David E. Bernstein, MD, FACG
Treatment of Genotype 2, 3, and 4
David E. Bernstein, MD, FACG
2
Global Prevalence of HCV
Messina JP, et al. Hepatology 2015; 61:77–87.* Excludes Oceania.
46.2
9.1
30.1
8.3
0.85.4
0
10
20
30
40
50
GT1 GT2 GT3 GT4 GT5 GT6
Tota
l glo
bal H
CV se
ropr
eval
ence
(%)
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 1 of 25
David E. Bernstein, MD, FACG
TREATMENT OF GENOTYPE 2
FISSION: SVR12 in GT 2 Patients:Treatment-naive
97 9891
78 82
62
0
20
40
60
80
100
Overall No Cirrhosis Cirrhosis
SOF/RBV 12 wks PEG/RBV 24 wks
4Lawitz E et al. N Engl J Med. 2013;368:1878-87.
SVR1
2 (%
)
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 2 of 25
David E. Bernstein, MD, FACG
FUSION: SVR12 in GT 2 Patients:Treatment-experienced
8696
60
94100
78
0
20
40
60
80
100
Overall No cirrhosis Cirrhosis
SOF/RBV 12 wks SOF/RBV 16 wks
5Jacobson IM et al. N Engl J Med. 2013;68:1867-77.
SVR1
2 (%
)
Treatment of Naïve Genotype 2 with Sofosbuvir + Daclatasvir (NS5A): 24 weeks
98 96 92 89
GT 1Naive
GT 1Experienced
GT 2 GT 3
SVR
(%)
GT 3: 1 lost to f/u1 viral failure
41126 41 18
Sulkowski M et al. N Engl J Med. 2014;370:211-21.
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 3 of 25
David E. Bernstein, MD, FACG
Genotype 2 treatment naïve without cirrhosis: Sustained virological response rates
98% 98%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Sofosbuvir/ribavirin for 12weeks
Daclatasvir/sofosbuvir for 12weeks
Jacobson et al. NEJM 2013, Sulkowski et al. NEJM 2014
Genotype 2 treatment naïve with cirrhosis: Sustained virological response rates
98% 98%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Sofosbuvir/ribavirin for 16weeks
Daclatasvir/sofosbuvir for 16weeks
Jacobson et al. NEJM 2013, Sulkowki et al. NEJM 2014
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Page 4 of 25
David E. Bernstein, MD, FACG
Genotype 2: Treatment Naïve and Experienced AASLD/IDSA Guidance Recommendations
• Sofosbuvir 400 mg and weight based RBV for 12 weeks [Class 1, level A]
• Daclatasvir 60 mg plus sofosbuvir for 12 weeks • Sofosbuvir 400 mg and weight based RBV for
16-24 weeks with compensated cirrhosis [Class 2a, level C]
• Daclatasvir 60 mg plus Sofosbuvir 400 mg with compensated cirrhosis [Class 2a, level B]
AASLD/IDSA Guidance Document March 20, 2016
Genotype 2: Treatment of Sofosbuvirplus RBV Failures*
• Daclatasvir 60 mg plus sofosbuvir 400 mg with or without RBV for 24 weeks (Class 2a, Level C)
• PEG-IFN plus RBV plus sofosbuvir 400 mg for 12 weeks (Class 2a, Level 3)
AASLD Guidance Document Accessed March 20, 2016
*Minimal data
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 5 of 25
David E. Bernstein, MD, FACG
NEW THERAPIES ON THE HORIZON FOR GENOTYPE 2
Sofosbuvir + Velpatasvir
1. Jacobson IM, et al. New Engl J Med 2013;368:1867-77; 2. Lawitz E, et al. New Engl J Med 2013;368:1878-87; 3. Cheng G, et al. EASL 2013, poster 1191; 4. German P, et al. EASL 2013, poster 1195; 5. Lawitz E, et al. EASL 2013, poster 1082. 6. Everson G, et al. EASL 2014, oral presentation. 3
SOF Nucleotide polymerase inhibitor
♦ Sofosbuvir (SOF)1,2
‒ Potent antiviral activity against HCV GT 1‒6
‒ Once-daily, oral, 400-mg tablet
♦ Velpatasvir3-5
– Picomolar potency against HCV GT 1‒6– PK supports once-daily dosing
♦ SOF + Velpatasvir6
– Treatment for 12 weeks resulted in high SVR in treatment-naïve patients with HCV GT 1‒6 without cirrhosis
GS-5816NS5A inhibitor
SOF GS-5816+
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Page 6 of 25
