Transcript Titolo

Pre e post-trapianto di fegato nell’era dei nuovi antivirali
Quali vantaggi dalle nuove terapie?
Nicola Caporaso
26 giugno 2014 Bari
HCV
19892014
NATURAL HISTORY HCV
SLOW
female, young age >30 years of disease
Healing 20%
Acute
Chronic
Cirrhosis
Liver
failure
for years
YEARS
Rapid
Alcohol, coinfection
(HBV,HCV)
years
Milestones in Therapy of Genotype 1 HCV
Direct-acting
antivirals
2011
100
Peginterferon
80
Standard
interferon
60
2001
Ribavirin
70+
1998
55
1991
42
40
34
39
16
20
6
0
IFN
IFN
6 mos
12 mos
IFN/RBV IFN/RBV PegIFN
6 mos
12 mos
12 mos
PegIFN/ PegIFN/
RBV
RBV/
12 mos
DAA
Adapted from US FDA Antiviral Drugs Advisory Committee Meeting; April 27-28, 2011; Silver Spring, MD.
CUPIC: TVR vs BOC safety findings
TVR
N=299
BOC
N=212
SAEs
161 (53.8)
94 (44.3)
Premature discontinuation
Due to SAEs
134 (44.8)
71 (23.8)
95 (44.8)
37 (17.5)
Death
Four septicemia, one pneumopathy, one variceal
bleeding, one encephalopthy, one pulmonary
neoplasia
8 (2.7)
3 (1.4)
Infection (Grade 3/4)
29 (9.7)
8 (3.8)
Hepatic decompensation (Grade 3/4)
14 (4.7)
9 (4.2)
16 (5.3)/0(0%)
2 (1.0)/0 (0%)
Anemia (Grade 3/4: Hb <8 g/dL)
38 (12.7)
19 (9.0)
EPO use
Blood transfusion
99 (33.1)
53 (17.7)
69 (32.6)
25 (11.8)
G-CSF use
2 (0.7)
6 (2.8)
TPO use
1 (0.3)
2 (0.9)
Patients, n (%) with at least one event
Rash Grade 3/SCAR
SCAR: severe cutaneous adverse reaction
G-CSF: granulocyte-colony stimulating factor; TPO: thrombopoietin
Fontaine H, et al. AFEF 2013
CUPIC: SVR12 and the risk of occurrence of
severe complications (multivariate analysis)*
Platelets count
≤100,000/mm3
Platelets count
>100,000/mm3
Albumin
<35 g/L
N
Complications, n (%)
SVR12, n (%)
37
19 (51.4%)
10 (27.0%)
31
5 (16.1%)
8 (29.0%)
Albumin
≥35 g/L
N
Complications, n (%)
SVR12, n (%)
74
9 (12.2%)
27 (36.5%)
306
19 (6.2%)
168 (54.9%)
*Missing data for 69 patients
Fontaine H, et al. AFEF 2013
Terapia antivirale cirrosi pre-OLT
Interferone no
Boceprevir/Telaprevir  no
Highlights From EASL 2014
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Summary of Direct-Acting Antivirals
Class
Drug
Dosing
ABT-450/RTV
150/100 mg
Asunaprevir
100 mg BID
NS3/4A protease inhibitor
MK-5172
100 mg QD
NS3/4A protease inhibitor
Simeprevir
150 mg QD
NS5B nonnucleoside polymerase inhibitor
Dasabuvir
250 mg BID
NS5B nucleotide polymerase inhibitor
Sofosbuvir
400 mg QD
NS5A inhibitor
Daclatasvir
60 mg QD
NS5A inhibitor
GS-5816
25 or 100 mg QD
NS5A inhibitor
Ledipasvir
90 mg QD
NS5A inhibitor
MK-8742
20 or 50 mg QD
NS5A inhibitor
Ombitasvir
25 mg QD
NS3/4A protease inhibitor
NS3 protease inhibitor
Linee guida AISF ( aggiornate a 24 giugno 2014 )
Highlights From EASL 2014
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ION 1: SOF/LDV FDC ± RBV for 12 or 24
Wks in Treatment-Naive GT1 Patients

Open-label phase III trial[1,2]

