Transcript HCV: come vorrei trattarlo, come dovrei trattarlo

Malattia da HCV:
l’inizio di una nuova era?
Antonio Craxì
GI & Liver Unit, Di.Bi.M.I.S.,
University of Palermo, Italy
[email protected]
•
Obiettivi e strategie di un
futuro IFN-free
•
Ottimizzare la gestione
clinica della monoinfezione
HCV oggi
HCV: a long list of problems
Efficacy = Difficult to Cure
Host
Virus
•
•
•
•
•
•
•
Prior non-responders
Unfavourable IL28B
Cirrhosis
Co-morbidities
- HIV/OLT/ESRD/DM
HCV genotype
HCV viral load
Resistance
Tolerability/Safety = Difficult to Treat
Host
•Age
•Cirrhosis
•Co-morbidities
• ESRD/Autoimmunity/Psych…
Treatment
•
•
•
•
RGT
Injections, pill burden,
Adverse reactions
Drug interactions
Identification/Access/Uptake
Second wave DAAs for Gt 1
Simeprevir + PR
x 24 weeks
Treatment Naïve
SVR12 (%)
80
84
80
60
80
50
50
40
211/
264
65/
130
QUEST 1
208/
257
67/
134
36
40
QUEST 2
206/
260
89
80
60
0
100
79
20
20
0
100
SVR12 (%)
100
Prior
Relapsers
Sofosbuvir + PR
X 12 weeks
SVR12 (%)
PR + SMV
PR
60
40
20
48/
133
0
PROMISE
261/
292
NEUTRINO
 Great data BUT – still requires IFN
Jacobson I, et al. EASL 2013. Abst. 1425.
Manns M, et al. EASL 2013. Abst. 1413.
Lawitz E, et al. NEJM 2013
Impact of cirrhosis on SVR12 with
Simeprevir + P/R
QUEST-1:
Simeprevir + P/R
Treatment-Naive GT1
Simeprevir + P/R
P/R
100
82
SVR12 (%)
80
60
53
58
40
20
n/N =
0
29
188/
229
60/
113
No Cirrhosis
Jacobson I, et al. EASL 2013. Abstract 1425.
18/
31
5/
17
Cirrhosis
The tornado of HCV drug development
Preclinical
Phase I
Ciluprevir
Phase II
ASV
BMS791325
MCB
Danoprevir (DNVr)
DCV
DBV
FDV
Vedroprevir
Phase III
ABT450r
DNVr
SOF
SOF
GS9669
LDV
Ombitasvir
MK5172
ASV
LDV
Filed
DCV
Sovaprevir
Faldaprevir (FDV)
ABT450r
Telaprevir (TVR)
Neceprevir
Boceprevir (BOC)
Alisporivir
(ALV)
SCY635
MK5172
Asunaprevir (ASV)
Samatasvir
Dasabuvir
Sofosbuvir (SOF)
PEG-IFN 
ITX5061
Narlaprevir
Vaniprevir
Simeprevir (SMV)
Dasabuvir
BIT225
IDX320
> 95% SVR
MK8742
VX985
MK8742
Daclatasvir (DCV)
Miravirsen
ACH2928
Ombitasvir
Mericitabine (MCB)
GS9620
VX135
IDN6556
IDX184
PPI461
PPI668
ABT072
GS9669
Deleobuvir
BMS791325
Tegobuvir
BMS986094
ACH3102
GSK2336805
Ledipasvir (LDV)
GS5816
BMS824393
Lomibuvir
Setrobuvir
TMC647055
PSI938
Coformulation
Status 04/2014 (selection)
New DAAs available over the next 12 months
Mid 2014
Sofosbuvir
Simeprevir
Nucleotide
polymerase inh.
All Gts (3)
Protease inh.
Gt 1, 4
Daclatasvir
NS5A inh.
Gt 1, 3, 4, 5, 6
Triple therapy
with PEG IFN
and ribavirin
Combination of one
DAA and ribavirin
Combination of two
DAAs  ribavirin
Mid 2015
Dasabuvir
Gt 1
(4?)
Non-Nuc
Polymerase
Inh.
ABT 450/R
Ombitasvir
Protease inh./
Ritonavir
NS5A inh.
Fixed dose combination of
three DAAs  ribavirin
Pangenotipic
(±)
Sofosbuvir
Ledipasvir
NS5A inh
Nucleotide
polymerase inh.
Fixed dose combination of
two DAAs  ribavirin.
Further DAA combos available within 2016
Late 2015
Fixed dose combination of two DAAs
Pangenotipic
(±)
Pangenotipic
MK 8742
2nd generation
NS5A inh
MK 5172
2nd generation
protease inh.
Idenix
Polymerase
Inh. ???
GS 5816
Sofosbuvir
2nd generation
NS5A inh.
Nucleotide
polymerase inh.
2016
Pangenotipic
BMS 325
Polymerase
Inh.
Asunaprevir
Protease inh.
Daclatasvir
NS5A inh.
Fixed dose combination
of three DAAs
- Ultra-short therapy
(6 weeks)
- Pangenotypic
- One-pill regimen
Direct-Acting Antiviral Class Profiles:
Backbone/Anchor Strategy
Direct-Acting Antiviral
NS31
NS32
NS5A1
NS5A2
Non
Nuc
NS5B
Nuc
NS5B
Efficacy
Resistance
Profile
Pangenotypic
Activity
Adverse events
Drug-drug
interactions
1
Good profile
1st generation.
2nd generation.
