Transcript Document

Hepatitis Journey
Breaking News in Hepatitis
Ospedaletto di Pescantina (VR)
25 Giugno 2014
Pre- e post-trapianto di fegato nell’era
dei nuovi antivirali
Quali vantaggi dalle nuove terapie ?
Stato dell’arte del paziente in lista d’attesa e del paziente trapiantato.
Patrizia Burra
Multivisceral Transplant Unit
Department of Surgery, Oncology and Gastroenterology
Padua University Hospital
Padua Italy
European Liver Transplant Registry
DONOR
Other risk factors
IMMUNOSUPPRESSION
ANTIVIRAL THERAPY
HCV+
Recipient
WORSE FIBROSIS PROGRESSION
Burra Seminars Liver Disease 2009
Progression of Severe Chronic Hepatitis
(Stage of Fibrosis 3 and 4) in
Protocol Liver Biopsies From All Recipients
35
31.0
31
30
25
%
22,2
Fibrosis stage 4
25,8
25.8
HCV
alcohol
20
16,7
15
10
5
0
12.5
12,5
HBV
11,1
10
11,1
11,8
9,4
9.4
0
6 months
alcohol/HCV
5
0
12 months
Fibrosis stage 3
3,4
3,2
0
24 months
Cholestatic
0
36 months
- -●- - HCV
months after liver transplantation
Burra Liver Transplantation 2009
Late retransplantation:
Padova experience
36%
Chronic rejection
HCV recurrence
64%
Crivellin Transpl Proc 2010
(1) TREATMENT OF CIRRHOTIC PATIENT BEFORE
LIVER TRANSPLANTATION
(2) TREATMENT OF POST-TRANSPLANT HCV
RECURRENCE
2013
On treatment response
292 Telaprevir
Hezode J Hep 2013
205 Boceprevir
Events
Serious adverse event, n (%)
Premature discontinuation/due to
SAE, n (%)
Death, n (%)
Infection, n (%)
Hepatic decompensation, n (%)
Asthenia, n (%)
Rash/SCAR, n (%)
Renal failure (creatinina clearance
<50 mL/min)
Anemia, n (%)
Erythropoietin use
Blood transfusion
RBV dose reduction or
discontinuation
Neutropenia, n (%)
Granulocyte-stimulating agent use
Thrombocytopenia, n (%)
PegIFN dose reduction or
discontinuation
TVR (n=292)
132 (45.2)
BOC (N=205)
67 (32.7)
66 (22.6)/43 (14.7)
54 (26.3)/15 (7.3)
5 (1.7)
19 (6.5)
1 (0.5)
5 (2.4)
6 (2.0)
6 (2.9)
16 (5.5)
14 (4.8)/0
12 (5.8)
0/0
5 (1.7)
0
89 (30.4)
157 (53.8)
47 (16.1)
57 (27.8)
95 (46.3)
13 (6.3)
50 (17.1)
30 (14.6)
8 (2.7)
9 (4.4)
7 (2.4)
9 (4.4)
37 (12.7)
13 (6.4)
89 (30.5)
71 (34.6)
Multivariate analysis
of factors related to death or severe complications
PLT < 100.000/mm3
albumin < 35g/l
TELAPREVIR AND BOCEPREVIR:
CAUTION IN PATIENTS WITH
DECOMPENSATED CIRRHOSIS !
All-oral combination of Daclatasvir (NS5A inhibitor) + Asunaprevir (NS3
inhibitor) in 222 IFN ineligible naïve/intolerant (IN/I) and non responder
(NR) Japanese patients infected with HCV G1b, 10% of whom with
compensated cirrhosis
K. Chayama, Hiroshima University, Japan
• SVR12 = 85%
• Basal factors (sex, age, liver cirrhosis, HCV-RNA basal load,
IL28 polymorphism) seem not to be associated with
antiviral response.
• Side effects: increased AST (13%) /ALT (16%), headache
(15%), diarrhoea (10%), fever (10%).
