Athens, March 24th 2018
Optimal current treatment of hepatitis C
Pr Christophe Hézode, Henri Mondor Hospital, Paris-Est University, Créteil, France
Links of interest
Adviser, speaker, investigator for:
Abbvie, BMS, Gilead, Janssen, MSD
Optimal HCV treatment
✓High efficacy (SVR > 95%)
✓High level of evidence
✓ Ribavirin free
✓ Very good safety profile
✓Oral treatment
✓ Easy to take
✓ Limited DDIs
✓ Pangenotypic
Optimal but non pangenotypic options
SOFOSBUVIRNucleotide NS5B
Polymerase Inhibitor
LEDIPASVIRNS5A Inhibitor
- Pangenotypic antiviral activity
- High barrier to resistance
Antiviral activity on genotypes 1, 4, 5, and 6
Non pangenotypic combination
Once-daily, oral fixed-dose combination tablet
Real-world cohorts support ION-3 clinical trial data in >6000 GT1 patients
Kowdley KV, et al. N Engl J Med 2014;370:1879-88; Buggisch P, et al. J Hepatol 2018, in press
0
20
40
60
80
100
0
20
40
60
80
100
8 weeks
12 weeks
LDV/SOF for 8 weeks in naïve non-cirrhotic GT1 patients
97 98.6 97.8 98.7 98
ION-3 German Hepatitis C-Registry (DHC-R)
119/123 707/717 311/316 739/749 389/397
ION-3 criteria* ION-3 criteria* SmPC criteria**
*TN, NC, VL<6 millions**TN, NC
ELBASVIRNS5A Inhibitor
GRAZOPREVIRProtease Inhibitor
Antiviral activity against GT1 and GT4 including most RASs
Negligible renal elimination
No food effect
Once-daily, oral fixed-dose (50/100 mg) combination tablet
Non pangenotypic combination
Efficacy of grazoprevir/elbasvir for 12 weeks in selected groups of patients
0
20
40
60
80
100
GRZ/EBR 12 semaines GRZ/EBR 12 semaines GRZ/EBR 12 semaines
98.6 99.396.0
SVR
12
(%
)
12 weeks
GT1b
Compensated
disease
12 weeks
GT1a
HCV RNA ≤0.8 M
Compensated
disease
12 weeks
GT4
Naïve
Compensated
disease
Zeuzem S, et al. AASLD 2016, Abs 874; Oliveira A, et al, EASL 2017, Abs THU-228; Asselah T, et al. Liver Int 2018
1040/1055 135/136 97/101
C-SURFER: EBR + GZR for 12 weeks in GT1 patients with stage 4-5 chronic kidney disease
Roth D et al. Lancet 2015;386:1537-45
First controlled study in patients with renal insufficiency treated with DAAs•
Stratification according to diabetes (• 3̴5%) and hemodialysis ( 7̴5%) status
Efficacy of EBR/GZR in patients with chronic HCV infection and inherited blood disorders
Hezode C et al, Hepatology 2017;66:736-45
SVR12 in the immediate treatment group (FAS)
Study design
*Compensated liver disease
Combinations Patients Patients Patients Patients
Sofosbuvir/Ledipasvir8 weeks
Genotype 1Naïve
No cirrhosis- -
Grazoprevir/Elbasvir12 weeks
Genotype 1b* Genotype 1a*VL <800.000
Genotype 4*Naïve
Severe CKD*(GFR<30)
Genotype 1
Summary for non pangenotypic options
Optimal and pangenotypic options
SOFOSBUVIRNucleotide NS5B
Polymerase Inhibitor
VELPATASVIRNS5A Inhibitor
- Pangenotypic antiviral activity
- High barrier to resistance
Pangenotypic antiviral activity including most RASs
Once-daily, oral fixed-dose(400/100 mg) combination tablet
Pangenotypic combination
28/28 25/27
Phase 2 data: SOF/VEL 8-Week treatment duration in treatment-naïve genotype 1 patients without cirrhosis
SVR
12
(%
)
3 relapses1 D/C for AE
