Management of HCV G4 Kasr Alainy
How would you treat HCV genotype 4 in 2017 How would you treat HCV genotype 4 in 2017
- Page 2 and 3: Management of Patients with HCV Gen
- Page 4 and 5: SVR12 (%) Sofosbuvir-RBV • 2 stud
- Page 6 and 7: SVR12, % Sofosbuvir-Ledipasvir N=35
- Page 8 and 9: SOF-RBV, SOF-LED, SOF-VEL • Integ
- Page 10 and 11: SVR12 % Grazoprevir-Elbasvir EBR +
- Page 12 and 13: SVR-12 % Sofosbuvir-Simeprevir •
- Page 14 and 15: Pariteprevir-ritonavir-Ombitasvir A
- Page 16 and 17: Pariteprevir-ritonavir-Ombitasvir A
- Page 18 and 19: Gelcaprevir-Pibrentasvir (GP) Surve
- Page 20 and 21: SVR 12 (%) Outcome of DAA Treatment
- Page 22 and 23: http://www.hcvguidelines.org, acces
- Page 24 and 25: EASL Recommendations 2016 Retreatme
- Page 26 and 27: Conclusion • Treatment of HCV G4
<strong>Management</strong> <strong>of</strong> Patients<br />
with <strong>HCV</strong> Genotype 4<br />
Cairo, February 23, 2017<br />
Imam Waked, MD, FAASLD<br />
Pr<strong>of</strong>essor <strong>of</strong> Medicine<br />
National Liver Institute, Egypt
Global Distribution <strong>of</strong> <strong>G4</strong><br />
<strong>G4</strong><br />
14%<br />
G5<br />
1%<br />
G6<br />
2%<br />
G2<br />
14%<br />
G3<br />
21%<br />
G1<br />
47%<br />
• <strong>G4</strong> mainly in Egypt, Middle East, Sub-Saharan Africa<br />
• Prevalence increasing in Europe: 15% in Belgium, 13.9% in Greece,10.1% in Switzerland<br />
• Over-represented in the <strong>HCV</strong>–HIV co-infected population, In the EUROSIDA cohort 14.7% in central,<br />
16.2% in southern Europe, 21.8% in France, 22.8% in Spain<br />
Messina J, et al. Hepatology. 2015 Alberti A, et al., J. Med. Virol. 2016
SVR12 (%)<br />
S<strong>of</strong>osbuvir-RBV<br />
• 2 studies SOF-RBV 12 or 24<br />
weeks<br />
• <strong>G4</strong> patients <strong>of</strong> Egyptian<br />
ancestry in the US (n=60)<br />
• <strong>G4</strong> patients in Egypt (n=103)<br />
• >30% with cirrhosis<br />
• >40% PEG-RBV experienced<br />
100<br />
80<br />
60<br />
40<br />
20<br />
0<br />
68<br />
21<br />
31<br />
US Study<br />
n=60<br />
12 weeks 24 weeks<br />
93 90<br />
77<br />
27<br />
29<br />
40<br />
52<br />
46<br />
51<br />
Egypt Study<br />
n=103<br />
Ruane PJ, et al. J Hepatol, 2015 Doss W. et al. J Hepatol. 2015
SVR-12 (%)<br />
SVR12 %<br />
S<strong>of</strong>osbuvir-Ledipasvir<br />
NIAID SYNERGY: SOF-LDV in <strong>HCV</strong> <strong>G4</strong><br />
Treatment-Naive and -Experienced<br />
Patients<br />
100 95<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20 20<br />
10 21<br />
0<br />
SVR12<br />
One patient dropped out<br />
Kohli A, et al. Lancet Infect Dis. 2015<br />
• 44 patients: 22 treatment naïve, 22 treatment experienced<br />
• <strong>G4</strong> subtypes: 4a= 25; 4d = 10; other subtypes, n = 9.<br />
• 10 (23%) had compensated cirrhosis.<br />
100<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
95<br />
21<br />
22<br />
Tretament<br />
Naïve<br />
91<br />
20<br />
22<br />
Treatment<br />
experiencd<br />
100<br />
10<br />
10<br />
. With<br />
cirrhosis<br />
91 93<br />
31<br />
34<br />
Without<br />
cirrhosis<br />
Abergel A et al. Hepatology 2016<br />
41<br />
44<br />
.. Overall
SVR12, %<br />
S<strong>of</strong>osbuvir-Ledipasvir<br />
N=355<br />
Treatment naïve,<br />
n=170<br />
Week 0 8 1<br />
