenesi multiffatoriale: m. colestatiche, deficit sintesi e metabolismo vit.D
deficit assorbimanto calcio, malnutrizione, ipoginadismo, allettamento, diuretici
rapida perdita massa ossea primo periodo post-OLT, terapia immunosoppressiva, IRC jatrogena
Calcio, vit. D e bifosfonati
evidenza utilità Orlistat
Complicanze pre e post Trapianto di fegato
SSD Coordinamento Trapianto di Fegato
A.O. Brotzu - Cagliari
fpost-OLT à NAFLD Insufficienza renale acuta più frequente nel post operatorio
Dott.ssa Laura Mameli Dott.Francesco Sanna
Direttore: Dott.ssa Maria Rosaria Piras
Patogenesi multifatoriale
e fattori in parte comuni a iperlipemia e diabete
Stile di vita, modifiche immunosoppressione Osteopenia e fratture spontanee frequenti
soprattutto I° semestre post-OLT
Centro Trapianti Fegato - Pancreas
Patogenesià m. colestatica, deficit
e sintesi ed
assorbimento vit.D,
A.O.Brotzu
- Cagliari
Malnutrizione, ipogonadismo, immobilità, diuretici,
rapida perdita massa, recente
Direttore: Dott.Cise
Fausto Zamboni
Osteopenia e fratture spontanee frequenti ° semestre post-OLT
Patogenesi multiffatoriale: m. colestatiche, deficit sintesi e metabolismo vit.D
deficit assorbimanto calcio, malnutrizione,
ipoginadismo, allettamento, diuretici
GRAZIE
rapida perdita massa ossea primo periodo post-OLT, terapia immunosoppressiva, IRC jatrogena
Calcio, vit. D e bifosfonati
evidenza utilità Orlistat
Treatment after LT
Paritaprevir/R
§ N=34
§ All GT1
§  F2=≤2
§ TN & TE
§ CNIs adjustement for
§  ABT450/RTV
§ Mild AEs
§ 5 patients recived EPO
Kwo et al, NEJM 2014
+
Ombitasvir
+
Dasabuvir
+
RBV
LDV/SOF+RBV for Treatment of FCH After Liver
Transplantation
SOLAR-1 and SOLAR-2: Fibrosing Cholestatic Hepatitis (US and EU)
12
Week 0
n=7
LDV/SOF + RBV
n=4
LDV/SOF + RBV
36
24
SVR12
SVR12
12 Weeks
LDV/SOF+RBV
n=7
24 Weeks
LDV/SOF+RBV
n=4
59 (56–65)
56 (52–64)
6 (86)
3 (75)
Median HCV RNA, log10 IU/mL (range)
6.6 (4.9–8.0)
6.4 (5.8–7.7)
Median years from transplant (range)
1.0 (0.4–1.6)
0.3 (0.2–0.4)
Median total bilirubin, mg/dL (range)
5.8 (1.6–12.4)
11 (1.5– 28.1)
Median GGT, U/L (range)
446 (234–1332)
602 (47–740)
Median ALT, IU/L (range)
174 (71–211)
165 (62–220)
89 (36–94)
75 (69–103)
Median age, y (range)
Male, n (%)
Median CLcr, mL/min (range)
FCH, fibrosing cholestatic hepatitis
Forns, EASL, 2015, P0779
100%
SVR
European DCV Compassionate Use Program
SVR (mITT) by Genotype
LDV/SOF+RBV for Treatment of FCH After Liver
Transplantation
12 Weeks
LDV/SOF+RBV
n=7
24 Weeks
LDV/SOF+RBV
n=4
50 (34–67)
56 (52–64)
85
3 (75)
Median HCV RNA, log10 IU/mL (range)
≥4 (4.0–8.0)
6.4 (5.8–7.7)
Median months from transplant (range)
1.0 (0.4–1.6)
0.3 (0.2–0.4)
Median total bilirubin, mg/dL (range)
5.8 (1.6–12.4)
11 (1.5– 28.1)
Median GGT, U/L (range)
446 (234–1332)
602 (47–740)
Median ALT, IU/L (range)
174 (71–211)
165 (62–220)
89 (36–94)
75 (69–103)
Median age, y (range)
Male, n (%)
Median CLcr, mL/min (range)
FCH, fibrosing cholestatic hepatitis
Forns, EASL, 2015, P0779
Results: Post-Transplant Virologic Response
SOF
N=40
GT1=83%
Cirrhosis 40%
+
RBV
N=104
GT1=85%
Cirrhosis 50%
FCH 50%
70%
24 weeks
N=40
GT1=83%
Cirrhosis 40%
70%
NO DDI
No rejection
59%
Charlton
SVR 12
Forns
SVR 12
Samuel
SVR 12
Charlton M et al , Gastroenterology 2015, Forns X et al Gastroenterology 2015, Samuel D et al EASL 2014
HCV Infection and Liver Transplantation
HCV infection is the 1° cause of liver transplantation
in industrialized countries
BUT
• Universal reinfection after LT
• Negative impact on long-term survival
• Up to 1/3 of HCV transplanted patients will develop an
accelerated course to cirrhosis within 5 yrs following LT
Recurrence prevention
Berenguer M et al Hepatology 2000;32:852-858Neumann UP et al Transplantation 2004: 77:226-231, Belli L et
al Liver Transpl 2007;13:733-740, Burra P et al J Hepatol 2013
Liver toxicity associated with antiviral therapy
Two case reports with SOF-based therapies
Sofosbuvir + NS5A inhibitors treatment in decompensated HCV
cirrhosis.