5 relapses 3 relapses 5 relapses1 LTFU
28/28 25/27
26/30
25‒
25/30 26/29 25/31
25+
100‒
100+
VEL, mg
RBV
Everson G et al. Ann Intern Med 2015
ASTRAL-1, -2, -3: SOF/VEL for 12 weeks in GT1–6 treatment-naive and -experienced* patients with and without cirrhosis
D/C, discontinued; LTFU, lost to follow-up.* Patients treated with pegIFN/RBV ± PI or IFN ± RBV. Feld JJ, et al. N Engl J Med 2015;373:2599–607
Foster GR, et al. N Engl J Med 2015;373:2608–17
98 99 100 97 10095
0
20
40
60
80
100
GT1 GT2 GT4 GT5 GT6 GT3
nN
323328
237238
116116
4141
3435
264277
12 weeks
ASTRAL-3 ASTRAL-1 & -2
SVR
12
(%
)
2 relapse1 D/C2 LTFU
1 D/C 1 death11 relapse
2 LTFU
*
0
20
40
60
80
100
No NS5A RAS NS5A RAS notY93H
Y93H
98 97
86
411/420 33/34 19/22
SVR
12
(%
)
Impact of NS5A RAS on efficacy of SOF + VEL for 12 weeks in DAA-naïve GT3 patients (pooled ASTRAL-POLARIS analysis)
Hezode C, et al. J Hepatol 2017, Dec 5
HCV GT Patients, N SVR % (n/N) HCV Subtype Patients, n SVR % (n/n)
1 694 99.0% (687/694)
1a 484 98.9% (479/484)
1b 206 99.5% (205/206)
1e 1 100.0% (1/1)
1h 1 100.0% (1/1)
1novel or mixed 2 (1/2)
2 316 100.0% (316/316)
2a 60 100.0% (60/60)
2b 192 100.0% (192/192)
2c 18 100.0% (18/18)
2d 2 (2/2)
2e 1 (1/1)
2i 9 (9/9)
2j 1 (1/1)
2k 5 100.0% (5/5)
2 novel or mixed 9 100.0% (9/9)
3 478 97.5% (466/478)
3a 472 97.5% (460/472)
3b 3 (3/3)
3g 2 (2/2)
3k 1 (1/1)
HCV Genotype and subtype and treatment outcome to SOF/VEL (pooled ASTRAL-POLARIS)
.
Hezode C, et al. J Hepatol 2017, Dec 5
• Hézode C, et al. J Hepatol 2017, Dec 5HCV GT Patients, N SVR % (n/N) HCV Subtype Patients, n SVR % (n/n)
4 197 99.5% (196/197)
4a113 99.1% (112/113)
4b 2 (2/2)
4c 2 (2/2)
4d41 100.0% (41/41)
4f 3 (3/3)
4g 1 (1/1)
4k 5 100.0% (5/5)
4n 7 100.0% (7/7)
4o 8 100.0% (8/8)
4r 3 (3/3)
4t 1 (1/1)
4 novel or mixed 11 100.0% (11/11)
HCV Genotype and subtype and treatment outcome to SOF/VEL (pooled ASTRAL-POLARIS)
Hezode C, et al. J Hepatol 2017, Dec 5
8388
50
10094 96 85 100
86
92
50
86
0
20
40
60
80
100
Overall GT1 GT3 GT 2, 4, and 6
SVR
12
(%
)
SOF/VEL 12 wk SOF/VEL+RBV 12 wk SOF/VEL 24 wk
SOF/VEL + RBV resulted in highest SVR12 in patients with decompensated liver disease
75/90 82/87 77/90 60/68 65/68 65/71 7/14 11/13 6/12 GT2 4/4GT4 4/4
GT2 4/4GT4 2/2
GT2 3/4GT4 2/2GT6 1/1
Sofosbuvir, velpatasvir and ribavirin in patients with decompensated cirrhosis
Curry MP, et al. N Engl J Med 2015;373:2618–28
SOFOSBUVIRNucleotide NS5B
Polymerase Inhibitor
VELPATASVIRNS5A Inhibitor
Pangenotypic antiviral activity including most RASs
Pangenotypic combination
VOXILAPREVIRNS3 Protease Inhibitor
6 patients with relapse (1 GT1a, 4 GT3 et 1 GT4)
97 96 100 100 95 91100 100
0
20
40
60
80
100
GT 1 GT 1a GT 1b GT 2 GT 3 GT 4 GT 5 GT 6
4545
2022
7478
66
97101
55
11
146150
GT1a GT2 GT3 GT4 GT5 GT6GT1bGT1
SVR
12
(%
)
SVR12 according to genotype
POLARIS-1: Sofosbuvir/velpastasvir/voxilaprevirfor 12 weeks in DAA-experienced patients with 1st
generation NS5A inhibitor
Bourlière M, et al. N Engl J Med 2017;376:2134-46
PIBRENTASVIRNS5A Inhibitor
GLECAPREVIRNS3 Protease
Inhibitor
Pangenotypicantiviral activity including most RASs
