Therapeutic Strategies for
HCV Non-Genotype 1
Fred Poordad, MDProfessor of Medicine
Chief, Hepatology
University of Texas Health Science Center
Vice President, Academic and Clinical Affairs
The Texas Liver Institute
San Antonio, Texas
Disclosures
• Dr. Poordad has received grant/research support from AbbVie,
Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex
Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb,
Genentech, Gilead Sciences, GlaxoSmithKline,
GlobeImmune, Idenix Pharmaceuticals, Idera
Pharmaceuticals, Intercept Pharmaceuticals, Janssen,
Medarex, Medtronic, Merck, Novartis, Santaris
Pharmaceuticals, Scynexis Pharmaceuticals, Vertex
Pharmaceuticals, and ZymoGenetics
Overview
• Genotype non 1 HCV
• Scope of the problem
• Who is the ‘hard-to-cure’ population?
• Is there truly one regimen and duration for everyone?
Distribution and Prevalence of HCV Genotypes: Genotype 1b is most common worldwide, followed by G3
Messina JP et al, Hepatology, 2015; 61: 77-87.
Geno 2/3 Therapy Today
98
82
91
62
61
71
34 30
0
20
40
60
80
100
SOF + RBV PEG-IFN + RBV
GT 2 GT 3
SV
R12 (
%)
No cirrhosis No cirrhosisCirrhosis Cirrhosis
58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37
SOF + RBV vs PEG + RBV in G2 and G3: FISSION
SVR12 by HCV Genotype and Cirrhosis Status
Lawitz et al. 2014
Wk 0 Wk 24 SVR4, SVR12, SVR24
Placebo*(n = 85)
Sofosbuvir + Ribavirin (n = 250)
Sofosbuvir + Ribavirin(n = 84)*
*Protocol amended to eliminate placebo arm and to extend treatment duration to 24 weeks for patients with genotype 3 HCV irrespective of prior treatment history.
Wk 12
VALENCE: Study Design
Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001
94 92 87
60
0
20
40
60
80
100
SV
R12
(%
)
Naïve,
Noncirrhotic
Naïve,
CirrhoticExperienced,
Noncirrhotic
Experienced,
Cirrhotic
86/92 12/13 27/4587/100
SVR12 in GT 3 Patients Treated for 24 Weeks
Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001
AASLD/IDSA Recommendations for Genotype 2 HCV Treatment-Naive Pts
• Alternative regimens: none
• Regimens specifically not recommended:
– PegIFN/RBV x 24 wks
– Monotherapy with pegIFN, RBV, or DAA
– TVR-, BOC-, SMV-based regimens
AASLD/IDSA treatment recommendations.
PopulationRecommended
RegimenDuration
Treatment naive and
previous relapsers,
genotype 2
Sofosbuvir 400 mg
+
RBV 1000-1200
mg/day
12 wks
• Regimens specifically not recommended:
– PegIFN/RBV ± TVR or BOC
– Monotherapy with pegIFN, RBV, or DAA
*Pts with cirrhosis may benefit by extension of therapy to 16 wks.
PopulationRecommended
RegimenDuration
Nonresponse to previous treatment with pegIFN/RBV
Sofosbuvir 400 mg + RBV 1000-1200 mg/day
12 wks*
PopulationRecommended
RegimenDuration
Nonresponse to previous
treatment with
pegIFN/RBV with IFN
eligibility
Sofosbuvir 400 mg +
pegIFN +
RBV 1000-1200 mg/day
12 wks
AASLD/IDSA Recommendations for Genotype 2 HCV Treatment-Experienced Pts
AASLD/IDSA treatment recommendations.
AASLD/IDSA Recommendations for Genotype 3 HCV Treatment-Naive Pts
• Not recommended:– PegIFN/RBV for 24-48 wks
– Monotherapy with pegIFN, RBV, or a DAA
– Telaprevir, boceprevir, simeprevir
AASLD/IDSA treatment recommendations.
PopulationRecommended
RegimenDuration
Regardless of IFN
eligibility
Sofosbuvir 400 mg +
RBV 1000-1200
mg/day
24 wks
PopulationRecommended
RegimenDuration
Only consider if eligible
for IFN
Sofosbuvir 400 mg +
pegIFN +
RBV 1000-1200
mg/day
12 wks
AASLD/IDSA Recommendations for Genotype 3 HCV Treatment-Experienced
• Not recommended:
– PegIFN/RBV ± telaprevir, boceprevir, simeprevir
– Monotherapy with pegIFN, RBV, or a DAA
AASLD/IDSA treatment recommendations.
