Maria Rosaria Piras SSD Coordinamento Trapianto di Fegato Azienda Ospedaliera Brotzu Cagliari

19 dicembre 2015

Trattamento con i nuovi farmaci nei pazienti

sottoposti a trapianto di fegato

Treatment Pre-LT with the Goal of Preventing HCV Recurrence

Strategy 1: Treat to Cure Antiviral Therapy LT Strategy 2: Treat to Achieve HCV RNA Undectability

SVR No SVR

LT

Antiviral Therapy for 12-24 wks

100% HCV-free post-LT

Antiviral Therapy until HCV RNA negative for ≥ 4 wks

Follow up

100% HCV- infected post-LT

On-Treatment Response 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 Therapy LT Strategy 2: Treat to Achieve HCV RNA Undectability

SVR No SVR

LT

Antiviral Therapy for 12-24 wks

100% HCV-free post-LT

Antiviral Therapy until HCV RNA negative for ≥ 4 wks

Follow up

100% HCV- infected post-LT

On-Treatment Response 95% HCV-free post-LT if HCV RNA negative at LT

High % of patients achieve TND HCV RNA on DAAs

Shorter duration of therapy

Post-Transplant HCV Recurrence in patients in whom HCV RNA was non detectable for 28 days prior to transplant

0 30 60 90 120 150 180 210 240 270 300 330 360 390

Days with HCV RNA Continuously TND Prior to Liver Transplant

No Recurrence (n=29) Recurrence (n=10)

No recurrence in 24/25 (96%) of patients who maintained HCV RNA TND >28 days

.

28 28

Curry MP et al, Gastroenterology 2015

Cirrhosis + HCC CTP ≤ 7 MELD exception for HCC 48 wks or LT No AEs due to SOF/RBV

47

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

100 pts OLT

47 patients HCV RNA negative for > 4 wks at OLT

44 pts stop therapy

Positive:5 pts Negative:39 pts SVR12: 87%

Negative:3 pts SVR12:100%

3 pts bridge therapy

53 pts HCV RNA negative for < 4 wks or still positive at OLT

53 pts

19 pts stop therapy

3 deaths

Positive:6 pts Negative:10 pts SVR12:62.5%

34 pts bridge therapy

Positive:1 pts Negative:31 pts SVR12: 97%

10 30 pts 87 pts completed treatment

30 pts discontinued therapy

10 pts died for complications of cirrhosis

1 pt: medical decision 1 donor anti-HCV 1 donor HCV RNA

2 deaths (MOF)

National program for early access to SOF therapy in Italy for patients with chronic hepatitis C in liver LT waiting list

ITACOPS, AISF 2016 (227/243 pazienti, 93.5%)

Advanced cirrhosis patients with treatment interrupted by LT could receive an additional 12 wks of treatment immediately post-LT

Advanced cirrhosis N=60

Post-LT N=53

DCV 60 mg QD

SOF 400 mg QD+RBV

Week 0 Week 12 Week 24 Week 36 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%

Follow-up

Cirrhotic Patients Transplanted During Treatment: Ally-1 Study

*Discontinued RBV after 11 days due to hyperbilirubinemia resulting from post-LT biliary obstruction

Cirrhotic Patient Transplanted During Treatment

Cirrhotic Patients Transplanted During Treatment:

*Discontinued RBV after 11 days due to hyperbilirubinemia resulting from post-LT biliary obstruction

PA 1b TND (23 days) HCV - None

Pre-transplant Post-transplant

Centro Trapianti di Fegato - Pancreas A.O. Brotzu Direttore Dott. Fausto Zamboni

Cirrhotic Patient Transplanted During Treatment

SOF+LDV

Post-Transplant Antiviral Therapy

Prevent graft loss

Prevent extra-hepatic complications

Reverse complications of decompensation

Timing of Post-LT Therapy

• Prevent histological injury/fibrosis • Reduce likelihood of cholestatic hepatitis • Simplify evaluation of abnormal liver tests

How early is “early” ? Safety and efficacy studies used ≥ 6 months post-LTà interpret as “clinically stable”

Basic requirements

Early therapy better

• Stable renal function, resolved anemia, low dose PPI,stable immunosuppression • Dose interruption very unlikely

• 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% Herzer K et al. AASLD 2015

European DCV Compassionate Use Program

Well tolerated No significant DDI No Rejection

24 wks

SVR (mITT) by Liver Disease Status

Herzer K et al. AASLD 2015

•  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

U.S. DCV Expanded Access: Post-transplant Cohort

Brown RS et al. EASL 2016, poster SAT-251 (modified)

32 33

8 8

97 100

0

20

40

60

80

100

GT 1 GT 3

SV

R12

(%)

32 33

8 8

Well tolerated No significant DDI No rejection

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%

•  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

Patients With Fibrosing Cholestatic Hepatitis

Brown RS et al. EASL 2016, poster SAT-251

Patient HCV GT Treatment

Weeks of Treatment

Reason for Discontinuation

Bilirubin Normalized

at EOT SVR12 1 1 DCV+SOF 24 - Yes Yes 2 3 DCV+SOF 17 Headachea Yes Yes 3 1a DCV+SOF 12 Insurance denial Yes Yes 4 3 DCV+SOF 10 Pruritusa No Yes 5 3 DCV+SOF 24 - Yes Yes

Treatment after LT: Solar-1 and Solar-2

Gane, AASLD, 2015, 1049

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).