15% to 17% of participants had cirrhosis
Wk 12
Wk 24
SOF/LDV (n = 214)
Treatment-naive pts
with HCV GT1
(N = 865)
SOF/LDV + RBV (n = 217)
SOF/LDV (n = 217)
SOF/LDV + RBV (n = 217)
Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day.
Mangia A, et al. EASL 2014. Abstract O164. Reproduced with permission. Afdhal N, et al. N Engl J Med.
2014;[Epub ahead of print].
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ION 1: SVR12 With 12 or 24 Wks SOF/LDV
± RBV in Tx-Naive Pts by Cirrhosis Status
99
100
94
97
100
98
94
99
100
SVR12 (%)
80
No cirrhosis
60
Cirrhosis
40
20
0
179/
180
32/
34
SOF/LDV
178/
184
33/
33
SOF/LDV + RBV
12 Wks
181/
184
31/
33
179/
181
SOF/LDV
36/
36
SOF/LDV + RBV
24 Wks

SVR12 rates did not differ by GT1a vs GT1b in any treatment arm

Virologic failure: 1 breakthrough in 24-wk SOF/LDV; 2 relapses (1 in 12-wk SOF/LDV, 1 in 24-wk
SOF/LDV)

16% of patients had NS5A resistance-associated variants at baseline; 96% of these achieved SVR12
Mangia A, et al. EASL 2014. Abstract O164. Reproduced with permission. Afdhal N, et al. N Engl J Med.
2014;[Epub ahead of print].
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ION 1: Adverse Events
12 Wks
24 Wks
SOF/LDV
(n = 214)
SOF/LDV +
RBV
(n = 217)
SOF/LDV
(n = 217)
SOF/LDV +
RBV
(n = 217)
169 (79)
185 (85)
178 (82)
200 (92)
Grade 3/4 AEs
4 (2)
14 (6)
21 (10)
12 (6)
Any serious AE
1 (< 1)
7 (3)
18 (8)
7 (3)
0
1 (< 1)
4 (2)
6 (3)
10 (5)
21 (10)
22 (10)
27 (12)
 Hemoglobin < 10 g/dL
0
20 (9)
0
16 (7)
 Hemoglobin < 8.5 g/dL
0
1 (< 1)
0
0
AEs, n (%)
Any AE
AE leading to discontinuation
Grade 3/4 laboratory
abnormalities
Mangia A, et al. EASL 2014. Abstract O164. Reproduced with permission. Afdhal N, et al. N Engl J Med.
2014;[Epub ahead of print].
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ION 2: SOF/LDV FDC ± RBV for 12 or 24
Wks in Treatment-Experienced GT1 Pts

Open-label phase III trial[1,2]

20% of participants had cirrhosis, 41% to 46% were previous nonresponders,
and 46% to 61% had failed a PI
Wk 12
Wk 24
SOF/LDV (n = 109)
Treatmentexperienced pts
with HCV GT1
(N = 440)
SOF/LDV + RBV (n = 111)
SOF/LDV (n = 109)
SOF/LDV + RBV (n = 111)
Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day.
1. Afdhal N, et al. EASL 2014. Abstract O109. Reproduced with permission. 2. Afdhal N, et al. N Engl J
Med. 2014;370:1483-1493.
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ION 2: SVR12 With 12 or 24 Wks of
SOF/LDV ± RBV by Cirrhosis Status
100
95
86
100
82
99
100
99
100
SVR12 (%)
80
No cirrhosis
60
Cirrhosis
40
20
0
83/
87
19/
22
LDV/SOF
89/
89
LDV/SOF + RBV
12 Wks

18/
22
86/
87
22/
22
LDV/SOF
88/
89
22/
22
LDV/SOF + RBV
24 Wks
SVR12 rates were significantly lower in cirrhotic vs noncirrhotic patients in the pooled
12-wk arms
Afdhal N, et al. EASL 2014. Abstract O109. Reproduced with permission. Afdhal N, et al. N Engl J Med.
2014;370:1483-1493.
ION-2 (LDV/SOF±RBV x 12 or 24 weeks)
SVR12: Cirrhotic Patients with Platelets < 90,000/mm3 and
Albumin < 3.5g/dL
% of Patients
100%
92%
80%
60%
40%
20%
12/13
0%
12/13*
SVR12
*The one patient who did not achieve an SVR, took 1 dose and withdrew consent
Data on File, Gilead Sciences
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ION 2: Adverse Events
12 Wks
24 Wks
SOF/LDV
(n = 109)
SOF/LDV +
RBV
(n = 111)
SOF/LDV
(n = 109)
SOF/LDV +
RBV
(n = 111)
73 (67)
96 (86)
88 (81)
100 (90)
Grade 3/4 AEs
2 (2)
3 (3)
10 (9)
8 (7)
Any serious AE
0
0
6 (6)
3 (3)
AE leading to discontinuation
0
0
0
0
5 (5)
15 (14)
9 (8)
27 (24)
 Hemoglobin < 10 g/dL
0
2 (2)
0
9 (8)
 Hemoglobin < 8.5 g/dL
0
0
0
2 (2)
AEs, n (%)
Any AE
Grade 3/4 laboratory
abnormalities
Afdhal N, et al. EASL 2014. Abstract O109. Reproduced with permission. Afdhal N, et al. N Engl J Med.
2014;370:1483-1493.
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ELECTRON 2: SOF/LDV FDC ± RBV in
Diverse Hard-to-Treat Patients

