Transcript Document

Hepatitis Journey:
Breaking News Post-EASL
Milano, 25 Giugno 2014
Pre e Post Trapianto di Fegato nell’era dei nuovi antivirali
Alessio Aghemo, MD
Unità Operativa di Gastroenterologia ed Epatologia
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico
Università degli Studi di Milano
Indication For Liver Transplantation
M. Angelico et al , Digestive and Liver Diseases 2011
Decreased Survival Among HCV-infected
Liver Transplanted Recipients
522 tranplanted pts (1991-2000);
283 pts HCV(+) and 239 HCV(-)
Berenguer et al, Hepatology 2001
HCV survival after transplant (database USA/Europe)
Autor
N.pts
Enrolment
5yr Surv
Donor Age, yr
Anti/HCV therapy
Forman 2002, UNOS
4449
1992/98
69%
36
no
Lake 2005, SRTR
3463
1995/01
71%
37
no
Mutimer 2006, ELTR
4736*
1987/01
68%
41
no
Thuluvath 2007, UNOS
7459**
1991/01
70%
34
Less than 5%
* vs Etoh
**vs non/HCV
Reduced Liver-related Mortality in SVR Liver Graft
Recipients with Recurrent HCV
Picciotto et al, J. Hepatology 2007
Berenguer, Am. J. of Transplant. 2008
Safety and Efficacy of TVR/BOC For HCV after OLT
BOC (n= 18)
TVR (n=19)
Death, No (%)
2 (11)
1 (5)
Infections, No (%)
5 (27)
5 (26)
Hb <8 g/dL, No (%)
7 (39)
5 (26)
Renal Failure, No (%)
1 (5)
4 (21)
Rehospitalization, No (%)
6 (33)
6 (32)
Coilly A et al, J Hepatol 2014;60:78-86
Recurrent HCV Treatment by TVR-BOC + PegIFN/Rbv:
Cohort and Clinical Studies
Faisal, et al
DAA
Pts
Population
HCV-1a
SVR-12
Disco
TVR
76
F0-F2
72%
58%
44%
BOC
Stravitz et al
TVR
125
F3-F4 =48%
58%
59%
20%
Coilly et al
TVR
79
F3-F4,FCH =78%
33%
46%
55%
Pungpapong et al
BOC
TVR
60
F3-F4 50%
68%
50%
20%
FCH 8%
SVR predictors: Cya; (RVR, EVR), Treatment Duration,
Predictors of infections: FCH, Bilirubin; Anemia, Trombocytopenia
Antiviral Treatment Strategies to Reduce Graft Loss in HCV
Biggins SW, Terrault NA. Infect Dis Clin N Am 2006; 20:155
ION-1 SOF/LDV ± Rbv in HCV-1 Naïve
Absence of Cirrhosis
100
100
97
Cirrhosis
100
100
99
97
178/178
33/33
181/182
31/32
100
100
179/179
36/36
SVR12 (%)
80
60
40
20
179/179
0
32/33
LDV/SOF
LDV/SOF + RBV
12 Weeks
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
LDV/SOF
LDV/SOF + RBV
24 Weeks
ION-2 LDV/SOF±RBV in Treatment Failure Patients
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
83/87
19/22
89/89
18/22
0
LDV/SOF
LDV/SOF + RBV
12 Weeks
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
LDV/SOF
LDV/SOF + RBV
24 Weeks
COSMOS (Cohort 2): Sofosbuvir/Simeprevir +/- RBV
in G1 Naives and Null Responders, F3-F4
Sub-type and Q80K
SVR12 (%)
100
90
80
100
Fibrosis score
95
96
98
38/40
25/26
44/45
95
Cirrhosis
96
94
70
60
50
40
30
20
10
0
18/18
G1b
G1a
G1a
wo
with
Q80K Q80K
Lawitz et al, EASL 2014, abs O165
F3
37/39
21/22 16/17
F4
Nulls
Naives
Ideal IFN Free Regimens For HCV-1
+
+
or
+
±
±
TURQUOISE-2: IFN-Free Regimens in Cirrhotic HCV-1
380 HCV-1 (1a 68%), TN/TE (Null Resp 36%)
Cirrhosis Child A (allowed: US ascites, Plt > 60,000, bili < 3, alb > 2.8, varices)