PopulationRecommended
RegimenDuration
Regardless of IFN eligibilitySofosbuvir 400 mg +
RBV 1000-1200 mg/dayRegardless of IFN eligibility
PopulationRecommended
RegimenDuration
Consider only if eligible for IFN
Sofosbuvir 400 mg + pegIFN
+ RBV 1000-1200 mg/day
12 wks
Daclatasvir + SofosbuvirN=101Treatment Naïve19% w/cirrhosis
ALLY-3Weeks0 12 24
N=51
90%
86%
SVR
Daclatasvir + SofosbuvirPrior Treatment25% w/cirrhosis
• Key demographics: Cirrhosis= 21%, Prior SOF failures = 7
• Most AE mild fatigue, headache, nausea, diarrhea
• Relapse occurred in 16/152 (11%), most relapsers were cirrhotic
SVR F0-F3 = 96% (105/19)
SVR F4 = 63% (20/32)
All-Oral 12-week Combination of Daclatasvir (NS5A) and
Sofosbuvir (NUC) in Patients with Genotype 3: ALLY-3
Nelson, AASLD 2014, LB-3
SOF + PegIFN + RBV 1000-1200 mg SVR12
0 12 24Study Week
GT 2/3 TE
N=47
Open-label, Phase 2 study of the efficacy of SOF + PegIFN + RBV for 12 weeks in
treatment-experienced patients with GT 2 or 3
Mean age (range), y 56 (39‒72)
Male, n (%) 32 (68)
White, n (%) 45 (96)
Hispanic, n (%) 21 (45)
Mean BMI (range), kg/m2 31 (21‒53)
IL28B CC, n (%) 17 (36)
HCV GT 3, n (%) 24 (51)
Mean BL HCV RNA (range), log10 IU/mL 6 (4‒7)
Cirrhosis, n (%) 26 (55)
Prior relapse/breakthrough, n (%) 40 (85)
Lawitz E, et al. AASLD 2013. Washington, DC. Oral #LB-4
LONESTAR-2 Study Design and Demographics
96 100 93
0
10
20
30
40
50
60
70
80
90
100
GT 2
SV
R1
2 (
%)
Overall
Non-cirrhotic
Cirrhotic
22/23 9/9 13/14*
*The 1 cirrhotic patient who did not achieve SVR prematurely discontinued therapy without <LLOQ
LLOQ, lower limit of quantification
Lawitz E, et al. AASLD 2013. Washington, DC. Oral #LB-4
SOF + PegIFN + RBV in HCV GT 2 Treatment-Experienced
Patients LONESTAR-2 Virologic Response
83 83 83
0
10
20
30
40
50
60
70
80
90
100
GT 3
SV
R1
2 (
%)
Overall
Non-cirrhotic
Cirrhotic
20/24* 10/12 10/12
*2 relapses; 2 lost to follow-up
Lawitz E, et al. AASLD 2013. Washington, DC. Oral #LB-4
SOF + PegIFN + RBV in HCV GT 3 Treatment-Experienced
Patients LONESTAR-2 Virologic Response
SOF/RBV/PegIFN for 12 Weeks vs. SOF/RBV for 16 or 24 Weeks in GT 2 or 3
Foster G, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. LO5.
n=196 SOF + RBV SVR12
n=199 SOF + RBV SVR12
n=197 SOF + PEG/RBV SVR12
Wk 0 12 16 24 28 36
SOF + RBV16 weeks
n=196
SOF + RBV24 weeks
n=199
SOF + PEG/RBV12 weeks
n=197Total
n=592
Mean age, y (range) 51 (20-69) 49 (23-71) 50 (19-73) 50 (19-73)
Male, n (%) 134 (68) 129 (65) 132 (67) 395 (67)
Asian, n (%) 28 (14) 26 (13) 25 (13) 79 (13)
Mean BMI, kg/m2 (range) 28 (18-50) 28 (18-55) 28 (19-45) 28 (18-55)
IL28B CC, n (%) 75 (38) 73 (37) 78 (40) 226 (38)
HCV genotype 3, n (%) 181 (92) 182 (92) 181 (92) 544 (92)
Mean baseline HCV RNA, log10 IU/mL (range)
6.3 (4.0-7.6) 6.2 (3.3-7.6) 6.3 (3.7-7.5) 6.3 (3.3-7.6)
Treatment experienced, n (%) 105 (54) 105 (53) 103 (52) 313 (53)
Cirrhosis, n (%) 72 (37) 73 (37) 74 (38) 219 (37)
SVR12
Foster G, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. LO5.