Average profile
Least favorable profile
2
Adapted from Schinazi et al, 2013
Direct-Acting Antiviral Class Profiles:
Multi-Drug Combination Strategy
Direct-Acting Antiviral
NS31
NS32
NS5A1
NS5A2
Non
Nuc
NS5B
Nuc
NS5B
Efficacy
Resistance
Profile
Pangenotypic
Activity
Adverse events
Drug-drug
interactions
1
Good profile
1st generation.
2nd generation.
Average profile
Least favorable profile
2
Adapted from Schinazi et al, 2013
Genotype 1
Sofosbuvir + PegIFN/RBV:
NEUTRINO Phase III Study Design
Wk
0
12
Sofosbuvir + PegIFN/RBV
(N = 327)
24
SVR12
• Open label
– Sofosbuvir 400 mg QD + pegIFN alfa-2a 180 µg/wk + RBV 1000-1200
mg/day for 12 wks (no response-guided therapy)
• Treatment-naive, genotype 1, 4, 5, and 6 HCV-infected patients
– 89% of patients had genotype 1 HCV
– 17% of patients with cirrhosis
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
NEUTRINO Study: Virologic Response
Sofosbuvir + P/R x 12 Wks
100
90
89
80
SVR (%)
80
60
40
20
0
ITT SVR12
n = 327
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
GT1
n=
291
Cirrhosis
54
NEUTRINO: SOF + P/R SVR12 Rates in
Genotype 1, 4-6 by Fibrosis
SVR12 Rates by
Biopsy Fibrosis Stage
100
91
89
78
80
60
40
20
0
n=
16/
16
124/
137
34/
38
32/
41
F0
F1-2
F3
F4
Patel K, et al. AASLD 2013. Abstract 1093.
97
100
SVR12 (%)
SVR12 (%)
100
SVR12 Rates by
FibroTest Stage
96
85
80
79
60
40
20
0
n=
76/
78
101/
105
46/
54
63/
86
F0
F1-2
F3
F4
ELECTRON: Sofosbuvir + RBV 12-Wk
Regimen in Genotype 1 Patients
Patients With HCV RNA < LOD* Over Time, n/N (%)
SOF + RBV
Naive
(n = 25)
Null
(n = 10)
Wk 1
8/25 (32)
1/10 (10)
Wk 2
17/25 (68)
7/10 (70)
Wk 4
25/25 (100)
10/10 (100)
EOT
25/25 (100)
10/10 (100)
SVR4
22/25 (88)
1/10 (10)
SVR12
21/25 (84)
1/10 (10)
*Analyzed by TaqMan HCV Test 2.0 with LOD of 15 IU/mL.
†Includes 1 patient who stopped all treatment due to a serious AE at Wk 8; this patient subsequently
achieved SVR12.
Gane E, et al. EASL 2013. Abstract 14.
NIH SPARE Study (No Interferon):
Sofosbuvir + RBV in HCV GT1-Infected Pts
•
•
•
24 wks sofosbuvir + WB or low-dose (600 mg) RBV in treatment-naive subjects
Primarily GT1a (70%), male (66%), black (83%), IL28B CT/TT (81%)
Advanced liver disease 23%; median BMI ranged from 26-30; high median HCV RNA
Part 1
(Stage F0-F2)
Patients (%)
100
90
Part 2
(All Stages)
90
96
88
80
68
60
48
40
20
0
Sofosbuvir +
WB RBV
N = 10
Sofosbuvir +
Sofosbuvir +
Low-Dose RBV
WB RBV
N = 50
Osinusi A, et al. JAMA. 2013;310:804-811.
EOT
SVR24
Simeprevir + PEG/RBV in GT1, Tx-Naive
Patients: QUEST-1/2 Phase III Trial Design
Response-Guided Treatment
N = 521*
SMV 150 mg
QD + P/R
P/R
N = 264†
Placebo +
P/R
P/R
Wk 0
•
•
12
P/R
P/R
24
48
RGT in simeprevir arm: if HCV RNA < 25 IU/mL at Wk 4 and undetectable at Wk 12, complete
treatment at Wk 24; otherwise, continue treatment to Wk 48
Stopping rules
–
–
If HCV RNA > 1000 IU/mL Wk 4, stop SMV/placebo
If HCV RNA < 2 log10 IU/mL reduction at Wk 12, or confirmed > 25 IU/mL at Wk 24 or 36, stop all
treatment
*QUEST-1: n = 264; QUEST-2: n = 257.
†QUEST-1: n = 130; QUEST-2: n = 134.
Jacobson I, et al. EASL 2013. Abstract 1425. Manns M, et al. EASL 2013. Abstract 1413.
72
Simeprevir + PEG/RBV: Phase III QUEST-1:
Impact of Subtype & Fibrosis Stage in GT1
Overall
SVR (%)
100
80
GT1a
GT1b
100
90
80
80
71
60
F0-F2
50 49 52
60
40
40
20
20
0
0
Simeprevir
PegIFN/RBV
F3
F4
83 78
58
60
26 29
Simeprevir
PegIFN/RBV
• SVR: GT1b > GT1a
• SVR: F0-F2 > F4
• SVR is lowest for patients with GT1a and baseline Q80K mutation
Jacobson I, et al. EASL 2013. Abstract 1425.
Prevalence of Q80K Mutations by
Region in Phase III Simeprevir Studies
Patients,
n/N (%)
All GT
HCV
GT1a HCV
GT1b HCV
Overall
274/2007 (13.7)
269/911 (29.5)
5/1096 (0.5)
Europe
76/1254 (6.1)
73/377 (19.4)
3/877 (0.3)
North America
185/538 (34.4)
185/385 (48.1)
0/153 (0)
South America
2/60 (3.3)
2/22 (9.1)
0/38 (0)
Includes 15 subjects with non-1a/b GT
• FDA advises Q80K polymorphism testing when
using simeprevir
Lenz O, et al. AASLD 2013. Abstract 1101.