ABT-450/r/Ombitasvir + Dasabuvir + Rbv 12/24 Weeks
94
89
100
98
SVR12, % Patients
12-week arm
24-week arm
SAE: 6%
Discontinuation due to AEs: 2%
Decompensation: 1%
124/140
114/121
67/68
GT 1a
Poordad F et al, ILC 2014 OC #163 & NEJM 2014
51/51
GT 1b
13
TURQUOISE-II :SVR12 Rates in HCV Subtype 1a
92.2
92.9
93.3
100
100 100
80.0
92.9
100
3D + RBV
12-week arm
SVR12, % Patients
80
24-week arm
60
40
20
0
59/64
52/56
Naïve
Poordad F et al, NEJM 2014
14/15
13/13
Prior Relapse
Response
11/11
10/10
Prior Partial
Response
40/50
39/42
Prior Null
Response
TURQUOISE-2: More Advanced Cirrhotics
30/45
32/33
151/163 133/139
Platelets
Poordad et al, EASL 2014 LB: NEJM 2014
21/25
16/18
170/183 149/154
Albumin
Pretransplant Sofosbuvir + Ribavirin
• Patient population
- DDLT candidates with HCV and HCC meeting MILAN criteria
- MELD exception for HCC
- CPT ≤7
• Enrollment at 16 sites
- 8 UNOS regions
- 2 international sites
• 61 patients enrolled
• Original protocol: until LT or up to 24 weeks of treatment
- Amendment: extend treatment duration to 48 weeks or LT
Curry MP et al, AASLD 2013 & APASL 2014
Results: Post-Transplant Virologic Response
*3 subjects were >LLOQ at transplant.
†1 subject has not reached pTVR12, 1 subject LTFU at Week 8 post transplant.
Curry MP et al, AASLD 2013 & APASL 2014
Days Continuously TND Prior to Transplant:
No Recurrence vs Recurrence in GT 1–4
Curry MP et al, AASLD 2013 & APASL 2014
Patients with an Indication of
Liver Transplantation
• Child-Pugh A with HCC:
• Sofosbuvir + ribavirin until liver transplantation
• Sofosbuvir + simeprevir or daclatasvir + ribavirin until
liver transplantation probably better
• Finite (12 weeks) PegIFNa, ribavirin and sofosbuvir also
acceptable
EASL online HCV treatment recommendations J Hepatol in press
HCV-1 Patients with Decompensated Cirrhosis
Arm-2: 20 HCV-1 Cirrhosis Child B
SOF + LDV 12 Weeks
GT 1
CPT Class B
1.5 (0.7-3.7)
Median serum albumin,
g/dL (range)
3.1 (2.3-3.8)
(%)
Median INR
(range)
1.2 (1.0-3.0)
SVR12
7 relapses
Median total bilirubin,
mg/dL (range)
Ascites, n (%)
4 (20)
Hepatic encephalopathy,
n (%)
6 (30)
Median platelet count,
103/µL (range)
Gane EJ et al, ILC 2014 OC #6
84 (44-162)
13/20
SOF+RBV in Cirrhosis + Portal HTN ± Decompensation
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
24
Wk 0
Arm 1
n=25
Wk
48
SOF 400 mg + RBV
1000‒1200 mg
Wk
72
Wk
96
SVR12
Observation
SOF 400 mg + RBV
1000‒1200 mg
Preliminary
results
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
Arm 2
n=25
SOF + RBV
n=25
GT, n (%)
Mean HVPG mmHg, n (range)
HVPG >12 mmHg, n (%)
Afdhal N, EASL, 2014, O68
Difficult-to-Treat Patients:
Decompensated Cirrhosis and Portal Hypertension
Afdhal N et al, ILC 2014 OC #68
Difficult-to-Treat Patients:
Decompensated Cirrhosis and Portal Hypertension (II)
MELD Changes During Treatment/Observation
Afdhal N et al, ILC 2014 OC #68
Decompensated Cirrhosis not
in the Transplant List
• Patients with decompensated cirrhosis not on a