2<br />
LDV/SOF<br />
LDV/SOF<br />
LDV/SOF + RBV<br />
LDV/SOF + RBV<br />
20<br />
SVR12<br />
24<br />
LDV/SOF 8 wk LDV/SOF + RBV 8 wk<br />
LDV/SOF 12 wk LDV/SOF + RBV 12 wk<br />
95 90 98 98 94 100 100<br />
IFN experienced,<br />
n=74<br />
LDV/SOF<br />
LDV/SOF + RBV<br />
SOF experienced,<br />
n=11<br />
LDV/SOF + RBV<br />
• Randomized, open-label study at 4 sites in Egypt<br />
• Treatment naïve and IFN experienced patients<br />
• Randomized to treatment, stratified by presence/absence <strong>of</strong><br />
cirrhosis<br />
• Approximately 25% with compensated cirrhosis<br />
• SOF experienced patients<br />
• prior treatment with SOF + RBV for 12 or 24 weeks or LDV/SOF ±<br />
RBV for 8 weeks<br />
• assigned to LDV + SOF + RBV for 12 weeks<br />
Shiha G. et al., AASLD 2016<br />
41<br />
43<br />
38<br />
42<br />
42<br />
43<br />
Treatment Naïve<br />
41<br />
42<br />
34<br />
36<br />
38<br />
38<br />
IFN<br />
Experienced<br />
11<br />
11<br />
SOF<br />
Experienced<br />
6
SVR12 %<br />
S<strong>of</strong>osbuvir-Velpatasvir<br />
• ASTRAL-1:<br />
• Treatment-naive and<br />
treatment-experienced<br />
patients<br />
• G-4: 116 Patients<br />
• Randomized 5:1 to 12-weeks<br />
<strong>of</strong> SOF-VEL or placebo<br />
• Subtypes:<br />
• 16 <strong>G4</strong>: 4a, 4b, 4c, 4d, 4f, 4k, 4l, 4n, 4o, 4r,<br />
4t, 4ad, 4ak, 4alv, 4dr, 4pt<br />
Feld JJ et al., N Engl J Med. 2015<br />
100<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
116<br />
116<br />
All Patients<br />
27<br />
27<br />
52<br />
52<br />
All Patients With cirrhosis PEG-RBV<br />
experienced
SOF-RBV, SOF-LED, SOF-VEL<br />
• Integrated Analysis <strong>of</strong> SOF+RBV, LDV/SOF or SOF/VEL for the<br />
Treatment <strong>of</strong> Genotype 4 Chronic <strong>HCV</strong> Infection<br />
100%<br />
80%<br />
60%<br />
40%<br />
20%<br />
0%<br />
Asselah T. et al. AASLD 2016<br />
74%<br />
SOF-RBV<br />
12 wks<br />
Study 114, 138<br />
n=83<br />
SVR12 in Patients with <strong>HCV</strong>-<strong>G4</strong><br />
91% 95% 100%<br />
SOF-RBV<br />
24 wks<br />
Study 114, 138<br />
n=80<br />
SOF-LDV<br />
12 wks<br />
Synergy<br />
n=73<br />
SOF-VEL<br />
12 wks<br />
Astral 1<br />
n=116
SOF-VEL-VOX<br />
NS-5A<br />
Experienced<br />
DAA<br />
Naiive<br />
Bouliere M. et al. AASLD 2016, Jacobson I. et al. AASLD 2016
SVR12 %<br />
Grazoprevir-Elbasvir<br />
EBR + GZR + RBV 12 wks<br />
• C-SCAPE<br />
• 12 weeks GZR + EBR with or<br />
without RBV<br />
• Treatment-naïve, non-cirrhotic<br />
genotype 2,4,5, and 6.<br />
• <strong>G4</strong>: 20<br />
100<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
100<br />
10<br />
10<br />
<strong>G4</strong><br />
EBR + GZR 12 wks<br />
90<br />
9<br />
10<br />
Brown A. et al. EASL 2015
SVR 12 (%)<br />
Grazoprevir-Elbasvir<br />
• C-EDGE<br />
100<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
100<br />
18<br />
18<br />
96<br />
27<br />
28<br />
78<br />
7<br />
9<br />
12 weeks 12 weeks 12 weeks 12 weeks + RBV 16 weeks 16 weeks + RBV<br />
93<br />
14<br />
15<br />
60<br />
3<br />
5<br />
100<br />
8<br />
8<br />
C-EDGE TN<br />
Treatment<br />
Naive<br />
C-EDGE<br />
HIV Coinfection<br />
C-EDGE TE<br />
Treatment Exp.<br />
Zeuzem S et al. Ann Intern Med. 2015 Rockstroh J et al. Lancet HIV 2015 Kwo P et al. EASL 2015.