87
71
100
84
9493
0
20
40
60
80
100
GT 2 GT 3
SVR
12
(%
)
SOF + RBV 16 weeks SOF + RBV 24 weeks SOF + PEG/RBV 12 weeks
13/15 17/17 15/16 128/181 153/182 168/181
83
57
76
47
90 82 82
77
96 91 9486
0
20
40
60
80
100
No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis
SVR
12
(%
)
5870
6572
6871
1221
1822
2123
4154
4454
4952
1736
2634
3035
Treatment Naïve Treatment Experienced
Foster G, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. LO5.
SVR12 By Prior Treatment and Cirrhosis
Safety
Foster G, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. LO5.
Patients, n (%)
SOF + RBV16 weeks
n=196
SOF + RBV24 weeks
n=199
SOF + PEG/RBV12 weeks
n=197
Overall Safety
AEs 185 (94) 188 (95) 195 (99)
Grade 3-4 AE 11 (6) 7 (4) 15 (8)
Serious AE 8 (4) 10 (5) 12 (6)
Treatment D/C due to AE
3 (2) 2 (1) 1 (<1)
Death 0 0 0
LaboratoryAbnormalities
Grade 3-4 30 (15) 29 (15) 74 (38)
Hb <10g/dL 7 (4) 12 (6) 24 (12)
Hb <8.5 g/dL 0 0 2 (1)
Platelets <50,000/mm3 1 (<1) 0 9 (5)
C-WORTHY: Study Design
• Treatment-naive patients with HCV GT3 infection
• Cirrhotic and HIV coinfected patients excluded
• Randomized 1:1
• Treatment durations of 12 or 18 weeks
• All patients received weight-based ribavirin
GZR 100 mg / EBR 50 mg / RBV
D1 TW4 TW8 TW12 TW18
Follow-up: Primary endpoint: SVR12
HCV RNA < 25 IU/mL (COBAS TaqMan V2.0 [LoQ 25 IU/mL])
FW4 FW8 FW12
GZR 100 mg / EBR 50 mg / RBVn=21
n=20
Gane E, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. P0776.
45%(23.1, 68.5)
57.1%(34.0, 78.2)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
HC
V R
NA
<1
5 IU
/mL
(%, 9
5%
CI)
C-WORTHY: SVR12 Results
Non-virologic failure, n
1 2
Rebound, n 3 2
Breakthrough, n 6 5
Futility, n 1 0
Relapse, n 0 0
920
1221
GZR + EBR + RBV 12 weeks
GZR + EBR + RBV 18 weeks
Gane E, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. P0776.
Intention to Treat
C-SWIFT: SVR Results - HCV 3
93 100 91
0
10
20
30
40
50
60
70
80
90
100
HC
V R
NA
<1
5 IU
/mL
(%, 9
5%
CI)
1415
Non-cirrhotic
Cirrhotic
1011
1414
Treatment Duration 8 Weeks 12 Weeks 12 Weeks
Breakthrough 0 0 0
Relapse 1 0 1
Early discon. 0 0 1*
Poordad F, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. O006.
Modified Intent To Treat Analysis
SVR12 by HCV Genotype
24
SVR12 by HCV Genotype in Ally-1
76
9710090
80 8391
100 100
0
20
40
60
80
100
SVR
12
, %
1a 1b 2 3 4 6
Genotype
1a 1b 2 3 4 6
Advanced cirrhosis cohort N = 60
Post-transplant cohort N = 53
Poordad, et al. EASL 2015
SVR12 48-Week Follow-up
SVR1248-Week Follow-up
Week 72Week 60Week 36Week 24Week 12Day 0
OBV/PTV/r with RBV in HCV GT4 +/- Cirrhosis
Doss W, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. P1351.
