4/30/2015
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AU Edited: 04-27-2015
David L. Wyles, MDAssociate Professor of Medicine
University of California San DiegoLa Jolla, California
Interactive Case-Based Presentations
and Audience Discussion
Los Angeles, CA: April 28, 2015 (ADVANCED)
Slide 2 of 50
Considerations in patients failing a DAA-based regimen
• Was interferon part of the regimen–What was the specific response?–Dose reductions on treatment?
• What specific medication classes were used–What role dose resistance play?
• Stage of liver disease• Indications of other problems
–Adherence?– Significant drug interactions?– Immunosuppression?
Slide 3 of 50
Case 1
57 yo male with DM and HCV GT1a, F3/4 on biopsy treated with PEG/RBV/TVR in 2011.
Treatment complicated by severe anemia and neutropenia
– Week 8: Required transfusion, RBV dose reduction
– Week 12: PEG dose reduction, GCSF
– HCV RNA 127 IU/ml at week 4; viral BT at week 26
• Treatment discontinued– Current HCV RNA 2.7 million
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Slide 6 of 50
HCV and HIV replication dynamics
Long-lived Reservoir
t1/2≈ 0.7 d
~ 2.0 d
<1%
>99%
t1/2≈ wks* t1/2 > 44 mo
~97%
t1/2≈ 10 hrs
~ 7.0 d*
Perelson A Science 1986. Markowitz M J Virol 2003. Finzi D Nat Med 1999. Neumann A, Science 1999. Guo J. J Virol 2003.
t1/2≈ 1 hrt1/2≈ 0.75 hr
Extra-hepatic
Reservoir
~3%
t1/2 ≈ 2.6 d
Slide 7 of 50
Virus characteristics and resistance potential
HCV10
12 virions/day
Error prone viral polymerase (x2)
No overlapping reading frames
Moderate infected cell turnover
Dynamic replication unit
Cytoplasmic replication(t1/2 ~10hrs)
No latent reservoir
Cure possible
HIV10
10 virions/day
Error prone viral polymerase
Overlapping reading frames
Rapid infected cell turnover (t1/2 ~24hrs)
Static replication unit
Integrated proviral DNA
Latently infected Tcells
Control, not cure
Viral Quasispecies
Slide 8 of 50
Resistance potential and HCV antiviral classes
ClassAntiviral Potency
GenotypeActivity
Mutational Barrier
FitnessResistance
barrier
Proteaseinhibitors
+++ to ++++ 1 (and 4) 1a<1b Variable
Low to moderate
NS5B Nucleoside/tide
++++ 1-6 -- Very low Very High
NS5BNon-nucleoside
++ to +++ 1 variable High Very low
NS5A inhibitors
++++ 1, 4-6(+/- 2,3)
1a<1b Moderate-High
Low
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Slide 9 of 50
Cross-resistance among HCV PIs
Telaprevir Boceprevir Simeprevir Asunaprevir ABT-450/r
V36A/M
T54A/S
V55A
Q80K
R155K
A156S
A156T,V
D168A/V/E
V170A/T
Slide 10 of 50
0.6
Pro
bab
ility
Time after failure (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.7
0.8
0.9
1.0
0 2 4 6 8 10 12 14 16 18
median
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
bab
ility
0 2 4 6 8 10 12 14 16 18
Time after treatment failure (months)
median
Decay of resistant variants
• Follow-up of all non-SVR subjects in phase 3 trials with Telaprevir
Time
(months)
Probability
0 26%
3 36%
6 48%
12 71%
16 96%
Probability of being WT 1
1 Based on Kaplan-Meier estimation using population sequencing; hash marks in plot
indicate censored observations
Sullivan JM et al. J Hepatol. 54: S4, 2011.
Slide 11 of 50
Loss varies by resistant variant
Pro
bab
ility
Time After Treatment Failure (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 4 6 8 10 12 14 16 18
R155K
V36M
A156S/T
V36A
T54A
Common 1a variants
Common 1b variants
median
Sullivan JM et al. J Hepatol. 54: S4, 2011.
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Slide 12 of 50
Similar pattern with decay of SMV resistant variants
Lenz O. EASL 2014.
91% of nonSVR with resistance1a: R155K +/- Q80K
1b: D168V
Slide 13 of 50
Case 1 continuedPatient returns in January 2015 requesting treatment with the “new drugs”. No acute events but has felt more fatigued. Updated labs show:
• ALB 3.8, AST 57/ALT 49, TB 0.9 DB 0.4 INR 1.2
• PLT 115, Hgb 13.5 g/dL
• US (11/2014) Nodular liver without focal lesions. PV 15mm, splenomegaly, no ascites
Slide 14 of 50
Review from Dr. Peters’ discussion
1. Does this patient need a repeat biopsy?
2. What other testing is indicated for this patient?
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Slide 16 of 50
• Treatment experienced
– 52% HCV PI failures
– 44% null responder
• 20% cirrhosis
All relapses were in 12 week arms (11; 2%)
– 82-86% SVR in cirrhotics
94 96
99 99
0
20
40
60
80
100
SVR
12 (
%)
12wk 12wk + R 24wk 24wk + R
Afdahl N. NEJM 2014.