SOF LDV +

N=667

Pre-Post LT CTP B/C N=323

Post-LT CTP B/C N=112

RBV ±

Safe and well tolerated irrespective of the degree of decompensation or whether patients were pre- or-post LT

Patient Disposition: Post-transplant

Cohort

Treatment outcome available N = 47

Ongoing treatment N =7

Completed treatment N = 48 (87%)

Discontinued prematurely N = 0

Adverse events anemia N =1 5 (27%)

Treatment outcome pending N = 1

Started treatment n=49 (+ 6 retreated) SOF+RBV (compassionate use) =20/ SOF+NS5A n=34/ SOF+RBV n=1

Started treatment n=49 (+ 6 retreated) SOF+RBV (compassionate use) =20/ SOF+NS5Ai n=34/ SOF+RBV n=1

Centro Trapianti di Fegato - Pancreas A.O. Brotzu Direttore Dott. Fausto Zamboni

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

• 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%

SOF + RBV

SOF/LDV ± RBV

Week 0 12 24 36

N=21

N=27

SVR 24

SVR12

SOF/ DAC + RBV N=8 SVR12

48

67%

100%

100%

SVR24 N=6

Centro Trapianti di Fegato - Pancreas A.O. Brotzu Direttore Dott. Fausto Zamboni

SOF + RBV

SOF/LDV + RBV

Week 0 12 24 36

N=21

N=27

SVR 24

SVR12 100% SVR SOF/ DAC + RBV N=8

67%

SVR12

48

SVR24 N=6

SOF + RBV NR= 7

FCH N=1 GT3

GT1b=3 (F3=1/cirrhosis=2) GT 3 =2 (F3=1/cirrhosis=1) GT4 =1 (cirrhosis=1)

100%

100%

Centro Trapianti di Fegato e Rene-Pancreas A.O. Brotzu Direttore Dott. Fausto Zamboni

Well tolerated No significant DDI No rejection

SOF+LDV+RBV (n=4)

SOF+DAC+RBV (n=2)

0 24 weeks

SOF/DAC +RBV

SOF/LDV + RBV

SVR 24 = 100% (N=6/6)

Centro Trapianti di Fegato - Pancreas A.O. Brotzu Direttore Dott. Fausto Zamboni

DAAs Failure: Retreatment with NS5Ai

4/4 2/2

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

fpost-OLT à NAFLD Insufficienza renale acuta più frequente nel post operatorio 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 Patogenesià m. colestatica, deficit e sintesi ed assorbimento vit.D, Malnutrizione, ipogonadismo, immobilità, diuretici, rapida perdita massa, recente 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 immunosop- pressiva, IRC jatrogena Calcio, vit. D e bifosfonati evidenza utilità Orlistat

Complicanze pre e post Trapianto di fegato

Cise

Centro Trapianti Fegato - Pancreas A.O.Brotzu - Cagliari Direttore: Dott. Fausto Zamboni

SSD Coordinamento Trapianto di Fegato A.O. Brotzu - Cagliari Dott.ssa Laura Mameli Dott.Francesco Sanna Direttore: Dott.ssa Maria Rosaria Piras

fpost-OLT à NAFLD Insufficienza renale acuta più frequente nel post operatorio 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 Patogenesià m. colestatica, deficit e sintesi ed assorbimento vit.D, Malnutrizione, ipogonadismo, immobilità, diuretici, rapida perdita massa, recente 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 immunosop- pressiva, IRC jatrogena Calcio, vit. D e bifosfonati evidenza utilità Orlistat

Complicanze pre e post Trapianto di fegato

Cise

Centro Trapianti Fegato - Pancreas A.O.Brotzu - Cagliari Direttore: Dott. Fausto Zamboni

SSD Coordinamento Trapianto di Fegato A.O. Brotzu - Cagliari Dott.ssa Laura Mameli Dott.Francesco Sanna Direttore: Dott.ssa Maria Rosaria Piras

GRAZIE

Treatment after LT

Kwo et al, NEJM 2014

§ N=34 § All GT1 §  F2=≤2 § TN & TE § CNIs adjustement for §  ABT450/RTV § Mild AEs § 5 patients recived EPO

