Management of HCV G4 Kasr Alainy

Management of Patients
with HCV Genotype 4
Cairo, February 23, 2017
Imam Waked, MD, FAASLD
Professor of Medicine
National Liver Institute, Egypt

Global Distribution of G4
G4
14%
G5
1%
G6
2%
G2
14%
G3
21%
G1
47%
• G4 mainly in Egypt, Middle East, Sub-Saharan Africa
• Prevalence increasing in Europe: 15% in Belgium, 13.9% in Greece,10.1% in Switzerland
• Over-represented in the HCV–HIV co-infected population, In the EUROSIDA cohort 14.7% in central,
16.2% in southern Europe, 21.8% in France, 22.8% in Spain
Messina J, et al. Hepatology. 2015 Alberti A, et al., J. Med. Virol. 2016

SVR12 (%)
Sofosbuvir-RBV
• 2 studies SOF-RBV 12 or 24
weeks
• G4 patients of Egyptian
ancestry in the US (n=60)
• G4 patients in Egypt (n=103)
• >30% with cirrhosis
• >40% PEG-RBV experienced
100
80
60
40
20
0
68
21
31
US Study
n=60
12 weeks 24 weeks
93 90
77
27
29
40
52
46
51
Egypt Study
n=103
Ruane PJ, et al. J Hepatol, 2015 Doss W. et al. J Hepatol. 2015

SVR-12 (%)
SVR12 %
Sofosbuvir-Ledipasvir
NIAID SYNERGY: SOF-LDV in HCV G4
Treatment-Naive and -Experienced
Patients
100 95
90
80
70
60
50
40
30
20 20
10 21
0
SVR12
One patient dropped out
Kohli A, et al. Lancet Infect Dis. 2015
• 44 patients: 22 treatment naïve, 22 treatment experienced
• G4 subtypes: 4a= 25; 4d = 10; other subtypes, n = 9.
• 10 (23%) had compensated cirrhosis.
100
90
80
70
60
50
40
30
20
10
0
95
21
22
Tretament
Naïve
91
20
22
Treatment
experiencd
100
10
10
. With
cirrhosis
91 93
31
34
Without
cirrhosis
Abergel A et al. Hepatology 2016
41
44
.. Overall

SVR12, %
Sofosbuvir-Ledipasvir
N=355
Treatment naïve,
n=170
Week 0 8 1
2
LDV/SOF
LDV/SOF
LDV/SOF + RBV
LDV/SOF + RBV
20
SVR12
24
LDV/SOF 8 wk LDV/SOF + RBV 8 wk
LDV/SOF 12 wk LDV/SOF + RBV 12 wk
95 90 98 98 94 100 100
IFN experienced,
n=74
LDV/SOF
LDV/SOF + RBV
SOF experienced,
n=11
LDV/SOF + RBV
• Randomized, open-label study at 4 sites in Egypt
• Treatment naïve and IFN experienced patients
• Randomized to treatment, stratified by presence/absence of
cirrhosis
• Approximately 25% with compensated cirrhosis
• SOF experienced patients
• prior treatment with SOF + RBV for 12 or 24 weeks or LDV/SOF ±
RBV for 8 weeks
• assigned to LDV + SOF + RBV for 12 weeks
Shiha G. et al., AASLD 2016
41
43
38
42
42
43
Treatment Naïve
41
42
34
36
38
38
IFN
Experienced
11
11
SOF
Experienced
6

SVR12 %
Sofosbuvir-Velpatasvir
• ASTRAL-1:
• Treatment-naive and
treatment-experienced
patients
• G-4: 116 Patients
• Randomized 5:1 to 12-weeks
of SOF-VEL or placebo
• Subtypes:
• 16 G4: 4a, 4b, 4c, 4d, 4f, 4k, 4l, 4n, 4o, 4r,
4t, 4ad, 4ak, 4alv, 4dr, 4pt
Feld JJ et al., N Engl J Med. 2015
100
90
80
70
60
50
40
30
20
10
0
116
116
All Patients
27
27
52
52
All Patients With cirrhosis PEG-RBV
experienced

SOF-RBV, SOF-LED, SOF-VEL
• Integrated Analysis of SOF+RBV, LDV/SOF or SOF/VEL for the
Treatment of Genotype 4 Chronic HCV Infection
100%
80%
60%
40%
20%
0%
Asselah T. et al. AASLD 2016
74%
SOF-RBV
12 wks
Study 114, 138
n=83
SVR12 in Patients with HCV-G4
91% 95% 100%
SOF-RBV
24 wks
Study 114, 138
n=80
SOF-LDV
12 wks
Synergy
n=73
SOF-VEL
12 wks
Astral 1
n=116

SOF-VEL-VOX
NS-5A
Experienced
DAA
Naiive
Bouliere M. et al. AASLD 2016, Jacobson I. et al. AASLD 2016