Arm B• GT4 treatment-naïve and treatment-experienced with
compensated cirrhosis• n=30
Arm C• GT4 treatment-naïve and treatment-experienced with compensated
cirrhosis• n=30
Arm A• GT4 treatment-naïve and treatment-experienced with
compensated cirrhosis• n=30
Treatment-Naïve Treatment-Experienced
RVR
SVR4
SVR12
100100 100 10010097.6
Pat
ien
ts (
%)
41/42 42/42 42/42 49/49 49/49 49/49
PEARL-I: Efficacy of OBV/PTV/r + RBV in Treatment-Naïve and Treatment-Experienced Noncirrhotic Subjects With GT4 Infection
LDV/SOF for GT4 or GT5 HCV Infection
Aberel A, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. O056.
Genotype 4 Genotype 5
Naïven=22
Experienced n=22
Naïven=21
Experienced n=20
Mean age, years (range) 52 (21-69) 50 (30-62) 61 (40-78) 64 (50-79)
Male, n (%) 11 (50) 17 (77) 11 (52) 10 (50)
White, n (%) 19 (86) 17 (77) 21 (100) 20 (100)
Mean BMI, kg/m2 (range) 25 (19-35) 25 (20-36) 24 (18-30) 27 (19-39)
Cirrhosis, n (%) 1 (5) 9-(41) 3 (14) 6 (30)
IL28B non-CC, n(%) 15 (68) 21 (95) 8 (38) 14 (70)
Mean HCV RNA, log10 IU/ml (range)
6.0 (5.1-6.8) 6.3 (5.6-7.5) 6.2 (5.3-6.9) 6.6 (5.7-7.1)
Genotype 4 Genotype 5
96 91 95 9791
100 9589
0
20
40
60
80
100
TN TETreatment Status
No YesCirrhosis
TN TETreatment Status
No YesCirrhosis
Pat
ien
ts (
%)
21/22 20/22 31/22 10/10 20/21 19/20 31/32 8/9
GZR 100mg / EBR 50mg / RBV
GZR 100mg / RBV
GZR 100mg / EBR 50mg / RBV
C-SCAPE: Study Design
• Treatment-naive, GT2, 4, 5, 6 • Non-cirrhotic, HCV monoinfected • G2 patients assessed for a polymorphism at amino position 31 within
NS5A – Preclinical data demonstrate a lower potency for EBR in methionine (M)
compared to leucine (L) at position 31
D1 TW4 TW8 TW12 FUW4 FUW8 FUW12
GZR 100mg / EBR 50mg
Follow-up: Primary endpoint: SVR12
HCV RNA < 25 IU/mL (COBAS TaqMan V2.0 [LoQ 15 IU/mL])
Patients per arm (n)
G2 G4 G5 G6 ALL
30 - - - 30
30 - - - 30
- 10 4 5 19
- 10 4 5 19
Brown A, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. P0771.
100 100 7590 25 75
GZR / EBR + RBV for 12 weeks
GZR + EBR for 12 weeks
80 73
0
25
50
75
100
Pat
ien
ts (
%)
GZR / EBR + RBV for 12 weeks
GZR + RBV for 12 weeks
C-SCAPE: SVR12 Results
Genotype 2 Genotype 4 Genotype 5 Genotype 6
Relapse (n) 3 3 0 0 0 2 1 0
Breakthrough (n) 1 3 0 0 0 1 0 1
Futility (n) 0 1† 0 0 0 0 0 0
LTFU/Admin discon (n) 2 0 0 1 0 0 0 0
24/30
19/26*
3/4*
3/4*
10/10
9/10
4/4
1/4
Brown A, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. P0771.
(Modified Intent to Treat)
Summary
• We currently have good therapy for geno 2, but it uses RBV
– Geno 2 cirrhotics can be challenging
• Geno 3 is the biggest challenge, esp cirrhotics
• Geno 4 responds well to most regimens
• Geno 5 has very little data
• Geno 6 appears to respond much like geno 1
Conclusion
• We may never have one therapy for all genotypes
• Small SVR differences between regimens will dictate how we treat them
• Cirrhotics clearly are different and need either longer duration, or different regimens in some cases