David E. Bernstein, MD, FACG
Astral 1: Velpatasvir (NS5A) + SOF for 12 weeks- Genotype 2, 4, 5 and 6
100 100 97 100
0
20
40
60
80
100
GT 2 GT 4 GT 5 GT 6
104/104 116/11634/35
41/41
SVR
Feld et al. NEJM 2015
Astral 2: Velpatasvir (NS5A) + SOF for 12 weeks in Genotype 2
99 94
0
20
40
60
80
100
SOF/VEL SOF/RBV
133/134124/132
• 14% cirrhosis• 14% PEG/RBV
treatment experienced• 1 patient in the SOF/VEL
took 1 dose and stopped due to dizziness
SVR
Mangia et al. NEJM 2015
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Page 7 of 25
David E. Bernstein, MD, FACG
THERAPY FOR GENOTYPE 3
Genotype 3 Is Associated With a Significantly Higher Risk of Cirrhosis and HCC vs GT 1
• VA HCV Clinical Case Registry (2000-2009)– 88,348 patients with genotype 1 (80%)
– 13,077 genotype 2 (12%)
– 8,337 genotype 3 (7.5%)
– Mean follow-up 5.4 years
• After adjustment for demographic, clinical and antiviral treatment factors, comparison between genotypes 3 and 1
Conclusion: GT 3 is associated with a significantly higher risk of cirrhosis and HCC vs GT 1, independent of age, diabetes, BMI or antiviral treatment Kanwal F et al, Hepatology 2014;60:98-105
Hazard RatioConfidence
Interval
Cirrhosis 1.31 1.22-1.39
HCC 1.80 1.61-2.03
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 8 of 25
David E. Bernstein, MD, FACG
Treatment of Genotype 3
Fission Naive
56 61
34
6371
30
0
20
40
60
80
100
Overall Nocirrhosis
Cirrhosis
SOF/RBV 12 wks PEG/RBV 24 wks
Fusion Treatment Experienced
3037
19
62 63 61
0
20
40
60
80
100
Overall Nocirrhosis
Cirrhosis
SOF/RBV 12 wks SOF/RBV 16 wks
Lawitz E, et al. N Engl J Med. 2013; 368: 1878-1887Jacobson et al. NEJM 2013,368: 1867-77
24 36Week 0 12
SVR12Sofosbuvir + RBV(n = 250)
GT 3
Drug DosingSofosbuvir 400 mg once dailyRibavirin (weight-based and divided bid): 1000 mg/day if <75 kg or 1200 mg/day if ≥75 kg
Original Study Protocol: Placebo versus 12 weeks treatment for GT 2 and 3. Amended Protocol: GT3 treatment extended from 12 to 24 weeks; Placebo arm offered alternative treatment
VALENCE: Sofosbuvir and Ribavirin
Zeuzem S, et al. NEJM 2014;370:1993-2001
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 9 of 25
David E. Bernstein, MD, FACG
VALENCE: 24 Wks SOF + RBV in GT 3 Patients
• Extending treatment duration to 24 weeks did not significantly increase the incidence of AEs
212/250 12/13
94
86/92
Naive,Non-cirrhotic
87
87/100
Experienced,Non-cirrhotic
92
Naive,Cirrhotic
60
27/45
Experienced,Cirrhotic
0
20
40
60
80
10085
Overall
212/250
SVR1
2 (%
)
Zeuzem S, et al. NEJM 2014;370:1993-2001
Follow-upDCV 60 mg +SOF 400 mg QD
Day 1 Week 24 Week 36
DCV 60 mg +SOF 400 mg QD
Week 12
Treatment-naiveN = 101
Treatment-experiencedN = 51
SVR12
Genotype 3: ALLY-3 Study Design
• Primary endpoint: SVR12• Eligible patients
– Age ≥18 years with chronic GT 3 infection and HCV RNA ≥10,000 IU/mL– Treatment-naive or -experienced (prior treatment failures), including patients
with cirrhosis– Those who received prior treatment with NS5A inhibitors were excluded
Nelson et al. Hepatology 2015; 61:1127-35
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 10 of 25
David E. Bernstein, MD, FACG
0
20
40
60
80
100 90 86S
VR
12 (
%)
Treatment-naive Treatment-experienced
91/101 44/51
DCV/SOF for GT 3: SVR12 in Treatment-naïve and Treatment-experienced patients Treated for 12 Weeks (ALLY-3)
Nelson DR, Hepatology 2015; 61: 1127-1135
96 97 94
63 5869
0
20
40
60
80
100
SV
R12
(%)
YesNo
Cirrhosis
YesNo YesNo
Overall Tx-naive Tx-experienced