ü  Mithocondrial damageà lactic acidosis (SOF/ RBV?)
à decompensation in 35 pts with advanced diseases
(Welker et al J Hepatol 2016 Editorial: Hoofnagle J Hepatol 2016)
Dyson et al. J. Hepatol 2016:64;234-238
SVR12 by HCV Genotype and by cohort: ALLY-1 Study
Patients with relapse: DCV + SOF
+ RBV 24 wks
§ No DDI
§ No graft rejection
§ Well tolerated
Poodard F et al EASL 2015
Patients With Dual Kidney / Liver Transplant
Post-transplant Cohort
Parameter
Age, median (range) years
Male, n (%)
Race, n (%)
White
Black / African American
HCV genotype, n (%)
1
3
Cirrhosis, n (%)
Diabetes, n (%)
Creatinine clearance,
median (range) mL/min/
1.73m3
SVR12, n (%)
DCV+SOF
N=4
68.5 (61–79)
4 (100)
3 (75)
1 (25)
2 (50)
2 (50)
3 (75)
4 (100)
73.3 (55.5–
91.2)
4 (100)
Brown RS et al., EASL 2016, poster SAT-251
•  Among the 62 enrolled
patients, 4 had dual
kidney / liver
transplants
•  3 with cirrhosis
•  All diabetic
•  All receiving
tacrolimus-based
immunosuppression
•  All patients completed
24-week of treatment
•  All patients achieved
SVR12
Results: Post-Transplant Virologic Response
SOF
N=40
GT1=83%
Cirrhosis 40%
+
RBV
N=104
GT1=85%
Cirrhosis 50%
FCH 50%
70%
24 weeks
N=40
GT1=83%
Cirrhosis 40%
70%
NO DDI
No rejection
59%
Charlton
SVR 12
Forns
SVR 12
Samuel
SVR 12
Charlton M et al , Gastroenterology 2015, Forns X et al Gastroenterology 2015, Samuel D et al EASL 2014
Treatment after Liver Transplantation
SOF
Author
+
N
Simeprevir
GT 1
±
RBV
Cirrhosis
12-24 weeks
RBV
SVR
Brown R 1
131
82%
60%
22%
91%
Pupapon S 2
109
100%
29%
22%
91%
Te H 3
40
100%
35% (F3F4)
0%
71%
Treatment safe and well tolerated
1-2 AASLD 2014, 3 EASL 2015
SVR12 Rates Among Patients with Recurrent HCV
Post-Liver Transplant
LDV/SOF+RBV 12 weeks
LDV/SOF+RBV 24 weeks
LDV/SOF 12 weeks
102/ 104/
107 105
F0–F3
58/
60
56/
58
CTP A
SOLAR-1 and SOLAR-2
40/ 11/
11
41
Kwok, et al.
28/
28
Shoreibah, et al.
18/
18
Hassett, et al.
Real-World
(Non-cirrhotic and cirrhotic)
Gane, AASLD, 2015, 1049; Kwok, AASLD 2015, 1101; Shoreibah, AASLD 2015, 1174;
Hassett, AASLD, 2015, LB-28