SVR-12 %<br />
S<strong>of</strong>osbuvir-Simeprevir<br />
• The PLUTO trial:<br />
• 40 patients <strong>G4</strong>, SVR12: 100%<br />
• The OSIRIS trial: 100 92<br />
F0-F3<br />
n=40<br />
F4<br />
n=23<br />
SOF+SMV 8 weeks<br />
SOF + SMV 12 weeks<br />
SOF + SMV 12 weeks<br />
0 8 12 24<br />
Buti M et al, EASL 2016 El-Raziky et al. J Viral Hepatitis, 2016<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
58<br />
63<br />
75<br />
15<br />
20<br />
Overall 8 weeks 12 weeks<br />
F0-F3<br />
100 100<br />
20<br />
20<br />
23<br />
23<br />
12 weeks<br />
F4
Pariteprevir-ritonavir-Ombitasvir<br />
Agate I: Study Design<br />
• Multinational<br />
• <strong>HCV</strong>-GT-4 with compensated<br />
cirrhosis<br />
Agate II: Study Design<br />
• Patients living in Egypt with <strong>HCV</strong> GT4 infection<br />
without cirrhosis or with compensated cirrhosis<br />
• N=160 Tx-naïve and prior PegIFN/RBVexperienced<br />
<strong>HCV</strong> GT4<br />
Naive or<br />
Peg/RBV<br />
Exp<br />
12 weeks<br />
2D+RBV: N=59<br />
16 weeks<br />
2D+RBV: N=61<br />
No cirrhosis,<br />
naive or<br />
experienced<br />
With Cirrhosis,<br />
naive or<br />
experienced<br />
2D + RBV (n=100)<br />
2D + RBV (n=31)<br />
2D + RBV (n=29)<br />
0 12 16<br />
Week<br />
All arms received 2-DAA OBV/PTV/r once-daily with weight based RBV.<br />
Asselah et al. Lancet Gastro Hep. 2016 Waked et al. Lancet Gastro Hep. 2016<br />
0 12 16<br />
24
Pariteprevir-ritonavir-Ombitasvir<br />
Asselah et al. Lancet Gastro Hep. 2016 Waked et al. Lancet Gastro Hep. 2016
SVR12 %<br />
SVR-12 %<br />
Pariteprevir-ritonavir-Ombitasvir<br />
Agate I: Results<br />
Agate II: Results<br />
100<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
97 98<br />
57<br />
58<br />
60<br />
61<br />
12 Weeks 16 Weeks<br />
100<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
94 97<br />
94<br />
100<br />
No cirrhosis<br />
12 weeks<br />
30<br />
31<br />
Compensated<br />
cirrhosis<br />
12 weeks<br />
93<br />
27<br />
29<br />
Compensted<br />
cirrhosis<br />
24 weeks<br />
Asselah et al. Lancet Gastro Hep. 2016 Waked et al. Lancet Gastro Hep. 2016
Pariteprevir-ritonavir-Ombitasvir<br />
Agate II: Liver Tests<br />
Waked et al. AASLD 2016
Pariteprevir-ritonavir-Ombitasvir<br />
SVR12<br />
100%<br />
90%<br />
80%<br />
70%<br />
60%<br />
50%<br />
40%<br />
30%<br />
20%<br />
10%<br />
0%<br />
100%<br />
France<br />
ANRS HEPATHER<br />
n=54<br />
96.20% 96%<br />
Spain<br />
Real Life<br />
n=122<br />
Saudi Arabia<br />
Real Life<br />
n=117<br />
Fontaine H. et al. AASLD 2016, Crespo J et al, AASLD 2016, Alswat K, et al. AASLD 2016
Gelcaprevir-Pibrentasvir (GP)<br />
Surveyor 4<br />
G2, 4-6, Without cirrhosis G/P 8 wks<br />
Expedition 4<br />
G1-6, Renal impairment, G/P 12 wks,<br />