SVR12 in Patients With and Without Cirrhosis Treated for 12 Weeks (ALLY-3)
Nelson DR, Hepatology 2015; 61: 1127-1135
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 11 of 25
David E. Bernstein, MD, FACG
Genotype 3 previously untreated without cirrhosis: Sustained virological
response rates
97%
100%
94%
95%
91%
92%
93%
94%
95%
96%
97%
98%
99%
100%
DAC/SOF 12 wks DAC/SOF/RBV 12 wks SOF/RBV 24 wks Sofosbuvir/RBV plusPEG-IFN for 12 weeks
Nelson et al Hepatology 2015Leroy et al. AASLD 2015Jacobson et al. NEJM 2013Lawitz et al. NEJM 2013
Genotype 3 previously untreated withcirrhosis: Sustained virological
response rates
86%
89%
92%
90%
83%
84%
85%
86%
87%
88%
89%
90%
91%
92%
93%
DAC/SOF 12 wks DAC/SOF/RBV 12 wks SOF/RBV 24 wks Sofosbuvir/RBV plusPEG-IFN for 12 weeks
Nelson et al Hepatology 2015, Leroy et al. AASLD 2015,Jacobson et al. NEJM 2013, Lawitz et al. NEJM 2013
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 12 of 25
David E. Bernstein, MD, FACG
Genotype 3 treatment experienced without cirrhosis: Sustained virological
response rates92%
91%
90%
91%
91%
91%
91%
91%
92%
92%
92%
92%
Daclatasvir/sofosbuvir for 12weeks
Sofosbuvir/RBV plus PEG-IFNfor 12 weeks
Nelson et al Hepatology 2015, Jacobson et al. NELM 2013
Genotype 3 treatment experienced with cirrhosis: Sustained virological
response rates92%
89%
91%
88%
88%
89%
89%
90%
90%
91%
91%
92%
92%
93%
DAC/SOF 24 wks DAC/SOF/RBV 16 wks Sofosbuvir/RBV plusPEG-IFN for 12 weeks
Nelson et al Hepatology 2015, Jacobson et al. NELM 2013Lawitz et al. NEJM Lancet Inf Des 2013
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Page 13 of 25
David E. Bernstein, MD, FACG
Genotype 3: Sofosbuvir/Daclatasvir +RBV for 12 weeks
95
45
9183
0
20
40
60
80
100
SOF/DCVSOF/DCV/RBV
2234 10/11SV
R
Bernstein et al. AASLD 2015
125133 5/6
Ally-3 and Ally-3+: SVR 12 in advanced fibrosis
28
All 12 week 16 week12 week
93
SVR1
2 (%
) + 9
5% C
I
ALLY-3(DCV+SOF)
ALLY-3+(DCV+SOF+RBV)
0102030405060708090
100100
1 relapsePrior SOF+RBV failure
NS5A-Y93H at baselineBaseline HCV RNA:
8.8 × 106 IU/mL
1415
1414
66
88
100 100
Kowdley et el. EASL 2016
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 14 of 25
David E. Bernstein, MD, FACG
ALLY-3 and ALLY-3+: SVR in Compensated Cirrhosis
29
0102030405060708090
100
64
86 83 89
2133
3136
1518
1618
ALLY-3+(DCV+SOF+RBV)
ALLY-3(DCV+SOF)
All 12 week 16 week12 weekVirologic Failure 12 4 2 2
Breakthrough 0 0 0 0Relapse 11 4 2 2Other (Detectable at EOT) 1 0 0 0
Non-virologic failure (death)a 0 1 1 0aDilated cardiomyopathy on Day 72 (not related to treatment)
SVR1
2 (%
) + 9
5% C
I
Kowdley et al. EASL 2016
Resistance Associated NS5A Variants at Baseline and Failure in Patients with cirrhosis
■ Across both studies, Y93H was present in 12/13 cirrhotic patients with available post-failure sequence data– Emergent in 8, present at baseline in 4
■ No SOF-associated RAVs in NS5B were observed at baseline or relapse– S282T or any substitution at L159, L320, or V321
Resistance assessed by population sequencing (sensitivity ≥ 10%)
No NS5A RAVs
n = 26
NS5ARAVsn = 7
14
Figure 5. Resistance-Associated NS5A Variants at Baseline and Failure in Patientswith Cirrhosis
Y93H
A30S+Y93H
A30K
A30TSVR12without
RAVs73%
(19/26)
4550
No NS5A RAVs
n = 12NS5A RAVs
n = 2 A30K(n = 4)
Y93H
A30T (n=1)
SVR12without
RAVs90%
(26/29)A30A/V+Y93Y/H
A30K
Y93H
Y93Y/HALLY-3 ALLY-3+
No NS5A RAVs
n = 29
NS5ARAVsn = 6
ALLY-3+ data excludes one patient without RAVs whodied of dilated cardiomyopathy on Day 72, unrelated to
treatment.
