1. Cirrosi scompensata e trapianto di fegato: l’esperienza in real world
Paola Carrai, MD
Chirurgia Epatica e del Trapianto di Fegato
Azienda Ospedaliero Universitaria Pisana

2. Most liver transplants (LT) in Europe due to cirrhosis are caused by hepatitis viruses
European analysis of 55,714 transplants in Europe (Jan 1998-Dec 2012)1
HCV-related cirrhosis accounts for 66% of virus-related LT, therefore approximately 25% of LT are a result of HCV2
European liver transplant registry LTR. (accessed June 2014)
2. European Association for the study of the liver. The burden of liver disease in Europe. (accessed June 2014)

3. LT in Pisa

4. Post-LT patient survival
Our center patient and graft survival rates are similar to the international experiences (ELTR)

5. Cumulative survival after LT (MHH 1998 and 2005)
1.0
0.8
0.6
Cumulative survival
0.4
Primary biliary cirrhosis (PBC)
Hepatitis B-cirrhosis
Blocked bile duct
HCC
Acute liver failure
Primary sclerosing cholangitis (PSC)
HCV-cirrhosis
0.2
0.0 2 4
Years
Schrem H, et al. Chirurg 2008;79:121–9.
MHH: Medizinische Hochschule Hannover

6. Rapid re-infection of graft with HCV post-LT
All grafts become infected after transplantation1
Kinetics vary between patients, but HCV viral load increases in some patients within hours of transplant2
108
107
106
Viral load (IU/mL)
105
104
103
102 P R 24 48 72 96
120 4 12 24 A
Hours
Weeks
1. Forman LM, et al. Gastroenterology 2002;122:889–96; 2. Garcia-Retortilla M, et al. Hepatology 2002;35:680–7
A: anhepatic phase; P: pre-transplantation; R: re-perfusion Copyright © Reprinted with permission of American Association for the Study of Liver Diseases

7. Middle-term (<24 months) mortality due to HCV recurrence after LT
Year #Dead HCV %
2008 8 42 19
2009 10 52
19.2
2010 4 40
2011 3 55
5.4
2012 46
6.5
2013 1 50 2
2014 39
SOFOSBUVIR

8. HCV Management Issues Unique to Pre- and Post-transplantation Patients
Pre-transplantation
Intolerance to Peg-interferon regimens
Impaired hepatic metabolism
Renal insufficiency
Post-transplantation
High HCV RNA/impact of immunosuppression
Fibrosing cholestatic hepatitis
Drug–drug interactions
Other medical comorbidities
HCV, hepatitis C virus. 8

9. Compassionate program with Sofosbuvir (I)
(August) June 2014 Inclusion criteria “Patients, who are post-transplant, with unusually recurrent HCV (including fibrosing cholestatic hepatitis-FCH) and in need of urgent therapy with no other options” Advanced liver disease (MELD≥12, CTP≥B7) Life expectancy ≤6 M No access to experimental treatment

10. Compassionate program with Sofosbuvir (II)
Since June 2014
Inclusion:
Patients in urgent need of therapy, with no other therapeutic option, who meet ALL the following criteria:
are in a  pre-transplant list
have HCV-related decompensated cirrhosis (CPT ≥ 7)
have a MELD score ≤ 24, calculated in the last 30 days
Patients in urgent need of therapy, with no other therapeutic option who are in a pre-transplant list for HCV-related hepatocellular carcinoma (HCC), have a MELD score ≤ 24, calculated in the last 30 days and meet one of the following criteria:
HCC within the MILAN criteria (a single HCC nodule with a maximum size of 5 cm or as many as 3 nodules with the largest not exceeding 3 cm and no macrovascular invasion) with a risk of neoplastic progression low enough to obtain the maximum benefit from the antiviral therapy (at least 30 consecutive days of negative HCV-RNA before LT – the expected average time on the waiting list should be of at least 3 months)
HCC in stage T1 which is not suitable for treatment with other drastic measures (e.g. surgical resection, radiofrequency, alcoholization)
Patients in urgent need of therapy, with no other therapeutic option who are post- liver transplant, with severe recurrent HCV (fibrosing cholestatic hepatitis - FCH - or chronic hepatitis with Metavir score  F2).
Exclusion:
• Pregnant/nursing women
• History of significant drug allergy to nucleoside/nucleotide analogs
• Creatinine clearance 30 mL/min