SVR12 %
Grazoprevir-Elbasvir
EBR + GZR + RBV 12 wks
• C-SCAPE
• 12 weeks GZR + EBR with or
without RBV
• Treatment-naïve, non-cirrhotic
genotype 2,4,5, and 6.
• G4: 20
100
90
80
70
60
50
40
30
20
10
0
100
10
10
G4
EBR + GZR 12 wks
90
9
10
Brown A. et al. EASL 2015

SVR 12 (%)
Grazoprevir-Elbasvir
• C-EDGE
100
90
80
70
60
50
40
30
20
10
0
100
18
18
96
27
28
78
7
9
12 weeks 12 weeks 12 weeks 12 weeks + RBV 16 weeks 16 weeks + RBV
93
14
15
60
3
5
100
8
8
C-EDGE TN
Treatment
Naive
C-EDGE
HIV Coinfection
C-EDGE TE
Treatment Exp.
Zeuzem S et al. Ann Intern Med. 2015 Rockstroh J et al. Lancet HIV 2015 Kwo P et al. EASL 2015.

SVR-12 %
Sofosbuvir-Simeprevir
• The PLUTO trial:
• 40 patients G4, SVR12: 100%
• The OSIRIS trial: 100 92
F0-F3
n=40
F4
n=23
SOF+SMV 8 weeks
SOF + SMV 12 weeks
SOF + SMV 12 weeks
0 8 12 24
Buti M et al, EASL 2016 El-Raziky et al. J Viral Hepatitis, 2016
90
80
70
60
50
40
30
20
10
0
58
63
75
15
20
Overall 8 weeks 12 weeks
F0-F3
100 100
20
20
23
23
12 weeks
F4

Pariteprevir-ritonavir-Ombitasvir
Agate I: Study Design
• Multinational
• HCV-GT-4 with compensated
cirrhosis
Agate II: Study Design
• Patients living in Egypt with HCV GT4 infection
without cirrhosis or with compensated cirrhosis
• N=160 Tx-naïve and prior PegIFN/RBVexperienced
HCV GT4
Naive or
Peg/RBV
Exp
12 weeks
2D+RBV: N=59
16 weeks
2D+RBV: N=61
No cirrhosis,
naive or
experienced
With Cirrhosis,
naive or
experienced
2D + RBV (n=100)
2D + RBV (n=31)
2D + RBV (n=29)
0 12 16
Week
All arms received 2-DAA OBV/PTV/r once-daily with weight based RBV.
Asselah et al. Lancet Gastro Hep. 2016 Waked et al. Lancet Gastro Hep. 2016
0 12 16
24

Pariteprevir-ritonavir-Ombitasvir
Asselah et al. Lancet Gastro Hep. 2016 Waked et al. Lancet Gastro Hep. 2016

SVR12 %
SVR-12 %
Pariteprevir-ritonavir-Ombitasvir
Agate I: Results
Agate II: Results
100
90
80
70
60
50
40
30
20
10
0
97 98
57
58
60
61
12 Weeks 16 Weeks
100
90
80
70
60
50
40
30
20
10
0
94 97
94
100
No cirrhosis
12 weeks
30
31
Compensated
cirrhosis
12 weeks
93
27
29
Compensted
cirrhosis
24 weeks
Asselah et al. Lancet Gastro Hep. 2016 Waked et al. Lancet Gastro Hep. 2016

Pariteprevir-ritonavir-Ombitasvir
Agate II: Liver Tests
Waked et al. AASLD 2016

Pariteprevir-ritonavir-Ombitasvir
SVR12
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
100%
France
ANRS HEPATHER
n=54
96.20% 96%
Spain
Real Life
n=122
Saudi Arabia
Real Life
n=117
Fontaine H. et al. AASLD 2016, Crespo J et al, AASLD 2016, Alswat K, et al. AASLD 2016

Gelcaprevir-Pibrentasvir (GP)
Surveyor 4
G2, 4-6, Without cirrhosis G/P 8 wks
Expedition 4
G1-6, Renal impairment, G/P 12 wks,
GT4: n= 20
Hassanein T. et al. AASLD 2016, Gane E. et al. AASLD 2016

Sofosbuvir + Daclatasvir
• ALLY-1: SOF+DCV in advanced cirrhosis or post-LTx
• 4 G4 patients, SVR-12 100%
• ALLY-2: SOF+DCV in HIV coinfection:
• 3 G4 patients, SVR12 100%
• ANRS CUPILT: Post LTx
• 11 G4 patients, SVR12 91% (10/11)
• Europe: Advanced Liver Disease, real world:
• 19 G4 patients, SVR12 100%
Poordad et al. Hepatology. 2016 Wyles DL, et al. N Engl J Med. 2015 Coilly et al., J Hepatol. 2016
Welzel TM, et al. Gut 2016