Partially randomized, open-label phase II trial
Wk 12
SVR12, %
SOF/LDV FDC (n = 25)
64
SOF/LDV FDC + RBV (n = 26)
100
GT1 and CTP class B
cirrhosis
(N = 20)
SOF/LDV FDC (n = 20)
65
GT1 relapsers after previous
SOF-based regimen*
(N = 19)
SOF/LDV FDC + RBV (n = 19)
100
Treatment-naive GT3
(N = 51)
Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day.
*Includes 10 patients who received SOF + RBV for 12 wks, 8 patients who received SOF/LDV + RBV for
6 wks, and 1 patient who received SOF + GS-9669 + RBV for 12 wks.
Gane EJ, et al. EASL 2014. Abstract O6. Reproduced with permission.
ELECTRON-2 (subgroup analysis): patients with CPT B cirrhosis
GT1
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)
Ascites, n (%)
4 (20)
Hepatic
encephalopathy,
n (%)
6 (30)
Median platelet count,
103/µL (range)
7 relapsers
SVR12 (%)
Median total bilirubin,
mg/dL (range)
n
N
13
20
84 (44–162)
CPT = Child Pugh Turcotte; INR = international normalized ratio;
Error bar represents the 95% confidence interval.
Gane E, et al. EASL 2014 [oral presentation 6].
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C-WORTHY: MK-5172 + MK-8742 ± RBV in
GT1 Cirrhotics and Null Responders

Interim results from a randomized phase IIb trial

Primary endpoint: SVR12
Wk 12
MK-5172 + MK-8742 + RBV (n = 31)
Treatment-naive pts
with GT1 HCV and
cirrhosis
(N = 123)
MK-5172 + MK-8742 (n = 29)
MK-5172 + MK-8742 + RBV (n = 32)
MK-5172 + MK-8742 (n = 31)
MK-5172 + MK-8742 + RBV (n = 31)
Pts with GT1 HCV
and null response
to pegIFN/RBV
(N = 130)
MK-5172 + MK-8742 (n = 33)
MK-5172 + MK-8742 + RBV (n = 33)
MK-5172 + MK-8742 (n = 32)
MK-5172 100 mg once daily; MK-8742 50 mg once daily, RBV 1000-1200 mg divided twice daily.
Lawitz E, et al. EASL 2014. Abstract O61. Reproduced with permission.
Wk 18
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C-WORTHY: Interim Results in TreatmentNaive Cirrhotic Pts and Null Responders
SVR4-8 (%)
100
97
97
97
90
100
94
97
91
80
60
12 wks + RBV
12 wks no RBV
18 wks + RBV
18 wks no RBV
40
20
28/
31
0
28/
29
30/
31*
29/
30*
Treatment-Naive Pts
With Cirrhosis
30/
32
30/
33
32/
32*
Null Responders
± Cirrhosis
*Excludes patients who have not yet reached SVR4 time point.
Lawitz E, et al. EASL 2014. Abstract O61. Reproduced with permission.
29/
30*
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C-WORTHY: Adverse Events in TreatmentNaive Cirrhotic Pts and Null Responders
AEs, n (%)
Treatment-Naive With
Cirrhosis
Null Responders
± Cirrhosis
With RBV
(n = 63)
No RBV
(n = 63)
With RBV
(n = 63)
No RBV
(n = 63)
Any serious AE, n (%)
1 (2)
2 (3)
2 (3)
2 (3)
AE leading to discontinuation, n (%)
2 (3)
0
1 (2)
0
 Hemoglobin < 10 g/dL
8 (13)
0
4 (6)
0
 Hemoglobin < 8.5 g/dL
1 (2)
0
0
0
 Total bilirubin > 2 x ULN
6 (10)
0
9 (14)
3 (5)
 Total bilirubin > 5 x ULN
0
0
0
0
 ALT/AST > 2 x ULN*
0
2 (3)
1 (2)
3 (5)
 ALT/AST > 5 x ULN*
0
0
1 (2)
0
Laboratory abnormalities, n (%)
*After initial normalization.
Lawitz E, et al. EASL 2014. Abstract O61. Reproduced with permission.
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HALLMARK-DUAL: Daclatasvir +
Asunaprevir in Patients With GT1b HCV