COSMOS: Simeprevir + Sofosbuvir ± RBV
in GT1 HCV: Phase IIa Study Design
0
4
12
24
36
Wk
Enrolment
ratio 2:1:2:1
•
•
•
Arm 1
SMV + SOF + RBV
Posttreatment follow-up
Arm 2
SMV + SOF
Posttreatment follow-up
Arm 3
SMV + SOF +
RBV
Posttreatment follow-up
Arm 4
SMV + SOF
Posttreatment follow-up
Cohort 1: previous null responders (METAVIR F0-F2)
Cohort 2: treatment naive and previous null responders (METAVIR F3-F4)
SMV 150 mg QD + SOF 400 mg QD ± RBV 1000/1200 mg/day
Jacobson I, et al. AASLD 2013. Abstract LB-3. Lawitz, et al. EASL 2014. Abstract 165.
48
Combination of Sofosbuvir (NUC) and
Simeprevir (PI): COSMOS
Cohort 1 (F0-F2 Nulls): SVR12
(N = 80, all arms)
100
92.9
79.2
100
93
93
93
25/27
13/14
80
60
40
60
40
20
20
19/24
14/15
26/27
13/14
0
0
24-Wk Arms
•
•
•
100
SVR12 (%)
SVR12 (%)
80
93.3
96.3
SMV + SOF + RBV
SMV + SOF
Cohort 2 (F3-F4 Naives/Nulls): SVR12
(N = 87, all arms)
12-Wk Arms
28/30
16/16
24-Wk Arms
12-Wk Arms
Relapse in 3 pts in Cohort 1 and 3 pts in Cohort 2; all with GT1a and GT2 with Q80K polymorphism at BL
AEs (anemia and indirect bilirubin increases) largely confined to RBV arms
SVR in patients with GT1a and Q80K+ = 88% to 100%
Jacobson I, et al. AASLD 2013. Abstract LB-3. Lawitz E, et al. EASL 2014. Abstract 165.
DCV + SOF for Previously Treated or
Untreated Chronic HCV Infection
Wk 1
Wk 12
Wk 24
SVR12, %
N = 15
126 HCV GT-1
Treatment Naive
41 HCV GT-1
TVR/BOC
Treatment
Failures
DCV + SOF
SOF
100
N = 14
DCV + SOF
100
N = 15
DCV + SOF + RBV
100
N = 41
DCV + SOF
100
N = 41
DCV + SOF + RBV
95
N = 21
DCV + SOF
100
N = 20
DCV + SOF + RBV
95
Sulkowski MS, et al. N Engl J Med. 2014;370:211-221.
EASL HCV Guidelines 2014: Genotype 1
Genotype
Options for Therapy
PegIFN/ribavirin + sofosbuvir: 12 wks (A1)
PegIFN/ribavirin + simeprevir†: 12 wks, followed by 12 wks of pegIFN/ribavirin in
previously untreated pts and prior relapsers (A1), or 36 wks of pegIFN/ribavirin in
previous partial responders and null responders (B1)
Genotype 1*
PegIFN/ribavirin + daclatasvir (genotype 1b only; B1): 12 wks followed by 12 wks of
pegIFN/ribavirin alone or a further 12 wks of pegIFN/ribavirin + daclatasvir
(response-guided therapy) (B2)
Sofosbuvir + ribavirin: 24 wks for interferon-intolerant pts only, where no other
interferon-free option available (B2)
Sofosbuvir + simeprevir: 12 wks (ribavirin may be added for previous nonresponders
& cirrhotics) (B1)
Sofosbuvir + daclatasvir: 12 wks in previously untreated pts; 24 wks in treatmentexperienced patients (including TVR/BOC-experienced patients) (ribavirin may be
added in previous nonresponders and cirrhotics) (B1)
*In settings where recommended options are not available, treatment with pegIFN/ribavirin + TVR or BOC remains
acceptable.
†Not recommended in pts with genotype 1a and detectable Q80K polymorphism.
EASL. J Hepatology. 2014;60:392-420.
Phase III Studies of SOF/LDV FDC ± RBV
for 12 or 24 Wks in GT1 Patients
Wk 12
ION-1[1,2]:
Treatment-naive
HCV GT1;
cirrhosis in 15%
to 17% per arm
(N = 865)
Treatmentexperienced
HCV GT1; 20%
cirrhotics
(N = 440)
•
SVR12, %
SOF/LDV (n = 214)
99
SOF/LDV + RBV (n = 217)
97
SOF/LDV (n = 217)
98
SOF/LDV + RBV (n = 217)
99
Wk 12
ION-2[3]:
Wk 24
Wk 24
SOF/LDV (n = 109)
94
SOF/LDV + RBV (n = 111)
96
SOF/LDV (n = 109)
99
SOF/LDV + RBV (n = 111)
99
ION-1,2: No difference in outcomes according to cirrhosis status, type of treatment failure
1. Mangia A, et al. EASL 2014. Abstract O164. 2. Afdhal N, et al. N Engl J Med. 2014;370:1889-1983.
3. Afdhal N, et al. N Engl J Med. 2014 ;370:1483-1493.
ION-3: Phase III Study of SOF/LDV FDC ±
RBV for 8-12 Wks in Tx-Naive
Noncirrhotic GT1 Patients
Wk 8
Treatment-naive,
noncirrhotic pts
with HCV GT1
(N = 647)
Wk 12
SVR12, %
SOF/LDV (n = 215)
94
SOF/LDV + RBV (n = 216)
93
SOF/LDV (n = 216)
Kowdley KV, et al. N Engl J Med. 2014;3701879-1888.