Abstract AASLD 2013
ELECTRON-2 (LDV/SOF±RBV)
LDV/SOF ± RBV in Difficult-to-Treat HCV Populations
Phase 2, open-label study of LDV/SOF ± RBV for 12 weeks in HCV
GT 1 prior SOF relapsers, GT 1 patients with decompensated cirrhosis,
and treatment-naïve GT 3 patients
Wk 0
•
•
Wk 24
SVR12
LDV/SOF + RBV
GT 1; n=20
CTP class B cirrhotics
LDV/SOF
Randomized
GT 1; n=19
Prior SOF exposure
GT 3; n=51
Treatment naïve,
including cirrhosis
Wk 12
LDV/SOF, n=25
LDV/SOF + RBV, n=26
Prior treatment history of SOF relapsers included SOF + RBV ± DAA
Cirrhosis was present in all CTP class B and 16% of GT 3 patients
Gane E, EASL 2014
Courtesy Dr Mirandola
ELECTRON-2 (LDV/SOF±RBV)
SVR12 Results with LDV/SOF±RBV for 12 Weeks
in Difficult-to-Treat HCV Populations
100
100
100
65
64
19/19
13/20
16/25
GT1 Retreatment
LDV/SOF + RBV
GT1 CPT Class B
LDV/SOF
GT3 Naïve
LDV/SOF
SVR12 (%)
80
60
40
20
0
Gane E, EASL 2014
26/26
GT3 Naïve
LDV/SOF + RBV
Ledipasvir/Sofosbuvir ± RBV for 12 or 24 weeks in 440 previously
treated G1 HCV+ patients (ION2) – 20% Cirrhosis
Absence of Cirrhosis
100
95
86
100
82
Cirrhosis
99
100
99
100
86/87
22/22
88/89
22/22
SVR12 (%)
80
60
40
20
0
83/87
19/22
LDV/SOF
89/89
18/22
LDV/SOF + RBV
LDV/SOF
12 Weeks
Afdhal N, et al. N Engl J Med 2014
LDV/SOF + RBV
24 Weeks
SOF+RBV for Treatment of Chronic HCV with Cirrhosis
and Portal HTN ± Decompensation: Week 24 Interim Results
Randomized, open-label, safety and efficacy study of SOF+RBV for 48 weeks compared to
observation for 6 months in patients with HCV cirrhosis and portal HTN (CTP 5–9)
Wk
0
Wk
24
Wk
48
Arm 1 SOF 400 mg + RBV
n=25 1000‒1200 mg
Arm 2
SOF 400 mg + RBV
n=25 Observation 1000‒1200 mg
Wk
72
Wk
96
SVR12
SOF + RBV
n=25
Observation
n=25
18 (72)
20 (80)
Median age, y (range)
56 (43‒69)
55 (44‒69)
BMI ≥30 kg/m2, n (%)
8 (32)
7 (28)
6.1 (4.4‒7.0)
6.1 (3.8‒6.9)
1a
10 (40)
9 (36)
1b
9 (36)
6 (24)
2
2 (8)
1 (4)
3
2 (8)
8 (32)
4
2 (8)
1 (4)
IL28B non-CC, n (%)
22 (88)
18 (72)
Prior HCV treatment, n (%)
17 (68)
23 (92)
16.9 (9‒29)
16.2 (7‒27)
19 (76)
20 (80)
Male, n (%)
Mean HCV RNA, log10 IU/mL
(range)
SVR12
GT, n (%)
Preliminary
results
Mean HVPG mmHg, n (range)
HVPG >12 mmHg, n (%)
Afdhal N, EASL 2014
Laboratory Changes
SOF+RBV
Platelets (103/µL)
20
15
10
5
0
-5
-10
-15
ALT (U/L)
Albumin (g/dL)
17 p=0.003
p=NS
1
-1
-9
CTP A
Observation 24 weeks
CTP B
0.6
0.5
0.4
0.3
0.2
0.1
0
-0.1
-0.2
p=0.001
0.5
p=0.001
20
13
0
0
0.4
-20
-40
0
-60
-80
-0.1
CTP A
Afdhal N, EASL 2014
CTP B
-72
CTP A
-75
CTP B
Clinical Event Changes
Ascites
Hepatic Encephalopathy
SOF + RBV
n=25
Observation
n=25
SOF + RBV
n=25
Observation
n=25
6
9
5
2
5
8
3
3
0
7
0
4
Patients, n
Baseline
Week 12
Week 24
Afdhal N, EASL 2014
SOF+RBV for Treatment of Chronic HCV with Cirrhosis
and Portal Hypertension ± Decompensation
100
HCV RNA < LLOQ (%)
100
100
94
100
93
75
80
60
94*
100
CTP A
CTP B
56
44
40
20
0
2
4
*1 patient was a non-responder at Week 8.