High barrier to resistance
Negligible renal elimination
G/P is co-formulated and dosed once daily as three 100 mg/40 mg pills for a total dose of 300 mg/120 mg
Pangenotypic combination
Integrated efficacy analysis: G/P for 8 Weeks in GT1–6 treatment-naive and -experienced* patients without cirrhosis
• BT, breakthrough; mITT, modified intent-to-treat.* Includes patients with prior SOF use (8-week G/P, n = 7); † One GT6 patient initially with missing SVR12 data is excluded from this analysis; ‡ All GT3 patients were treatment naive. Bernstein D, et al. ACG 2017 (oral presentation)
98 99 98 95 95100 10099 99 99 97 100 100 100
0
20
40
60
80
100
Overall GT1 GT2 GT3 GT4 GT5 GT6
mIT
T, S
VR
12
(%
)
‡
470471
202204
198204
5959
22
12†
12943†
952nN
2 BT
7 RL
5 D/C
7 LTFU
470474
202205
198208
5962
22
1313
944965
1 BT
2 D/C
1 LTFU
2 RL
2 D/C
1 BT
5 RL
4 LTFU
1 D/C
2 LTFU
ITT mITT
Integrated efficacy analysis: G/P for 12 weeks in GT1–6 treatment-naive patients with cirrhosis
Krishnan P, et al. J Hepatol 2017; 66(Suppl):S500 (poster presentation FRI-205)
98 97 100 99 100
0
20
40
60
80
100
Overall GT1 GT2 GT3 GT4–6
ITT,
SV
R1
2 (
%)
119126
6971
2626
6465
22
2020
179182
nN
SURVEYOR-II, Part 3: G/P for 12 or 16 weeks in GT3 patients with prior treatment failure and/or cirrhosis
• *Includes SOF-experienced patients Wyles DL, et al. AASLD 2016
9196 98 96
0
20
40
60
80
100
1 2 3 4
SVR
12
(%
)
TE*Non-cirrhotic
12 weeks
TE*Non-cirrhotic
16 weeks
TNCirrhotic12 weeks
TE*Cirrhotic16 weeks
2 relapses 1 relapse 1 LTFU1 breakthrough
1 relapse
2022
2122
3940
4547
nN
Efficacy
Pol S, et al. EASL 2017: SAT27* mITT was not reported in this analysis.
98 98 98 97 98
0
20
40
60
80
100
Overall CKD1 CKD2 CKD3 CKD4-5
SVR
12
(%
) -
mIT
T
nN
21882238
10241045
3536
101103
10281054
No impact of the grade of renal insufficiency on Glecaprevir / Pibrentasvir efficacy
Naïve / Treatment-experiencedŦ
Ŧ Naive and treatment-experienced patients for GT1,2,4,5,6
Glecaprevir/pibrentasvir in patients with kidney disease
MAGELLAN: Glecaprevir/pibrentasvir (G/P)in DAA-experienced patients
Poordad F, et al. Hepatology 2017, Nov 20
weeks
SVR12
0 12 24
G/P
20
n = 44 (43 GT1, 1 GT4)
12 weeks
SVR12G/P
16 28
n = 47 (43 GT1, 3 GT4)
16 weeks
Ran
do
mis
atio
n1
:1
0
20
40
60
80
100
SVR
12
, %
12 weeks
89
16 weeks
91
3944
4347
1 (2 %) 4 (9 %)
4 (9 %) 0
Breakthrough
Relapsee
Impact of baseline RASs
0
20
40
60
80
100
RV
S12
, % p
atie
nts
None
1313
NS3alone
22
45
1313
G/P - 12 weeks G/P - 16 weeks
BaselineRAS
2024
2223
NS5Aalone
100 80 100 2583 96100 100
44
14
3 relapses 1relapse
NS3 +NS5A
None NS3alone
NS5Aalone
NS3 +NS5A
Patients GlecaprevirPibrentasvir
SofosbuvirVelpatasvir
No cirrhosisAll genotypes
8 weeks* 12 weeks
Compensated cirrhosis All genotypes
12 weeks* 12 weeks
Peg-IFN/RBV experiencedGenotype 3
No 12 weeks
Severe CKD (GFR <30 ml/mn)All genotypes
8-12 weeks No
Child-Pugh B7-9 cirrhosisAll genotypes
No + RBV 12 weeks
1st generation DAA failureAll genotypes
No + Voxilaprevir12 weeks
Summary for pangenotypic options
*Except GT3 PR treatment-experienced
Thank you very much for your attention