95
Sofosbuvir (NUC) + Ledipasvir (NS5A) in
Genotype 1: ION-2 Special Subgroups
Wk 12
Wk 24
SVR12, %
SOF + LDV
86%
N = 22
SOF + LDV + RBV
82%
N = 22
SOF + LDV
100%
N = 22
SOF + LDV + RBV
100%
SOF + LDV
94%
ION-2
N = 22
TreatmentExperienced
Cirrhotics
ION-2
N = 66
TreatmentExperienced
PI Failures
N = 64
SOF + LDV + RBV
97%
N = 50
SOF + LDV
98%
N = 51
SOF + LDV + RBV
100%
Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
SOF + GS-5816 in Treatment-Naive
Noncirrhotic Patients With GT1-6 HCV
• Open-label phase II study
• N = 154 patients randomized to 12 wks SOF + GS-5816 25 mg or 100 mg
daily
• GS-5816: investigational NS5A inhibitor
100
93
93
SOF + GS-5816 25 mg
SOF + GS-5816 100 mg
SVR12 (%)
80
60
40
20
0
25/27
25/27
Genotype 3
Everson GT, et al. EASL 2014. Abstract O111.
ELECTRON: Sofosbuvir/Ledipasvir ± RBV or
GS-9669 in Cirrhotic GT1 HCV Pts
• Open-label phase II trial
• SVR12 rate enhanced with addition of RBV or
GS-9669
Wk 12
SVR12, %
SOF/LDV FDC (n = 10)
70
SOF/LDV FDC + RBV (n = 9)
100
SOF/LDV FDC + RBV (n = 25)
100
SOF/LDV FDC + GS-9669 (n = 26)
100
Treatment-experienced
pts with HCV GT1, F4
(N = 19)
Treatment-experienced pts
with HCV GT1, F3 or F4
(N = 51)
Sofosbuvir 400 mg QD/ledipasvir 90 mg QD; GS-9669 500 mg QD; weight-based RBV 1000-1200 mg/day
Gane EJ, et al. Gastroenterol. 2014;146:736-743.
SAPPHIRE I & II: Phase III Studies of ABT450/RTV/Ombitasvir (NS5A) + Dasabuvir (NNI) +
RBV in Noncirrhotic GT1 Pts
Wk 12
SAPPHIRE-I
Treatment-naive
noncirrhotic pts with
HCV GT1[1,2]
(N = 631)
SAPPHIRE-II
Treatment-experienced
noncirrhotic pts with
HCV GT1[3,4]
(N = 394)
•
ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 473)
SVR12, %
96
Placebo (n = 158)*
ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 297)
96
Placebo (n = 97)
SAPPHIRE: no difference in outcomes according to 1a/1b subtype, type of treatment
failure
*Placebo recipients crossed over to active treatment regimen at Wk 12.
1. Feld JJ, et al. EASL 2014. Abstract O60. Reproduced with permission. 2. Feld JJ, et al. N Engl J Med.
2014;370:1594-1603. 3. Zeuzem S, et al. EASL 2014. Abstract O1. 4. Zeuzem S, et al. N Engl J Med.
2014;370:1604-1614.
TURQUOISE II: Phase III Study of ABT450/RTV/Ombitasvir (NS5A) + Dasabuvir (NNI) +
RBV in Cirrhotic GT1 Patients
Wk 12
Wk 24
SVR12, %
DAA-naive cirrhotic pts
with HCV GT1; 58% of
patients were treatment
experienced, and 36%
were previous null
responders
ABT450/RTV/Ombitasvir +
Dasabuvir + RBV
(n = 208)
ABT450/RTV/Ombitasvir + Dasabuvir + RBV
(n = 172)
92
96
(N = 380)
•
No significant difference in 12 vs 24 wks; high SVR in all subgroups analyzed
ABT-450/RTV/ombitasvir 150/100/25 mg once daily; dasabuvir 250 mg twice daily; RBV 1000-1200 mg/day.
Poordad F, et al. N Engl J Med. 2014;370:1973-1982.
Ribavirin-Free Therapy in GT1b
Wk 12
PEARL-II[1]
ABT450/RTV/Ombitasvir + Dasabuvir (n = 95)
100
ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 91)
97
ABT450/RTV/Ombitasvir + Dasabuvir (n = 209)
99
ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 210)
99
ABT450/RTV/Ombitasvir + Dasabuvir (n = 205)
90
ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 100)
97
GT1b
Tx-Experienced
PEARL-III[2]
GT1b
Tx-Naive
PEARL-IV[2]
SVR12, %
GT1a
Tx-Naive
1. Andreone P, et al. Gastroenterology. 2014. Epub ahead of print. 2. Ferenci P, et al. N Engl J Med. 2014.
22;370:1983-1992.
C-WORTHY: MK-5172 + MK-8742 ± RBV in GT1
Patients With Cirrhosis and in Null Responders
Wk 12
Wk 18
SVR4/8, %
Treatment-naive
patients with GT1
HCV and cirrhosis
(N = 123)
Patients with GT1
HCV and null
response to
pegIFN/RBV
(N = 130)
MK-5172 + MK-8742 + RBV (n = 31)
90
MK-5172 + MK-8742 (n = 29)
97
MK-5172 + MK-8742 + RBV (n = 32)
97
MK-5172 + MK-8742 (n = 31)
97
MK-5172 + MK-8742 + RBV (n = 31)
94
MK-5172 + MK-8742 (n = 33)
91
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.