8
Week
Afdhal N, EASL 2014
12
24
SOF+RBV for Treatment of Chronic HCV with Cirrhosis
and Portal HTN ± Decompensation: Conclusions
SOF+RBV for up to 24 weeks resulted in:
– High rates of virologic suppression irrespective of severity of
liver disease
– Decreased necroinflammation with ALT normalization
– Improvements in platelet count, albumin, ascites and
hepatic encephalopathy
– No patient with worsening or new hepatic decompensation
Afdhal N, EASL 2014
48 weeks of pre-transplant SOF/RBV to prevent recurrence of HCV infection
after liver transplantation for HCC
Curry, AASLD 2013/EASL 2014/ILTS 2014
61 patients with compensated cirrhosis (CP<7) and
HCC awaiting liver transplantation.
40 transplanted, 37/40 HCV-RNA < 25 UI/L.
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)
No recurrence in 24/25 (96%) of
patients who maintained HCV RNA
TND >28 days
0
28
28
30
*Wilcoxon rank sum test.
Curry AASLD 2013
60
90
120 150 180 210 240 270 300 330 360
Days with HCV RNA Continuously TND Prior to Liver Transplant
390
Take Home Message
Cirrhotic patient in the waiting list for transplant
• Telaprevir and Boceprevir not to be used in
decompensated cirrhosis and compensated patients should
be treated if liver transplantation is available in case severe
decompensation will occur.
• IFN-free regimens are promising in terms of safety and
efficacy, but more data are needed to confirm the time
interval from SVR and transplant and the potential reduced
rate of HCV recurrence after transplant.
(1) TREATMENT OF CIRRHOTIC PATIENT BEFORE
LIVER TRANSPLANTATION
(2) TREATMENT OF POST-TRANSPLANT HCV
RECURRENCE
RECOLT
Italian multicenter retrospective study (AISF)
200 patients who underwent antiviral therapy for HCV
recurrence after liver transplantation between 1999 and 2009
with at least two liver biopsies (pre- and post- antiviral therapy)
were evaluated.
Antiviral therapy: combined PEG-IFN and Ribavirin at standard
doses, according to center policy.
SVR 35%
De Martin AISF 2010
De Martin AISF 2012
Mean stage fibrosis:
SVR + vs SVR -
P=.029
P=.037
P=.031
Mea fibrosis stage
P=ns
AT interval time
De Martin AISF 2012
P=ns
2014
Virological responses during triple therapy after liver transplantation
18 pz
19 pz
Coilly J Hep 2014
Adverse events during triple therapy after liver transplantation
Coilly J Hep 2014
A Clinical Case: 61 year old man
May 2011
Liver transplantation for HCV-related end stage liver disease
MELD 25
Child Pugh C 10
No HCC
May 2012, 1 year after liver transplantation
• Bilirubin 1.01 mg/dL
AST/ALT 108/174 U/L
GGT/ALP 69/139 U/L
AFP 1.9, albumin 46, PT 67%
• Tacrolimus trough level 6 ng/mL
• HCV-RNA 6.17 log10 IU/mL
Liver Biopsy (May 2012)
Hepatitis Activity Index 7 (Ishak score)
Portal lymphoid infiltrate + interface
hepatitis + parenchyma necrosis
(focal and bridging)
Fibrosis stage 2 (Ishak score)
Pericellular and central fibrosis.