GT4: n= 20<br />
Hassanein T. et al. AASLD 2016, Gane E. et al. AASLD 2016
S<strong>of</strong>osbuvir + Daclatasvir<br />
• ALLY-1: SOF+DCV in advanced cirrhosis or post-LTx<br />
• 4 <strong>G4</strong> patients, SVR-12 100%<br />
• ALLY-2: SOF+DCV in HIV coinfection:<br />
• 3 <strong>G4</strong> patients, SVR12 100%<br />
• ANRS CUPILT: Post LTx<br />
• 11 <strong>G4</strong> patients, SVR12 91% (10/11)<br />
• Europe: Advanced Liver Disease, real world:<br />
• 19 <strong>G4</strong> patients, SVR12 100%<br />
Poordad et al. Hepatology. 2016 Wyles DL, et al. N Engl J Med. 2015 Coilly et al., J Hepatol. 2016<br />
Welzel TM, et al. Gut 2016
SVR 12 (%)<br />
Outcome <strong>of</strong> DAA Treatment in Egypt: 2015-2016<br />
100%<br />
80%<br />
95%<br />
96% 98% 97% 95%<br />
76%<br />
60%<br />
40%<br />
20%<br />
0%<br />
SOF-PEG-RBV<br />
12 weeks<br />
n=16,418<br />
SOF-PEG-RBV<br />
12 weeks<br />
SOF-RBV<br />
24 weeks<br />
n=8,091<br />
SOF-RBV<br />
24 weeks<br />
SOF-SMV<br />
12 weeks<br />
n=10,747<br />
SOF-SMV<br />
12 weeks<br />
SOF-DCV<br />
12 weeks<br />
n=43,870<br />
SOF-DCV<br />
12 weeks<br />
SOF-DCV-<br />
SOF-DCV-RBV<br />
12 weeks<br />
n=29,581 RBV<br />
12 weeks<br />
Total<br />
n=109,572<br />
Number 17,283 8,091 10,747 43,870 29,581 109,572<br />
SVR12 # (%) 16,418 6,149 10,339 43,015 28,711 104,633<br />
Non-response # (%) 432 970 290 430 590 2,712<br />
Relapse # (%) 432 970 118 425 280 2,225<br />
Total
SVR 24 (%)<br />
S<strong>of</strong>osbuvir + Ravidasvir<br />
• 300 patients<br />
• 130 (43%) with<br />
cirrhosis<br />
100.0<br />
80.0<br />
98<br />
92<br />
100 96<br />
• 50% treatment naive<br />
• 12 weeks SOF+RVD<br />
+/-RBV<br />
• Experienced with<br />
cirrhosis: 16 wks<br />
+RBV<br />
60.0<br />
40.0<br />
20.0<br />
0.0<br />
167<br />
170<br />
No<br />
cirrhosis<br />
87<br />
95<br />
cirrhosis<br />
12 weeks<br />
35<br />
35<br />
cirrhosis<br />
16 weeks<br />
289<br />
300<br />
Overall<br />
Esmat et al. EASL 2016
http://www.hcvguidelines.org, accessed September 10, 2016<br />
AASLD Recommendations<br />
• <strong>G4</strong>: without and with compensated-cirrhosis<br />
• PAR-r-OMB + RBV 12 weeks<br />
• SOF-VEL 12 weeks<br />
• SOF-LDV 12 weeks<br />
• GZR-EBR 12 weeks (treatment naïve or PEG-RBV relapse)<br />
16 weeks + RBV (PEG-RBV on-treatment failure<br />
(null response or breakthrough)
EASL 2016<br />
EASL Recommendations 2016<br />
Treatment <strong>of</strong> <strong>HCV</strong>-mono-infected or <strong>HCV</strong>/HIV co-infected patients<br />
Genotype 4<br />
Previous<br />
Treatment<br />
SOF-<br />
LDV<br />
SOF-<br />
VEL<br />
OMB-<br />
PAR-r<br />
GRZ-<br />
ELB<br />
SOF-<br />
DCV<br />
SOF-<br />
SMV<br />
Naive<br />
12 wk<br />
No RBV<br />
12 wk<br />
No RBV<br />
12 wk<br />
WITH RBV<br />