One relapse without A30K or Y93H had baseline M28I polymorphism not present at failure. M28I does not affect DCV susceptibility in vitro.
Two ALLY-3 patients with virologic failure had two AVs at baseline (indicated in yellow)
Achieved SVR12 Did not achieve SVR12
Kowdley et al. EASL 2016
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Page 15 of 25
David E. Bernstein, MD, FACG
Daclatasvir/Sofosbuvir + RBV for genotype 3 F3 and F4 patients: The French Compassionate
Study
96 100100
81
0
20
40
60
80
100
DCV/SOF DCV/SOF/RBV
F3 Results
12 week 24 week
SVR
Hezode et al. AASLD 2015. Abstract 206
Daclatasvir/Sofosbuvir + RBV for genotype 3 F3 and F4 patients: The French Compassionate Study
69
100
85 81
0
20
40
60
80
100
DCV/SOF DCV/SOF/RBV
F4 Results
12 week 24 week
SVR
Hezode et al. AASLD 2015. Abstract 206
4/4
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Page 16 of 25
David E. Bernstein, MD, FACG
SOF + RBV 16 weeks SOF + RBV 24 weeks SOF + PEG/RBV 12 weeks
94/112 83/100 10/11
83
5776
47
90 82 8277
96 91 9486
0
20
40
60
80
100
TN no cirrhosis TN cirrhosis TE no cirrhosis TE cirrhosis
5870
6572
6871
1221
1822
2123
2634
1736
3035
4454
4952
4154
SV
R12
(%
)
Treatment Naïve Treatment Experienced
No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis
SOF+PEG/RBV x 12 Wks vs SOF+RBV x 24 Weeks: SVR12 in GT 3Patients By Subgroup (BOSON Study)
Foster et al., Abstract #L-05, EASL 2015
NEW THERAPIES ON THE HORIZON FOR GENOTYPE 3
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Page 17 of 25
David E. Bernstein, MD, FACG
Foster et al. NEJM 2015
Astral 3 Results: SVR 12
35
95
80
0
20
40
60
80
100SV
R12
(%)
264/277 221/275
p <0.001*
SOF/VEL12 Weeks
SOF + RBV24 Weeks
Astral 3: SVR12 by Cirrhosis and Treatment History
36Foster et al. NEJM 2015
98 93 91 8990
73 71
58
0
20
40
60
80
100
SOF/VEL SOF + RBV
SVR1
2 (%
)
160163
4043
3134
3337
141156
3345
2231
2238
CirrhosisNo Yes
Treatment Naïve Treatment Experienced
No Yes
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 18 of 25
David E. Bernstein, MD, FACG
C-Crest: Grazoprevir and MK-3682 (NS5B) + either elbasvir or MK-8408 (NS5A) for 8 weeks
45
95 91
0
20
40
60
80
100
GZR/EBR+RBV for 12 wks GZR/8408/3682 300 mg for 8wks
GZR/8408/3682 450 mg for 8wksGT 3
SVR
Gane et al. AASLD 2015 Abstract LB-15
•SURVEYOR-II is an open-label, multicenter phase 2 trial evaluating the safety and efficacy of co-administered ABT-493 and ABT-530, at varying doses, ± ribavirin (RBV), in patients with HCV GT2 or GT3 infection
SURVEYOR-II Part 1 (GT3): Study Design
ClinicalTrials.gov: NCT02243293.N=121.aIncludes one patient who was incorrectly assigned to treatment in the GT2 cohort.bDaily dose of 1000 mg or 1200 mg RBV dosed BID based on patient body weight being <75 kg or ≥75 kg.