Porto-periportal fibrosis, with septa.
Triple antiviral therapy with Telaprevir
DAY 1
PEG-IFN 180 µgr/week
RIBAVIRIN 1000 mg/day
TELAPREVIR 750 mg 3 times/day
Tacrolimus – Telaprevir interaction in healthy volunteers
Telaprevir increases Tacrolimus exposure by 70-fold
and 1/2-life from mean 40.7 to 196 hours
Garg, Hepatol 2011
Triple antiviral therapy with Telaprevir
STOP
Tacrolimus 0.5 mg + 0.5 mg 2 days before
DAY 5: Skin rash (Grade 1-2, mild/moderate)
Dermatological Side Effects of Telaprevir
Cacoub, J Hep 2012
WEEK 2: JAUNDICE + LFTs 
• Bilirubin 5 mg/dL
• AST/ALT 134/170 U/L
• GGT/ALP 590/229 U/L
• WBC 3.37 *109/L, N 1.81 *109/L, Hb 15.6 g/L,
Plts 167 * 103/L
• Tacrolimus trough level 7.1 ng/mL

Severe fatigue
Weight loss
Depression
Evaluation of causes of jaundice
• Biliary tract disease
• Vascular diseases
• Infections
• Chronic rejection/Immune mediated graft dysfunction
• Pharmacological toxicity
Clinical case
Tacrolimus trough levels during triple antiviral therapy
Trough Levels (ng/mL
TAC
9
8
7
6
5
4
3
2
1
0
TAC
DAY -1
DAY 1
Tacrolimus 0.5 mg/d
once a week
DAY 4
Day 3
DAY 7
Day 10
DAY 15
Discussion on causes of jaundice
✓
• Vascular disease
✓
• Infections
✓
• Chronic rejection/Immune mediated graft dysfunction ✓
• Biliary tract disease
• Pharmacological toxicity
Clinical case: LFTs after admission for jaundice
12.02.13
14.02.13 15.02.13
18.02.13
Bilirubin
mg/dl
8.4
1.6
1.5
1.4
GGT
590
433
396
326
ALP
229
199
182
147
AST
134
82
72
49
ALT
170
134
126
79
STOP TELAPREVIR
PEG-IFN + RBV therapy was continued for 48 weeks
Week 12, HCV-RNA undetectable
May 2014, HCV-RNA undetectable
TELAPREVIR AND BOCEPREVIR:
SVR IS HIGHER BUT ADVERSE EVENTS
ARE COMMON IN LIVER TRANSPLANT
RECIPIENTS !
SOF for Patients with Severe Recurrent HCV
Following Liver Transplant (including Fibrosing
Cholestatic Hepatitis)
Severe
recurrent
HCV following
LT
N=104
SOF 400 mg + RBV* ±
PegIFN*
SVR12
Up to 48 weeks
*Appropriate dose of RBV and/or PegIFN may be added at discretion of investigator
Patients approved for compassionate use on an individual request basis
X. Forns, EASL 2014
Initial evaluation of the Sofosbuvir Compassionate Use
Program for 104 Patients with Severe Recurrent HCV
Following Liver Transplantation
100
Patients HCV RNA < LLOQ (%)
87
80
62
60
40
20
81/93
53/85
EOT
SVR12
0
X. Forns, EASL 2014
Clinical Outcome: significant decrease in hepatic
encephalopathy, improvement or disappearance of ascites, or
improvement in liver-related laboratory values
100
80
Patients (%)
62
60
40
21
21
60/104
22/104
22/104
Improved*
Stable
Worsened/Deceased
20
0
 All patients who received ≥1 dose of SOF are included
X. Forns, EASL 2014
HCV RNA < LLOQ (%)
SOF+RBV in HCV recurrence after liver transplantation
(including experienced patients and patients with cirrhosis)
100
100
100
73
80
70
70
29/40
28/40
28/40
SVR4
SVR12
SVR24
60
40
40/40
40/40
20
0
Week 4
EOT
LLOQ, lower limit of quantification (25 IU/mL)
Samuel D EASL 2014
Courtesy Dr Mirandola
Sofosbuvir for Patients with HCV-related Fibrosing
Cholestatic Hepatitis Following Liver Transplantation
*Bilirubin normalized at Week 9. TE, transient elastography.