AI447-028: double-blinded, placebo-controlled phase III trial
Wk 12
GT1b HCV
Daclatasvir + Asunaprevir (n = 203)
Treatment-naive
(N = 305)
Placebo* (n = 102)
Previous null or partial
responders
(N = 205)
Daclatasvir + Asunaprevir (n = 205)
Interferon
ineligible/intolerant
(N = 235)
Daclatasvir + Asunaprevir (n = 235)
Daclatasvir 60 mg once daily; asunaprevir 100 mg twice daily.
*Patients allocated placebo crossed over into a separate study after 12 wks.
Manns M, et al. EASL 2014. Abstract O166. Reproduced with permission.
Wk 24
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HALLMARK-DUAL: SVR12 With
Daclatasvir + Asunaprevir in GT1b HCV
SVR12, % (n/N)
Daclatasvir + Asunaprevir
Treatment naive
90
(182/203)
Null responders
82
(98/119)
Partial responders
81
(68/84)
All IFN ineligible/intolerant
Advanced fibrosis/cirrhosis with thrombocytopenia
82
(192/235)
73
(56/77)

Breakthrough: 9 (4%) treatment naive, 26 (13%) nonresponders, 20 (9%) IFN ineligible/intolerant

Relapse: 5 (3%) treatment naive, 7 (4%) nonresponders, 12 (6%) IFN ineligible/intolerant

28 of 73 patients with NS5A-L31 and/or Y93 variants at baseline achieved SVR12
Manns M, et al. EASL 2014. Abstract O166. Reproduced with permission.
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SOF + RBV in Patients With Cirrhosis and
Portal Hypertension ± Decompensation

Interim results of an open-label phase II trial

Primary endpoint: SVR12
Wk 24
Current analysis
HCV-infected
patients with portal
hypertension ±
decompensated liver
disease*
(N = 50)
Wk 48
Wk 72
Sofosbuvir + Ribavirin (n = 25)
Observation (n = 25)
Sofosbuvir + Ribavirin (n = 25)
Sofosbuvir 400 mg once daily; ribavirin 1000-1200 mg/day divided twice daily.
*Among 25 patients allocated sofosbuvir + ribavirin, 10 had GT1a HCV, 9 had GT1b, 2 had GT2, 2 had
GT3, and 2 had GT4.
Afdhal N, et al. EASL 2014. Abstract O68. Reproduced with permission.
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Virologic Response to SOF + RBV in
Patients With Portal Hypertension
HCV RNA < LLOQ (%)
100
94
94
100
93
75
80
60
100
100
100
56
44
CTP A
CTP B
40
20
0
Wk 2
Wk 4
Wk 8
Wk 12
Ascites
Clinical Events, n
Wk 24
Hepatic Encephalopathy
SOF + RBV
(n = 25)
Observation
(n = 25)
SOF + RBV
(n = 25)
Observation
(n = 25)
Baseline
6
9
5
2
Wk 12
5
8
3
3
Wk 24
0
7
0
4
Afdhal N, et al. EASL 2014. Abstract O68. Reproduced with permission.
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TURQUOISE II: ABT-450/RTV/Ombitasvir +
Dasabuvir + RBV in Cirrhotic GT1 Pts