Paritaprevir/R Ombitasvir Dasabuvir + + + RBV

LDV/SOF+RBV for Treatment of FCH After Liver Transplantation

FCH, fibrosing cholestatic hepatitis Forns, EASL, 2015, P0779

LDV/SOF + RBV

LDV/SOF + RBV

Week 0 12 24 36

n=7

n=4

12 Weeks LDV/SOF+RBV

n=7

24 Weeks LDV/SOF+RBV

n=4

Median age, y (range) 59 (56–65) 56 (52–64)

Male, n (%) 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)

Median CLcr, mL/min (range) 89 (36–94) 75 (69–103)

SVR12

SVR12

SOLAR-1 and SOLAR-2: Fibrosing Cholestatic Hepatitis (US and EU)

100% SVR

European DCV Compassionate Use Program SVR (mITT) by Genotype

LDV/SOF+RBV for Treatment of FCH After Liver Transplantation

FCH, fibrosing cholestatic hepatitis Forns, EASL, 2015, P0779

12 Weeks LDV/SOF+RBV

n=7

24 Weeks LDV/SOF+RBV

n=4

Median age, y (range) 50 (34–67) 56 (52–64)

Male, n (%) 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)

Median CLcr, mL/min (range) 89 (36–94) 75 (69–103)

• 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%

70%

59%

70%

Results: Post-Transplant Virologic Response

SOF RBV + 24 weeks

Charlton M et al , Gastroenterology 2015, Forns X et al Gastroenterology 2015, Samuel D et al EASL 2014

Charlton Forns Samuel SVR 12 SVR 12 SVR 12

NO DDI No rejection

N=40 GT1=83%

Cirrhosis 40%

N=104 GT1=85%

Cirrhosis 50% FCH 50%

N=40 GT1=83%

Cirrhosis 40%

HCV Infection and Liver Transplantation

• 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

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

HCV infection is the 1° cause of liver transplantation

in industrialized countries

BUT

Recurrence prevention

Liver toxicity associated with antiviral therapy Two case reports with SOF-based therapies

Dyson et al. J. Hepatol 2016:64;234-238

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)

Sofosbuvir + NS5A inhibitors treatment in decompensated HCV cirrhosis.

SVR12 by HCV Genotype and by cohort: ALLY-1 Study

§ No DDI § No graft rejection § Well tolerated

Poodard F et al EASL 2015

Patients with relapse: DCV + SOF + RBV 24 wks

•  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

Patients With Dual Kidney / Liver Transplant Post-transplant Cohort

Brown RS et al., EASL 2016, poster SAT-251

Parameter DCV+SOF

N = 4 Age, median (range) years 68.5 (61–79) Male, n (%) 4 (100) Race, n (%)

White 3 (75) Black / African American 1 (25)

HCV genotype, n (%)

1 2 (50) 3 2 (50)

Cirrhosis, n (%) 3 (75) Diabetes, n (%) 4 (100) Creatinine clearance, median (range) mL/min/1.73m3

73.3 (55.5–91.2)

SVR12, n (%) 4 (100)

70%

59%

70%

Results: Post-Transplant Virologic Response

SOF RBV + 24 weeks

Charlton M et al , Gastroenterology 2015, Forns X et al Gastroenterology 2015, Samuel D et al EASL 2014

Charlton Forns Samuel SVR 12 SVR 12 SVR 12

NO DDI No rejection

N=40 GT1=83%

Cirrhosis 40%

N=104 GT1=85%

Cirrhosis 50% FCH 50%

N=40 GT1=83%

Cirrhosis 40%

Treatment after Liver Transplantation

SOF Simeprevir + 12-24 weeks RBV ±

Author N GT 1 Cirrhosis RBV SVR

Brown R 1 131 82% 60% 22% 91%

Pupapon S 2 109 100%

29% 22% 91%

Te H 3 40 100%

35% (F3-F4)

0% 71%

1-2 AASLD 2014, 3 EASL 2015

Treatment safe and well tolerated

SVR12 Rates Among Patients with Recurrent HCV Post-Liver Transplant

F0–F3 CTP A Kwok, et al. Shoreibah, et al. Hassett, et al.

LDV/SOF+RBV 12 weeks LDV/SOF+RBV 24 weeks LDV/SOF 12 weeks

SOLAR-1 and SOLAR-2 Real-World (Non-cirrhotic and cirrhotic)

40/ 41

11/ 11

28/ 28

18/ 18

102/ 107

104/ 105

58/60

56/ 58

Gane, AASLD, 2015, 1049; Kwok, AASLD 2015, 1101; Shoreibah, AASLD 2015, 1174; Hassett, AASLD, 2015, LB-28