11. Pre-LT patient disposition (As of December 15, 2014)
Enrolled for SOF-based schedule
(48 weeks or until LT)
N= 37
1 patient died
4-week treatment completed
N= 29
LT N=4 (2 HCV neg)
> 8-week treatment
N= 20
LT N=5
Completed 4 weeks FU post LT
N= 6

12. LT patient disposition (As of December 15, 2014)
Enrolled for SOF-based schedule (12/24weeks)
N=180
4-week treatment completed
N=100
1 patient died
12-week treatment completed
N= 27
24-week treatment completed
N= 12
1 patient prolonged treatment
up to 48 weeks
4-week FU completed
N= 7
12-week FU completed
N= 6
24-week FU completed
N= 6

13. Overall pre and post-LT treatment schedules 217 patients

14. LT patients baseline clinical data Compassionate use (I)
Variable
N = 15
Male, gender (%)
11 (73.3 )
Age, years (median, range)
54 (50-65)
Treatment experienced/naÏve
12/3
HCV RNA, IU/mL (median, range)
(88, ,000,000)
GT 1a/1b/2/3/4, n
3/8/0/4/0
Bilirubin, mg/dL (median, range)
2.6 mg/dL (1.5-29)
Albumin, g/dL (median, range)
3.4 g/L ( )
INR (median, range)
1.18 (1-1.46)
Creatinine mg/dL ( median, range)
1.45 mg/dl ( )
Child Pugh B/C
MELD (median, range)
16 (8-24)
Time after LT, months (median, range)
15 (6-103)

15. Changes in clinical condition
*Improvement = significant decrease in hepatic encephalopathy, improvement or disappearance of ascites
or improvement in liver-related laboratory values

16. Changes in liver function

17. Changes in liver function

18. Sustained virological response

19. Post-LT safety data by regimen
(in patients receiving at least 4 W therapy)
Total patients
SOF + RBV
N =92
SOF + PEG RBV
N =3
SOF + SMV
SOF + DCL
Anemia (any grade) 44 1
Arthralgia 31
Headache 37
Insomnia 25
Irritability 7
Anorexia 11
Cough
Pruritus
Asthenia 5
Fatigue 18
Hyperbilirubinemia

20. SAEs to date by treatment regimen
SAFETY post OLT
SAEs to date by treatment regimen
Total patients N
SOF RBV
N= 206
SOF PEG RBV
N=3
SOF SMV
SOF DCL
SAE N 5
SAEs:
Anemia ( grade 3)
2 Ascites/SBP = ESLD (Fatal in 1 case)
Severe encephalopaty and hyperbilirubinemia with ALT/AST increase
Spinal cord lesion, not otherwise defined

21. Baseline clinical data Pre-LT patients
Variable
N = 37
Males, n (%)
27 (71 %)
Age, years (median, range)
57 (43-70)
HCV RNA, IU/mL (median, range)
( )
GT 1a/1b/2/3/4, n
10/20/1/5/1
Bilirubin, mg/dL ( median, range)
1.8 ( )
Albumin, g/dL (median, range)
3.4 ( )
INR (median, range)
1.37 (1-1.8)
Creatinine mg/dL ( median, range)
0.76 (0.6-2)
Child Pugh A/B/C, n
5/26/6
MELD (median, range)
12 (8-21)
HCC, n 9

22. Pre-LT safety data by regimen
Total patients
SOF RBV
N =37
SOF DCL
N =1
Anemia (any grade) 2
Arthralgia 10
Headache 5
Insomnia 3 1
Irritability 8
Anorexia
Encephalopaty
Asthenia 9
Fatigue 20
Hyperglycemia
Hyperbilirubinemia

23. SAFETY pre-LT SAEs to date SAE’S:
Progression of ESLD with variceal bleeding
(Fatal)
Cerebral hemorrhage

24. Three patients categories……..

25. Conclusions
In our experience, SOF-based regimens are safe and associated with rapid viral clearance
Ribavirin was frequently reduced due to AEs (anemia)
No drug discontinuation due to AEs
No episode of acute rejection in transplant patients