100
97
AI443-014: Phase IIb Study of Daclatasvir +
Asunaprevir + BMS-791325 in Noncirrhotic GT1
HCV Patients
Stratified by GT1 subtype and
biopsy-confirmed cirrhosis
Wk 12
SVR12*, %
Tx-naive pts
with GT1 HCV
(N = 166)
Daclatasvir + Asunaprevir + BMS-791325 75 mg BID
(n = 80)
89
Daclatasvir + Asunaprevir + BMS-791325 150 mg BID
(n = 86)
90
Daclatasvir 30 mg BID; asunaprevir 200 mg BID
*Modified ITT analysis: missing data, breakthrough, relapse, or addition of P/R equals failure.
Everson GT, et al. AASLD 2013. Abstract LB-1.
Undetectable HCV RNA (%)*
SOF + RBV ± PegIFN Administered ≤ 48 Wks
at Physician’s Discretion
100
80
SVR4
SVR12
*Defined as LLOD or LLOQ, depending on center.
74
69
60
57
60
56
50
40
20
25/
36
16/
28
20/
27
12/
20
5/9
4/8
0
Overall
Response, n/N (%)
SOF + RBV
SOF + PEG/RBV
Overall
SOF + RBV
SOF + PEG/RBV
SVR2
SVR12
SVR4
SVR12
SVR4
SVR12
25/36 (69)
16/28 (57)
20/27 (74)
12/20 (60)
5/9 (56)
4/8 (50)
Relapse
2/36 (6)
4/28 (14)
1/27 (4)
2/20 (10)
1/9 (11)
2/8 (25)
On-treatment nonresponse
1/36 (3)
1/28 (4)
0
0
1/9 (11)
1/8 (13)
Death
8/36 (22)
7/28 (25)
6/27 (22)
6/20 (30)
2/9 (22)
1/8 (13)
SVR
Overall failure
Forns X, et al. AASLD 2013. Abstract 1084.
Outcomes in Patients With Cirrhosis
Trial
Regimen
COSMOS[1,2]
SMV + SOF ± RBV
Electron[3]
Duration, Wks
SVR in Advanced
Fibrosis, %
12-24
93-100
SOF + LDV
12
70
SOF + LDV + RBV
12
100
SOF + GS9669
12
100
SOF + LDV
12
65
SOF + LDV ± RBV
12
82-86
SOF + LDV ± RBV
24
100
Electron-2[4]
Child B
ION-2[5]
Turquoise-II[6]
GT1a
ABT-450/r + OBV + DSB ± RBV
12-24
89-94
GT1b
ABT-450/r + OBV + DSB ± RBV
12-24
99-100
1. Sulkowski M, et al. EASL 2014. Abstract O7. 2. Lawitz E, et al. EASL 2014. Abstract O165. 3. Gane EJ, et
al. AASLD 2013. Abstract 73. 4. Gane EJ, et al. EASL 2014. Abstract O6. 5. Afdhal N, et al. N Engl J Med.
2014;370:1483-1493. 6. Poordad F, et al. N Engl J Med. 2014;370:1973-1982.
Genotype 2
FISSION: SVR12 in Genotype 2 Patients by
Fibrosis Level
Wk 12
•
•
Randomized, open-label phase III trial
20% to 21% had cirrhosis; 72% had GT3
100
98
Genotype 2
82
91
SVR12 (%)
80
Treatmentnaive pts with
GT2/3 HCV
(N = 499)
Sofosbuvir 400 mg QD
+ RBV 1000-1200 mg/day
(n = 256)
PegIFN + RBV 800 mg/day
(n = 243)
62
60
40
20
n/N =
0
58/59
44/54
No Cirrhosis
10/11
8/13
Sofosbuvir + RBV
PegIFN + RBV
Cirrhosis
Gane E, et al. EACS 2013. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
Wk 24
FISSION: Better Tolerability Profile
With Sofosbuvir/RBV vs PegIFN/RBV
•
•
Grade ≥ 3 AEs: 7% with SOF/RBV vs 19% for pegIFN/RBV
Discontinuations due to AEs: 1% for SOF/RBV vs 11% for pegIFN/RBV
GT2/3 Pts, AEs Occurring in
≥ 15% in Either Arm, %
SOF/RBV
(n = 256)
PegIFN/RBV
(n = 243)
P Value
Fatigue
36
55
< .0001
Headache
25
44
< .0001
Nausea
18
29
.0057
Insomnia
12
29
< .0001
Rash
9
17
.0052
Diarrhea
9
17
.0075
Irritability
10
17
.0328
Decreased appetite
7
18
.0001
Myalgia
8
17
.0060
Pruritus
7
17
.0009
Influenzalike symptoms
3
18
< .0001
Chills
3
18
< .0001
Gane E, et al. EASL 2013. Abstract 5.
FUSION: Sofosbuvir + RBV by Fibrosis Level in
Treatment-Experienced GT2 Pts
• Randomized, double-blind, phase III trial
– 62% to 64% had GT3 HCV; 33% to 35% had cirrhosis; 75% to 76% were
previous relapsers
100
96
SOF + RBV for 12 wks
SOF + RBV for 16 wks
100
78
SVR12 (%)
80
60
60
40
20
n/N = 25/26 23/23
0
Jacobson IM, et al. N Engl J Med.
2013;368:1867-1877.
No Cirrhosis
6/10
7/9
Cirrhosis
Genotype 2
POSITRON: Sofosbuvir + RBV in GT2/3 IFNUnwilling/Intolerant/Ineligible Pts
• Randomized, double-blind, placebo-controlled phase III trial
No cirrhosis
Wk 12
SOF 400 mg QD +
RBV 1000-1200 mg/day
(n = 207)
Placebo
(n = 71)
92
94
80
SVR12 (%)
IFN-unwilling,
IFN-intolerant,
or IFN-ineligible
pts with
GT2/3 HCV
(N = 278)
100
Cirrhosis
60
40
20
0
85/92 16/17
GT2
Jacobson I, et al. EASL 2013. Abstract 61.