transplant waiting list should be offered an IFN-free
regimen
• This should be done only within a clinical trial, an
expanded access program or within experienced
centres, because the efficacy, safety and outcomes
have not yet been established for this group
EASL online HCV treatment recommendations J Hepatol in press
Patients with an Indication of
Liver Transplantation
• Patients with decompensated cirrhosis awaiting liver
transplantation (Child-Pugh B or C)
• Sofosbuvir + ribavirin in experienced centers under close
monitoring
• Sofosbuvir + daclatasvir + ribavirin probably better
EASL online HCV treatment recommendations J Hepatol in press
Antiviral Treatment Strategies to Reduce Graft Loss in HCV
Biggins SW, Terrault NA. Infect Dis Clin N Am 2006; 20:155
SOF + RBV for Recurrent HCV Post-liver Transplant
 Primary endpoint: pTVR (SVR12 post-LT)
 Study inclusion criteria:
 Liver transplant ≥ 6 months and ≤ 150 months
 CPT ≤ 7 and MELD ≤ 17\
 Treatment-naïve or experienced
 CPT ≤7 and MELD ≤17
Samuel D, EASL 2014, P1232
Virologic Response with SOF + RBV in
Post-LT Patients Treated for 24 weeks
40/40
40/40
29/40
28/40
28/40
 Relapse was not influenced by RBV dose or exposure
 No interactions reported between SOF and any immunosuppressive agents
during the study
Samuel D, EASL 2014, P1232
ABT450/r + Ombitasvir + Dasabuvir + RBV
for 24 Weeks for Post-LT HCV
100%
Phase 2 Study
 N=34
 G1, post-LT treatment
naive
 F0-2
 CNI doses adjusted for
ABV450/r use
Kwo P, EASL, London 2014
96%
SOF Compassionate Use for Severe Recurrent
Hepatitis C Including FCH following LT
Severe recurrent hepatitis C post-LT likely to have <1 yr life expectancy
SOF 400 mg/d for 24-48 weeks plus RBV ± Peg-IFN
Severe acute hepatitis/early recurrence
(<12 mo from LT with typical biochemicalhistological findings), n=48
Post-LT compensated (F4) or decompensated
cirrhosis, n=56
Early term due to AE
n=7
Liver transplant
n=12
SOF Compassionate Use Program
SOF + RBV ± PEG,
n=104
Death
n=13
Completed 24-48 weeks
treatment
n=72
Forns X. ILC 2014
Results: Baseline Characteristics
Overall
(n=104)
Age, years
55 (16-76)
Male recipient
76 (73%)
HCV RNA, log10 IU/mL
8.4 (1.3-8.9)
GT HCV, 1 / 4 vs 2 / 3
88 / 8 vs 1 / 7
Bilirubin, mg/dL
3.1 (0.4-45)
Albumin, g/dL
3.1 (1.3-4.2)
INR
1.3 (0.8-4.5)
ALT, IU/L
71 (8-1162)
MELD
15 (6-43)
Time from LT to treatment, months
17 (1-262)
Results: Overall Virologic Response in 104 HCV Rec
4/85
15%
13/85
Patients (%)
18%
87%
62%
Results: Clinical Outcomes
Patients (%)
All patients who received ≥1 dose of SOF are included
* Significant decrease in hepatic encephalopathy, improvement or
disappearance of ascites, or improvement in liver-related laboratory values.
33
Post-Transplant Recurrent
Hepatitis C
• Patients with post-transplant recurrence of HCV
infection should be considered for therapy
• IFN-free treatment is recommended
• No dose adjustment is required for tacrolimus or
cyclosporine with any of the available combinations