Forns et al. APASL 2014
A Clinical Case: 63 year old man
8-year post transplant follow up
Fibrosis F3, HCV-RNA 29.000 UI/ml, IFN intolerant
12 December 2013 - Compassionate use of Sofosbuvir plus Ribavirin
6-month therapy: normal AST and ALT, undetectable HCV-RNA
A clinical case: SOF + RBV in HCV recurrence after liver transplant
•
•
•
•
•
TC, M, 49 years.
21.01.2012: liver transplant (HCV-related cirrhosis with HCC).
14.02.2013: HCV recurrence in liver transplant recipient (HAI 4, F3, Ishak score).
Peg-IFN + RBV (06.2013-03.2014): non responder, severe antiviral therapy side
effects (asthenia, anaemia).
4.04.2014: SOF + RBV.
Baseline
4W
AST (U/L)
194
89
ALT (U/L)
50
25
Total Bilirubin (mg/dL)
1.6
1.3
HCV-RNA (UI/mL)
6.031.356
27
Clinical condition
Severe hepatic
encephalopathy
Improved, no hepatic encephalopathy
Immunosuppression
No adjustements of tacrolimus dosage
LONG TERM OUTCOME OF MILD HEPATITIS C RECURRENCE
AFTER LIVER TRANSPLANTATION: A LARGE PROSPECTIVE STUDY
Martina Gambato1, Gonzalo Crespo1, María-Carlota Londoño, Zoe Mariño, Sabela Lens1,
Jose A Carrión1, Pablo Ruiz1, Ignacio Alfaro1, Jaime Bosch1, Rosa Miquel2,
Miquel Navasa1 and Xavier Forns1
Liver Unit1, Pathology Department2
Hospital Clínic, IDIBAPS, CIBEREHD
Barcelona, Spain
Study population
Liver Transplantation due to HCVcirrhosis
May 1999-March 2012
(n=426)
Not included:
• Graft survival shorter than 1 year (N=44)
• Patients achieved SVR in waiting list (N=20)
• Lack of an adequate assessment of HCV
recurrence 1 year after LT (N=14)
Severe recurrence within 1
year
(F≥2/HVPG≥6 mmHg or
cholestatic hepatitis C)
1 YEAR
Mild recurrence 1 year after LT
(F0-1±HVPG<6 mmHg/liver
stiffness<8.7 kPa)
(n=172)
(N=176)
Results
Log-rank=0.038
Log-rank=0.001
AST≥60 IU/L
Donor age≥50 yrs
AST<60 IU/L
Donor age<50 yrs
AST≥ 60 IU/L
36
26
14
6
≥50 years
40
27
15
5
AST < 60 IU/L
92
58
40
19
< 50 years
89
58
40
20
AST 12 months after LT and donor age were able to stratify slow fibrosers
according to the risk of cirrhosis development
Results
Log-rank<0.001
AST≥60 IU/L + donor age ≥50 years
N=28
AST<60 IU/L + donor age <50 years
N=80
The combination of AST 12 months after LT and donor age
predict cirrhosis development in slow fibrosers
Liver stiffness (kPa)
Results
18
Cirrhosis group
16
y (kPa)= 5.8 + 1.8 x (t)
14
12
10
8
6
Non-Cirrhosis group
4
y (kPa)= 6.03 + 0.1 x (t)
2
0
12
18
24
Months after LT
Patients at higher risk of cirrhosis showed a high slope of
liver stiffness progression between 12 and 24 months after LT
Conclusions
•Up to 30% of slow fibrosers developed cirrhosis due to disease
progression during a long follow-up of 10 years after LT
•Aspartate aminotransferase 1 year after LT and donor age,
and especially their combination, identified slow fibrosers