LONESTAR-2: Sofosbuvir + P/R for 12 Wks
in Treatment-Exp’d GT2/3 HCV Pts
• Single-arm trial of pts with treatment failure on P/R
• Approximately 50% with compensated cirrhosis
Wk 12
SOF 400 mg QD +
PegIFN wkly +
RBV 1000 mg or 1200 mg
100
SVR12 (%)
Pts with HCV
GT2 or GT3 and
previous
treatment
failure with P/R
(N = 47)
96
100
93
80
60
40
20
0
n/N = 22/23
GT2
All
Lawitz E, et al. AASLD 2013. Abstract LB-4.
13/14
9/9
GT2
F4
GT2
F0-3
SOF + GS-5816 in Treatment-Naive
Noncirrhotic Patients With GT1-6 HCV
•
•
•
Open-label phase II study
N = 154 patients randomized to 12 wks’ SOF + GS-5816 25 mg or 100 mg/day
GS-5816: investigational NS5A inhibitor
100
100
SOF + GS-5816 25 mg
SOF + GS-5816 100 mg
91
SVR12 (%)
80
60
40
20
0
n/N =
10/11
10/10
Genotype 2
Everson GT, et al. EASL 2014. Abstract O111.
Genotype 3
FISSION: SVR12 in Genotype 3 Patients
by Fibrosis Level
• Randomized, open-label phase III trial
• 20% to 21% had cirrhosis; 72% had GT3
Genotype 3
100
SVR12 (%)
80
71
61
Treatment-naive
patients with
GT2/3 HCV
(N = 499)
60
34
40
0
89/145
99/139
No Cirrhosis
13/38
Sofosbuvir 400 mg QD
+ RBV 1000-1200 mg/day
(n = 256)
PegIFN + RBV 800 mg/day
(n = 243)
30
20
n/N =
Wk 12
11/37
Sofosbuvir + RBV
PegIFN + RBV
Cirrhosis
Gane E, et al. EACS 2013. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
Wk 24
FUSION: SVR12 With Sofosbuvir + RBV
by Genotype and Fibrosis Level
• Randomized, double-blind, phase III trial
– 62% to 64% had GT3 HCV; 33% to 35% had cirrhosis; 75% to 76% were previous
relapsers
100
Sofosbuvir + RBV for 12 wks
Sofosbuvir + RBV for 16 wks
SVR12 (%)
80
63
61
60
40
37
19
20
0
14/38 25/40
5/26 14/23
Cirrhosis
No Cirrhosis
Genotype 3
Jacobson IM, et al. N Engl J Med.
2013;386:1867-1877.
VALENCE: Sofosbuvir + RBV for 24 Wks
in GT3 IFN-Naive/Ineligible/Tx Failures
• Phase III study in Europe
• Genotype 2/3, naive/experienced
100
Genotype 3
92
87
94
SVR12 (%)
80
60
60
40
20
0
86/92
12/13
87/100
27/45
Noncirrhotic
Cirrhotic
Noncirrhotic
Cirrhotic
Naive
Zeuzem S, et al. AASLD 2013. Abstract 1085.
Treatment
Experienced
Impact of Duration on Efficacy of SOF
in Treatment-Experienced GT3 Pts
FUSION: 12 wks of SOF/RBV
FUSION: 16 wks of SOF/RBV
VALENCE: 24 wks of SOF/RBV
100
87
SVR12 (%)
80
63
61
60
14/
23
27/
45
60
40
37
19
20
n/N =
0
14/
38
25/
40
87/
100
No Cirrhosis
5/
26
Cirrhosis
Genotype 3
Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. Zeuzem S, et al. N Eng J Med. 2014.
[Epub ahead of print]
SOF + RBV Retreatment in GT3 Patients
With Previous SOF + RBV Failure
• Open-label, nonrandomized trial
• 34% to 41% compensated cirrhosis
100
93
No cirrhosis
88
80
SVR12 (%)
Cirrhosis
74
60
47
40
20
0
n=
13/14
7/8
12 Wks of SOF + PEG/RBV
Esteban R, et al. EASL 2014. Abstract O8.
17/23
7/15
24 Wks of SOF + RBV
LONESTAR-2: Sofosbuvir + P/R for 12 Wks
in Treatment-Experienced GT3 HCV Pts
• Single-arm trial of pts with treatment failure on
P/R
• Approximately 50% with compensated cirrhosis
Pts with HCV GT2
or GT3 and
previous
treatment failure
with P/R
(N = 47)
Sofosbuvir 400 mg QD +
PegIFN + RBV 1000-1200 mg
(%)
SVR12(%)
SVR12
100
Wk 12
83
83
83
n/N = 20/24
10/12
10/12
GT3
All
GT3
F4
GT3
F0-3
80
60
40
20
0
• Similar rates of SVR12 in pts with and without
cirrhosis
Lawitz E, et al. AASLD 2013. Abstract LB-4.