12 wk<br />
No RBV<br />
12 wk<br />
No RBV<br />
12 wk<br />
No RBV<br />
PEG-RBV<br />
12 wk<br />
with RBV<br />
or<br />
24 wk<br />
NO RBV<br />
12 wk No RBV if<br />
RNA 800,000<br />
12 wk<br />
with RBV<br />
or<br />
24 wk<br />
NO RBV<br />
12 wk<br />
with RBV<br />
or<br />
24 wk<br />
NO RBV
EASL Recommendations 2016<br />
Retreatment <strong>of</strong> <strong>HCV</strong>-mono-infected or <strong>HCV</strong>/HIV co-infected patients who failed<br />
prior DAA therapy: Genotype 4<br />
Previous<br />
Treatment<br />
SOF-<br />
LDV<br />
SOF-<br />
VEL<br />
OMB-<br />
PAR-r<br />
GRZ-<br />
ELB<br />
SOF-<br />
DCV<br />
SOF-<br />
SMV<br />
SOF-<br />
OMB-<br />
PAR-r<br />
SOF-<br />
GRZ-<br />
ELB<br />
SOF-<br />
DCV-<br />
SMV<br />
SOF<br />
SOF-RBV<br />
SOF-PEG-<br />
RBV<br />
NS5A<br />
containing<br />
regimen<br />
(DCV, LDV,<br />
VEL, OMB,<br />
ELB)<br />
EASL 2016<br />
12 wk<br />
with RBV<br />
(F0-F3)<br />
or<br />
24 wk<br />
with RBV<br />
(F3-F4<br />
12 wk<br />
with RBV<br />
(F0-F3)<br />
or<br />
24 wk<br />
with RBV<br />
(F3-F4<br />
12 wk<br />
with RBV<br />
(F0-F3)<br />
or<br />
24 wk<br />
with RBV<br />
(F3-F4)<br />
12 wk with RBV<br />
(F0-F3) and<br />
RNA 800,000<br />
and (F3-F4)<br />
12 wk<br />
with RBV<br />
(F0-F3)<br />
or<br />
24 wk<br />
with RBV<br />
(F3-F4<br />
12 wk<br />
with RBV<br />
(F0-F3)<br />
or<br />
24 wk<br />
with RBV<br />
(F3-F4)<br />
NO NO NO NO NO NO<br />
NO NO NO<br />
12 wk<br />
with RBV<br />
(F0-F3)<br />
or<br />
24 wk<br />
with RBV<br />
(F3-F4<br />
12 wk<br />
with RBV<br />
(F0-F3)<br />
or<br />
24 wk<br />
with RBV<br />
(F3-F4<br />
12 wk<br />
with RBV<br />
(F0-F3)<br />
or<br />
24 wk<br />
with RBV<br />
(F3-F4)
de Ledinghen V, et al. AASL D2016<br />
New DAAs for Re-Treatment <strong>of</strong> NS5A Failures<br />
SOF + Grazoprevir-Elbasvir + RBV (ANRS REVENGE study)<br />
• SOF-GRZ-ELB-RBV retreatment<br />
• G1 or <strong>G4</strong> with NS5A or NS3 RASs<br />
• SOF-LDV or SOF-DCV or SOF-SMV treatment failure<br />
• 16 vs 24 wks<br />
• 26 patients, 20 G1, 6 <strong>G4</strong><br />
• NS-5A RASs in 24 patients (Y93H, n=17; L31M, n=7; Q30R, n=4)<br />
• NS3 RAS in 2 patients<br />
• SVR-4: 25 (96%), one died after LTX and was RNA –ve<br />
• No relapse<br />
• No treatment related SAE, no discontinuation due to SAEs.
Conclusion<br />
• Treatment <strong>of</strong> <strong>HCV</strong> <strong>G4</strong> has become very effective<br />
• Most regimens <strong>of</strong> DAAs associated with high SVR rates<br />
(>90%): SOF +: LDV, VEL, SMV, DAC; PAR-r-OMB, GZR+EBR<br />
• Real-life data with several regimens confirmed high SVR<br />
rates in clinical trials<br />
• Shorter duration treatment (8 weeks) coming soon<br />
• Generic DAAs effective
Thank You