Day 1 Week 12 PT Week 24
n=30
Post-treatment (PT) periodTreatment period
ABT-493 300 mg + ABT-530 120 mg
ABT-493 200 mg + ABT-530 120 mg
ABT-493 200 mg + ABT-530 40 mg
ABT-493 200 mg + ABT-530 120 mg + RBVb
n=30a
n=31
n=30
Kwo et al AASLD 2015
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Page 19 of 25
David E. Bernstein, MD, FACG
SURVEYOR-II Part 1 (GT3): Per Protocol SVR12 Rates by Treatment*
200 mg+
120 mg
300 mg+
120 mg
200 mg+
120 mg+ RBV
200 mg+
40 mg
ABT-493+
ABT-530*Excluding non-virologic failures.
Kwo et al AASLD 2015
Treatment Recommendations for Treatment Naïve Genotype 3
Population Recommended Regimen Duration
Treatment naïve without cirrhosis SOF 400 mg + Daclatasvir 60 mg 12 weeks
SOF 400 mg + peg-IFN + RBV 1000-1200 mg/day 12 weeks
Sofosbuvir 400 mg + RBV 1000-1200 mg/day 24 weeks
Treatment naïve cirrhosis Sofosbuvir + daclatasvir 60 mg with or without ribavirin 24 weeks
SOF 400 mg + peg-IFN + RBV 1000-1200 mg/day 12 weeks
AASLD Guidance Document Accessed March 20, 2016
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Page 20 of 25
David E. Bernstein, MD, FACG
Recommendations for Treatment of Treatment Experienced Genotype 3
PEG/RBV Treatment experienced without cirrhosis
SOF 400 mg + Daclatasvir60 mg 12 weeks
SOF 400 mg + peg-IFN + RBV 1000-1200 mg/day 12 weeks
PEG/RBV Treatmentexperienced with cirrhosis
SOF 400 mg + daclatsavir60 mg plus RBV 1000-1200
mg/day24 weeks
SOF 400 mg + peg-IFN + RBV 1000-1200 mg/day 12 weeks
SOF/RBV treatment experienced (with and without cirrhosis)
SOF 400 mg + daclatasvir60 mg with RBV 1000-1200
mg 24 weeks
SOF 400 mg + peg-IFN + RBV 1000-1200 mg/day 12 weeks
AASLD Practice Guidelines Accessed March 20, 2016
TREATMENT OF GENOTYPE 4
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Page 21 of 25
David E. Bernstein, MD, FACG
Genotype 4•Accounts for about 1-2% of HCV infections in US
•Common in Egypt, Saudi Arabia, North Africa, and Southern Europe and immigrants from these regions
•Approximately 70% of patients with genotype 4 HCV have moderate to severe steatosis with or without sinusoidal fibrosis (similar to GT3)
•Historic SVR rates with IFN-based therapy between GT1 and GT 2,3
Genotype 4: SVR (combined naïve and treatment experienced)
99% 99%
100%
98%
99%
99%
99%
99%
99%
100%
100%
100%
100%
ELB/GRZ 12 wks SOF/LDV 12 wksParitaprevir/r/ombitasvir plus RBV for 12 weeks
Zeuzem et al. J of Hepatology 2015Kohli et al. Lancet Inf Dis 2014
Herzode et al. Lancet 2015 , Jacobson et al. AASLD 2015 Abstract 42
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Page 22 of 25
David E. Bernstein, MD, FACG
Treatment Recommendations for Genotype 4: Treatment Naive
Recommended Regimen Duration
Elbasvir / grazeprevir 12 weeks
Ledipasvir/sofosbuvir 12 weeks
Paritaprevir/ritonavir/ombitasvir + RBV 1000-1200 mg/day 12 weeks
AASLD/IDSA treatment recommendation acessed 11/25/2015s.
Treatment Recommendations for Genotype 4: IFN/RBV Treatment experienced
Recommended Regimen Duration
Elbasvir / grazprevir + RBV 1000-1200 mg/day 16 weeks
Ledipasvir/sofosbuvir 12 weeks
Paritaprevir/ritonavir/ombitasvir + RBV 1000-1200 mg/day 12 weeks
AASLD/IDSA treatment recommendations accessed 11/25/2015
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Page 23 of 25
David E. Bernstein, MD, FACG
NEW THERAPIES ON THE HORIZON FOR GENOTYPE 4
Astral 1: Velpatasvir (NS5A) + SOF for 12 weeks- Genotype 4, 5 and 6
100 97 100
0
20
40
60
80
100
GT 4 GT 5 GT 6
SVR
Feld et al. NELM 2015
116/116 34/35 41/41
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 24 of 25
David E. Bernstein, MD, FACG
Summary
• All oral DAA’s highly effective for all non-genotype 1 genotypes
• What’s ahead in the future– Pangenotypic therapies– Shorter duration of treatment?
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 25 of 25