Open-label phase III trial

Inclusion criteria: GT1, compensated cirrhosis (Child-Pugh A), DAA naive,
radiographic ascites and varices permitted, serum albumin ≥ 2.8 g/dL,
total bilirubin < 3 mg/dL, serum AFP ≤ 100 ng/mL, INR ≤ 2.3, platelets
≥ 60,000 cells/mL
Wk 12
DAA-naive cirrhotic
pts with HCV GT1
(N = 380)
Wk 24
ABT-450/RTV/Ombitasvir +
Dasabuvir + RBV
(n = 208)
ABT-450/RTV/Ombitasvir + Dasabuvir + RBV
(n = 172)
ABT-450/RTV/ombitasvir 150/100/25 mg once daily; dasabuvir 250 mg twice daily; RBV 1000-1200 mg/day.
Poordad F, et al. EASL 2014. Abstract O163. Reproduced with permission.
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TURQUOISE II: Baseline Characteristics
 58% of patients were peginterferon/ribavirin experienced, and 36%
were previous null responders
3 DAA + RBV
Characteristic, %
12-Wk Arm
(n = 208)
24-Wk Arm
(n = 172)
Treatment naive
41.3
43.0
Treatment experienced
58.7
57.0
 Relapse
13.9
13.4
 Partial response
8.7
7.6
 Null response
36.1
36.0
Platelet count < 100 x 109/L
21.6
19.2
Serum albumin < 3.5 g/dL
12.0
10.5
Child-Pugh score > 5
18.3
18.6
Poordad F, et al. EASL 2014. Abstract O163. Reproduced with permission.
TURQUOISE-II: ITT SVR12 rates by surrogates of portal
hypertension and hepatic function
100
88.9 97.0
92.6 95.7
84.0 88.9
92.9 96.8
3D + RBV
12-week
SVR12 (%)
80
24-week
60
40
20
n 40
N 45
0
32
33
<100
151
163
133
139
≥100
Baseline platelet count
(x109/L)
21
25
16
18
<35
170
183
149
154
≥35
Baseline serum albumin
count (g/L)
Poordad F, et al. EASL 2014. (Abstract 164) [late breaker oral presentation].
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TURQUOISE II: Adverse Events
3 DAAs + RBV
AEs, %
12-Wk Arm
(n = 208)
24-Wk Arm
(n = 172)
Any AE
91.8
90.7
AE leading to discontinuation
1.9
2.3
6.3/6.7
4.7/7.6
ALT > 5 x ULN
2.9
0
Total bilirubin > 3 x ULN
13.5
5.2
 < 10 g/dL
7.2
11.0
 < 8 g/dL
1.4
0.6
Any serious/severe AE
Hemoglobin

ALT elevation asymptomatic, transient, improved/resolved with continued dosing

Bilirubin elevation transient, predominantly indirect, did not result in discontinuation

Hemoglobin decrease managed with RBV dose reduction in 34 of 380 pts (8.9%)
Poordad F, et al. EASL 2014. Abstract O163. Reproduced with permission.
Promising IFN-Free Regimens in Genotype 1
Cirrhotic Patients
SVR12, %
Regimen
Tx Naive
Tx Exp
PI Failure
Sofosbuvir + ledipasvir[1,2]
---
70 (N = 10)
91 (N = 11)
Sofosbuvir + ledipasvir + RBV[1,2]
---
100 (N = 25)
100 (N = 11)
Sofosbuvir + ledipasvir + GS-9669[1]
---
100 (N = 26)
---
90 (N = 203)†
82 (N = 205)†
---
Daclatasvir + asunaprevir + BMS-791325 75 mg[4]
94 (N = 16)
---
---
Daclatasvir + asunaprevir + BMS-791325 150 mg[4]
89 (N = 18)
---
---
ABT-450/ritonavir/ombitasvir + dasabuvir + RBV[5]
94 (N = 86)
87-97 (N = 122)
---
ABT-450/ritonavir/ombitasvir + dasabuvir + RBV[5]*
95 (N = 74)
95-100 (N = 98)
---
Daclatasvir + asunaprevir[3]*
*Treatment duration: 24 weeks; all others 12 weeks.
†Genotype 1b HCV-infected patients only
1. Gane EJ, et al. AASLD 2013. Abstract 73. 2. Lawitz. E et al. AASLD 2013, Abstract 215.
3. Manns M, et al. EASL 2014. Abstract 166. 4. Everson GT, et al. Gastroenterol. 2014;146:420-429.
5. Poordad F, et al. N Engl J Med. 2014;[Epub ahead of print].
Incontro CPR AIFA - Gilead per processo negoziazione terapia Epatite C
11/06/2014
Comunicato stampa AIFA N. 367
In occasione della riunione straordinaria del Comitato Prezzi e Rimborso di
AIFA del 9 giugno c.a., il Comitato, come previsto nell’accordo iniziale, ha
preso atto della richiesta di Gilead di sospendere la negoziazione di
Sofosbuvir per un periodo di 30 giorni al fine di definire i dettagli dell’accordo.
Durante questo periodo AIFA e Gilead hanno previsto una soluzione per
fornire da subito il farmaco ai pazienti affetti da epatite C nei casi più urgenti
[ovvero pazienti con recidiva severa di epatite dopo trapianto di fegato
(epatite fibrosante colestatica o epatite cronica con grado di fibrosi >F2
METAVIR) oppure pazienti con cirrosi scompensata in lista per trapianto
epatico (MELD < 25)].
Fonte: agenziafarmaco.gov.it
26 giugno 2014 Bari
Fight against HCV
HCV
26 giugno 2014 Bari
Multi enim sunt vocati, pauci
vero electi
Matthaeus, 20: 16
Many are called,
few are chosen
(The Gospel according Matthew, 20: 16)
Savoldi ( Beppe)  Sovaldi ( Sofosbuvir)
HCV
26 giugno 2014 Bari