with a higher risk of progression to cirrhosis over time
•Slow fibrosers at higher risk of progression to cirrhosis may
benefit from antiviral therapy
2014 Joint International Congress
ILTS ELITA LICAGE
London 4-7 June 2014
The influence of CNIs selection on the
outcome of HCV recurrence in liver
transplant recipients: a meta-analysis
Zhiyong Guo ILTS 2014, O65
8 RCTs
734 patients
Incidence of severe fibrosis
Fibrosing cholestatic hepatitis
Patient survival
No differences between Cyclosporine and Tacrolimus
Zhiyong Guo ILTS 2014, O65
Patients (%)
Immunosuppression in 40 patients treated with
Sofosbuvir for HCV recurrence after liver transplantation
Tacrolimus
Mycophenolate
mofetil
Prednisone
Cyclosporin
Azathioprine
No interactions reported between SOF and any immunosuppressive agents during study.
Charlton MR EASL 2014
ERADICATE Study (NIAID, LDV/SOF)
No Changes in Renal Parameters in Transplanted
Patients
treated with Ledipasvir/Sofosbuvir
select KT mean CR CHANGES
SELECT GFR NARV vs ARV
Estimated Glomerular
Filtration Rate
0.9
ARV Untreated
ARV Treated
0.6
0.3
0.0
-0.3
-0.6
-0.9
Day Wk Wk Wk Wk SVR SVR
0
2
4
8 12
2 12
30
Mean eGFR change (mL/min)
Mean creatinine change (mg/dL)
Serum Creatinine
ARV Untreated
ARV Treated
20
10
0
-10
-20
-30
Osinusi A, EASL 2014
Day Wk Wk Wk Wk SVR SVR
12
12 2
8
4
2
0
Interferon-free regimen of ABT450-ABT267-ABT333 (3D)
plus Ribavirin in liver transplant recipient with
genotype 1 HCV recurrence
• ABT450/ABT267(Ombitasvir)/(150mg/25mg)
plus ABT333 (Dasabuvir) (250mgx2)
• Ribavirin 1000-1200mg
• 24 weeks
• Liver biopsy F=<2
• CNIs adjustment required
• 34 patients enrolled
Kwo EASL 2014
Interferon-free regimen of ABT450-ABT267-ABT333 (3D)
plus Ribavirin in liver transplant recipient with
genotype 1 HCV recurrence
•
•
•
•
•
RVR 34/34 patients
EOTR 13/13 patients
SVR4 92%
1 Relapse
Adverse events reported in 88.2% of cases (mild)
–
–
–
–
Fatigue (38%)
Headache (35%)
1 patient discontinued the study
5 patients received erythropoietin
Kwo EASL 2014
Interferon-free regimen of ABT450-ABT267-ABT333 (3D)
plus Ribavirin in liver transplant recipient with
genotype 1 HCV recurrence
• 3D ABT regimen plus RBV quite well
tolerated.
• High virological response.
• Longer follow-up is needed.
Kwo EASL 2014
Take Home Message
Liver transplantation
• Telaprevir and Boceprevir to be used with caution in liver
transplant recipients.
• Immunosuppression dose adjustments are always required.
• IFN-free regimens studies have confirmed the efficacy,
safety and tollerability.
• Immunosuppression dose adjustments are not required
except for 3D ABT treatment.
• Renal function is not affected.
• Data on virological relapse rate and how to treat it are
needed.