EASL HCV Guidelines 2014: Genotype 2-6
Genotype
Genotype 2*
Options for Therapy
Sofosbuvir + ribavirin: 12 wks (16-20 weeks in cirrhotic patients, especially treatment experienced) (A1)
PegIFN/ribavirin + sofosbuvir: 12 wks for cirrhotic and/or treatment-experienced patients (B1)
Sofosbuvir + ribavirin: 24 wks (unsuitable for treatment-experienced cirrhotics, no specific alternative
proposed) (A2)
Genotype 3*
PegIFN/ribavirin + sofosbuvir: 12 wks (A2)
Sofosbuvir + daclatasvir: 12 wks (24 wks for treatment-experienced patients) (B1)
PegIFN/ribavirin + sofosbuvir 12 weeks (B1)
PegIFN/ribavirin + simeprevir: 12 wks, followed by 12 wks of pegIFN/ribavirin in previously untreated
patients & prior relapsers (B1), or 36 wks of pegIFN/ribavirin in previous partial responders & null
responders (B1)
Genotype 4*
PegIFN/ribavirin + daclatasvir: 12 wks followed by 12 wks of pegIFN/ribavirin alone or a further 12 wks of
pegIFN/ribavirin + daclatasvir (response-guided therapy) (B1)
Sofosbuvir + ribavirin: 24 wks for interferon-intolerant patients (C2)
Sofosbuvir + simeprevir: 12 wks (ribavirin may be added in previous nonresponders and cirrhotics) (B2)
Sofosbuvir + daclatasvir: 12 wks in previously untreated patients; 24 wks in treatment-experienced
patients (ribavirin may be added in previous nonresponders and cirrhotics) (B2)
Genotype
5/6*
PegIFN/ribavirin + sofosbuvir 12 wks (B1)
Sofosbuvir + ribavirin: 24 wks for interferon-intolerant patients (C2)
*In settings where recommended options are not available, treatment with pegIFN/ribavirin remains acceptable.
EASL. J Hepatology. 2014;60:392-420.
Daclatasvir + Sofosbuvir ± Ribavirin
for GT2/3 HCV Treatment-Naive Patients
Wk 24
Rx naive
GT2 or GT3
(N = 44)
n = 16
SOF × 7 days, then DCV + SOF
SVR12 = 88%
n = 14
DCV + SOF
SVR12 = 93%
n = 14
DCV + SOF + RBV
SVR12 = 86%
Phase III Trial (NCT02032901): Currently enrolling
Wk 12
Naive or
experienced
GT3
(N = 150)
Drug Dosing
DCV + SOF
DCV 60 mg once daily
SOF 400 mg once daily
Sulkowski MS, et al. N Engl J Med. 2014;370:211-221. ClinicalTrials.gov.
ELECTRON 2: SOF/LDV FDC ± RBV in
Diverse Hard-to-Treat Patients
• Partially randomized, open-label phase II trial
Treatment-naive
patients with GT3 HCV
(N = 51)
Wk 12
SOF/LDV FDC (n = 25)
64
SOF/LDV FDC + RBV* (n = 26)
100
Phase II Trial (NCT01826981): Currently enrolling
•
SVR12, %
Genotype 3, treatment-naive and treatment-experienced patients
– Study regimens include SOF/LDV ± RBV, SOF + GS-5816 ± RBV
*Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day.
Additional nonrandomized arms conducted in patients with GT1 HCV not shown.
Gane EJ, et al. EASL 2014. Abstract O6. Reproduced with permission.
Antiviral Activity of Simeprevir in
Patients With Genotypes 2-6 HCV
• TMC435-C202: open-label phase IIa study
Mean (± SE) Change From
Baseline in HCV RNA (log10 IU/ml)
• Simeprevir active against all HCV genotypes except GT3
Simeprevir 200 mg QD
1
PegIFN/RBV
Genotype
Genotype
Genotype
Genotype
Genotype
0
-1
-2
-3
-4
-5
-6
10h 2 3 4 5 6 7 8 9 10 11
Time (Days)
Moreno C, et al. J Hepatol. 2012;56:1247-1253.
21
37-42
2
3
4
5
6
Future treatment of hepatitis C
• IFN-free and partially RBV-free
• 8–12 (24) weeks of therapy
• Different regimens for different genotypes
• Response rates >>90%
•
Obiettivi e strategie di un
futuro IFN-free
•
Ottimizzare la gestione
clinica della monoinfezione
HCV oggi
IFN free DAA will expand the pool of
treatable patients
Mild
Severe
Decomp
HCV chronic disease spectrum
Currently treated
We must strive to obtain appropriate and effective
treatment for all patients
Factors affecting treatment choice
Disease
stage/type
Probability
of SVR
Urgency of
HCV clearance
Inability to
tolerate P/R
Costs and availability
of drug (s)
HCV related
extrahepatic
disease
Costs and
availability of
drug (s)
Patient’s
preference
Comorbidity
Expectancy
for newer
regimens
HCV therapy 2014: three different scenarios
•
•
•
•
Access to new DAAs after «breakthrough»registration mostly unrestricted
Off-label and combo use feasible (ATU)
P/R containing regimens on the way out
Modest warehousing of patients for even better regimens
•
•
•
•
P/R containing regimens, mostly with 1st generation PIs, available
Access to new DAAs absent or severely limited (EAPs, RCTs)
Off-label and combo use scarcely feasible
Extensive warehousing of patients for IFN free DAAs
•
•
•
•
P/R available as the only therapeutic options
1st generation PIs unavailable
Access to new DAAs absent
Warehousing limited
Who should be treated: EASL recommendations 2014
In principle, all patients with chronic HCV
infection, but in a situation of limited availability:
• F3-F4: Priority
• F2: Reasonable
• F0-F1: Debatable
Informed deferral of treatment for patients with mild disease
EASL Online Recommendations on Treatment of Hepatitis C, April 2014
How to optimize HCV therapy in a
limited-resource scenario
• Is still a role left for dual P/R therapy?
• What is the cost-effective use for triple therapy with
1st generation PIs?
• How to allocate money on sofosbuvir and simeprevir
(daclatasvir, ABT450/R-333-267…)?
Identification of naïve HCV Gt1 patients who may
benefit from dual therapy with P/R
SVR rates following PegIFN/RBV in 1045 HCV genotype 1 patients.