SVR 12 (%)
Outcome of DAA Treatment in Egypt: 2015-2016
100%
80%
95%
96% 98% 97% 95%
76%
60%
40%
20%
0%
SOF-PEG-RBV
12 weeks
n=16,418
SOF-PEG-RBV
12 weeks
SOF-RBV
24 weeks
n=8,091
SOF-RBV
24 weeks
SOF-SMV
12 weeks
n=10,747
SOF-SMV
12 weeks
SOF-DCV
12 weeks
n=43,870
SOF-DCV
12 weeks
SOF-DCV-
SOF-DCV-RBV
12 weeks
n=29,581 RBV
12 weeks
Total
n=109,572
Number 17,283 8,091 10,747 43,870 29,581 109,572
SVR12 # (%) 16,418 6,149 10,339 43,015 28,711 104,633
Non-response # (%) 432 970 290 430 590 2,712
Relapse # (%) 432 970 118 425 280 2,225
Total

SVR 24 (%)
Sofosbuvir + Ravidasvir
• 300 patients
• 130 (43%) with
cirrhosis
100.0
80.0
98
92
100 96
• 50% treatment naive
• 12 weeks SOF+RVD
+/-RBV
• Experienced with
cirrhosis: 16 wks
+RBV
60.0
40.0
20.0
0.0
167
170
No
cirrhosis
87
95
cirrhosis
12 weeks
35
35
cirrhosis
16 weeks
289
300
Overall
Esmat et al. EASL 2016

http://www.hcvguidelines.org, accessed September 10, 2016
AASLD Recommendations
• G4: without and with compensated-cirrhosis
• PAR-r-OMB + RBV 12 weeks
• SOF-VEL 12 weeks
• SOF-LDV 12 weeks
• GZR-EBR 12 weeks (treatment naïve or PEG-RBV relapse)
16 weeks + RBV (PEG-RBV on-treatment failure
(null response or breakthrough)

EASL 2016
EASL Recommendations 2016
Treatment of HCV-mono-infected or HCV/HIV co-infected patients
Genotype 4
Previous
Treatment
SOF-
LDV
SOF-
VEL
OMB-
PAR-r
GRZ-
ELB
SOF-
DCV
SOF-
SMV
Naive
12 wk
No RBV
12 wk
No RBV
12 wk
WITH RBV
12 wk
No RBV
12 wk
No RBV
12 wk
No RBV
PEG-RBV
12 wk
with RBV
or
24 wk
NO RBV
12 wk No RBV if
RNA 800,000
12 wk
with RBV
or
24 wk
NO RBV
12 wk
with RBV
or
24 wk
NO RBV

EASL Recommendations 2016
Retreatment of HCV-mono-infected or HCV/HIV co-infected patients who failed
prior DAA therapy: Genotype 4
Previous
Treatment
SOF-
LDV
SOF-
VEL
OMB-
PAR-r
GRZ-
ELB
SOF-
DCV
SOF-
SMV
SOF-
OMB-
PAR-r
SOF-
GRZ-
ELB
SOF-
DCV-
SMV
SOF
SOF-RBV
SOF-PEG-
RBV
NS5A
containing
regimen
(DCV, LDV,
VEL, OMB,
ELB)
EASL 2016
12 wk
with RBV
(F0-F3)
or
24 wk
with RBV
(F3-F4
12 wk
with RBV
(F0-F3)
or
24 wk
with RBV
(F3-F4
12 wk
with RBV
(F0-F3)
or
24 wk
with RBV
(F3-F4)
12 wk with RBV
(F0-F3) and
RNA 800,000
and (F3-F4)
12 wk
with RBV
(F0-F3)
or
24 wk
with RBV
(F3-F4
12 wk
with RBV
(F0-F3)
or
24 wk
with RBV
(F3-F4)
NO NO NO NO NO NO
NO NO NO
12 wk
with RBV
(F0-F3)
or
24 wk
with RBV
(F3-F4
12 wk
with RBV
(F0-F3)
or
24 wk
with RBV
(F3-F4
12 wk
with RBV
(F0-F3)
or
24 wk
with RBV
(F3-F4)

de Ledinghen V, et al. AASL D2016
New DAAs for Re-Treatment of NS5A Failures
SOF + Grazoprevir-Elbasvir + RBV (ANRS REVENGE study)
• SOF-GRZ-ELB-RBV retreatment
• G1 or G4 with NS5A or NS3 RASs
• SOF-LDV or SOF-DCV or SOF-SMV treatment failure
• 16 vs 24 wks
• 26 patients, 20 G1, 6 G4
• NS-5A RASs in 24 patients (Y93H, n=17; L31M, n=7; Q30R, n=4)
• NS3 RAS in 2 patients
• SVR-4: 25 (96%), one died after LTX and was RNA –ve
• No relapse
• No treatment related SAE, no discontinuation due to SAEs.

Conclusion
• Treatment of HCV G4 has become very effective
• Most regimens of DAAs associated with high SVR rates
(>90%): SOF +: LDV, VEL, SMV, DAC; PAR-r-OMB, GZR+EBR
• Real-life data with several regimens confirmed high SVR
rates in clinical trials
• Shorter duration treatment (8 weeks) coming soon
• Generic DAAs effective

Thank You