(A) Stratified according to independent predictors for SVR at baseline;
(B) Stratified according to baseline predictors and on-treatment virologic response.
A. Andriulli, et al J Hepatol 2013
Identification of naïve HCV Gt 1 patients who may
benefit from dual therapy with P/R
0
50
426/1259 (34%)
<25%
Outcome after P/R
Strategy
SVR
68 (16%)
- No P/R
- Treat with 1st generation
triple therapy (BOC or TPV)
- Wait for new regimens
when feasible
100
80% 188/1259 (15%)
Outcome after P/R
SVR
167 (89%)
Andriulli et al, submitted
Treatment decisions for 2014
in a limited-resource scenario
Can be treated with P/R (all naives):
• Gt 1, F0 to F2 plus IL 28 cc or RVR after
lead-in, no factors reducing IFN
responsiveness (obesity, metabolic
syndrome)
Expected
SVR
>80%
Priority
Low
• Gt 2 and 3, F2 - F3
50 to 70%
High
• Gt 4, 5, 6, F2 - F3
40 to 60%
High
How to optimize HCV therapy in a
limited-resource scenario
• Is still a role left for dual P/R therapy?
• What is the cost-effective use for triple therapy with
1st generation PIs?
• How to allocate money on sofosbuvir and simeprevir
(daclatasvir, ABT450/R-333-267…)?
Cost-effective use of 1st generations PIs for HCV Gt 1
Telaprevir
Boceprevir
Dual
No CC
No RVR
RVR - CC
Relapsers
+++
++
Partial responders
++
+
>1 log drop HCVRNA in lead-in
>1 log drop HCVRNA in lead-in
Naive
Null responders
Cammà et al. Hepatology 2012
Cammà al. J Hepatol 2013
Predictors of SVR to Boc in HCV Gt 1 naive pts
1
2
3
4
Poordad et al. Gastroenterology 2012
Boceprevir plus PR in HCV Gt 1 treatment experienced F3-F4:
SVR according to week 8 virological response
80
HCV RNA Undetectable
HCV-RNA < 1000 UI/mL
HCV RNA Detectable
HCV-RNA > 1000 UI/mL
72,3%
67,1%
70
60
50
40
32,9%
27,7%
30
20
10
115
159
73
222
0
SVR
44
159
149
222
No SVR
PPV=72,3%
100
90
80
70
60
50
40
30
20
10
0
91,7%
55,3%
44,7%
184
333
8,3%
4
48
SVR
149
333
44
48
No SVR
NPV=91,7%
Bruno S et al. , submitted
Treatment decisions for 2014
in a limited-resource scenario
Can be treated with P/R plus a 1st
generation PI (BOC or TPV):
•
Naive Gt 1, F3 - F4 plus IL 28 not cc or no RVR after
lead-in
Expected
SVR
Priority
50 to 65%
High
70 to 85%
High
•
Gt 1 relapsers to P/R, F3 - F4
•
Gt 1 partial responders to P/R, F3 - F4
40 to 50%
High
•
Naive Gt 1 with HIV coinfection, F3 - F4
50 to 65%
High
How to optimize HCV therapy in a
limited-resource scenario
• Is still a role left for dual P/R therapy?
• What is the cost-effective use for triple therapy with
1st generation PIs?
• How to allocate money on sofosbuvir and simeprevir
(daclatasvir, ABT450/R-333-267…)?
Direct costs of HCV Gt1 therapy in naïves
(assuming treatment of F2 to F4)
Cost
PegIFN/
RBV
48 wks
BOC/TPV Sofosbuvir Simeprevir Sofosbuvir Sofosbuvir +
+ P/R
+ P/R
12wks +
+ RBV
simeprevir 
36-48 wks
12 wks P/R 48 wks 24 wks
RBV 12 wks
- drugs
6-9.000
25- 30.000
46-51.000
44.000
85-98.000
100.000
-monitoring
8.000
10-12.000
4.000
8.000
6.000
5.000
- EPO, G-CSF, blood
1.000
20-25.000
500
1.00
≈0
≈0
15-18.000
55-67.000
49-55.500
53.000
91-103.000
105.000
Expected efficacy
≈ 40%
≈ 65%
>90%
>90%
>70%
>95%
Euros for 1 SVR
≈ 3845.000
≈ 85103.000
≈ 5460.000
≈ 59.000
≈ 110130.000
≈ 110.000
tx, others
TOTAL
Direct costs of HCV Gt2 therapy in naïves
(assuming treatment of F2 to F4)
PegIFN/RBV
24 wks
Sofosbuvir + P/R
12 wks
- drugs
6.000
46-51.000
-monitoring
5.000
4.000
-EPO, G-CSF, blood
tx, others
1.000
500
≈ 12.000
49-55.500
85%
>90%
≈ 14.000
≈ 54-60.000
Cost
TOTAL
Expected efficacy
Cost (Eu) for 1 cure
Cost-Effectiveness of Sofosbuvir-Based Triple Therapy for
Untreated Patients With Genotype 1 Chronic Hepatitis C
In untreated Gt 1 chronic hepatitis C patients, at a
willingness-to-pay threshold of Eu 25,000 per life year
gained, sofosbuvir:
• was cost effective compared with boceprevir in all
strategies with the exception of cirrhosis and IL28B
CC patients
• was cost effective compared with telaprevir in IL28B
non-CC and Gt 1a patients, but not cost-effective in
IL28B CC and in cirrhosis
Petta S et al. , Hepatology 2014
THERAPY OF HEPATITIS C IN 2014 :
WHOM TO TREAT
OLISTIC VIEW : all infected individuals
RISK / BENEFIT
REALISTIC VIEW : treat according to
COST / BENEFIT