SOF/LDV
SOF/LDV/r
SOF/LDV
SOF/LDV/r
12 24Weeks
N=109
N=111
N=109
N=111
ION
-2
Nucleotide plus NS5A for treatment experienced GT1: ION-2
Slide 17 of 50
SOF + LDV: Responses in PI treated subjects
12 + R12 24 + R24
94 97 99 100
0
20
40
60
80
100
12wk 12wk + R 24wk 24wk + R
SVR
12 (
%)
66 64 50 51
ION-2 Afdahl N. NEJM 2014.
Slide 18 of 50
SOF + LDV ± RBV
• Double-blind study
• Treatment experienced cirrhotic patients– All failed both Peg/RBV then P/R/PI
– Groups were well matched• Plt <100k: 18% vs 17%
• ALB <3.5: 8% vs. 17%
SIRIUS Bourliere M. #LB-6 AASLD 2014.
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Slide 19 of 50
SOF + LDV ± RBV: 12 vs 24 Wks
SIRIUS Bourliere M. #LB-6 AASLD 2014. Bourliere M. #82 AASLD 2014
Slide 20 of 50
Real World Data: Impact of prior PI therapy?
Dieterich D. #46 AASLD 2014. Jensen D. #45 AASLD 2014.
8185
79
0
8992
87
75
0
20
40
60
80
100
All NC Cirr DC
SVR
4 (%
)
PI failure No PI
No data on Q80K; vast majority did not have it tested.97% concordance between SVR4 and SVR12.
TARGET
80 82
0
20
40
60
80
100
SVR12
SVR
12 (
%)
PI failure No PI
Slide 22 of 50
SOF Resistance• AASLD 2013: No S282T in 4 phase 3 studies
– Studies across GTs 1-4 (NEUTRINO, FISSION, FUSION, POSITRON)
– 226 non-SVRs: 221 UDS (1% detection level)
• No S282T identified
– 1/294 non-SVRs with S282T (Svarovskaia E. CID 2014)
• AASLD 2014: No S282T in phase 3 SOF/LDV
– L159F +/- V321A seen as TEVs
– 15% L159F with SOF; 1% with SOF/LDV
– impact on response?
• 1.6% at baseline w/ L159F: 100% SVR in SOF/LDV (23/23)
Svarovskaia E. AASLD 2013. Gane E. #43 AASLD 2014.
4/30/2015
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Evolution of sofosbuvir resistance in the subject with S282T.
Svarovskaia E S et al. Clin Infect Dis. 2014;59:1666-1674
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases
Society of America. All rights reserved. For Permissions, please e-mail:
Slide 25 of 50
Retreatment of SOF failure with SOF/LDV + RBV: GS-US-342-1118
Wk 0 Wk 12 Wk 36Wk 24
LDV/SOF + RBV SVR12SOF failures
(n=51)
LDV/SOF SVR12LDV/SOF failures
LDV/SOF + RBV SVR12SOF failures (advanced liver disease)
Wyles D. AASLD 2014.
Slide 26 of 50
Baseline CharacteristicsLDV/SOF + RBV 12 weeks
n=51
Mean age, y (range) 54 (27‒68)
Men, n (%) 31 (61)
Black/African American, n (%) 8 (16)
Hispanic/Latino, n (%) 4 (8)
Mean BMI, kg/m2 (range) 30.4 (21.1‒47.9)
IL28B non-CC, n (%) 47 (92)
GT 1a, n (%) 30 (59)
Mean HCV RNA, log10 IU/mL (range) 6.2 (4.4‒7.3)
HCV RNA ≥800,000 IU/mL, n (%) 38 (75)
Prior HCV treatment, n (%)
SOF + PEG/RBV 25 (49)
SOF ± RBV* 21 (41)
SOF placebo† 5 (10)
Cirrhosis, n (%) 15 (29)
Wyles D. AASLD 2014.
4/30/2015
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Slide 27 of 50
24
98 100 100 98 98 98
0
20
40
60
80
100
Wk 1 Wk 4 Wk 8 EOT SVR4 SVR12 SVR24
HC
V R
NA
<LLO
Q,
%
Error bars represent 95% CIs.EOT, end of treatment.
51/5112/51 51/51
HC
V R
NA
<LLO
Q,
%
50/5150/51 50/5150/51
On-Treatment Viral Kinetics and SVR Rates
Wyles D. AASLD 2014.
14/14 SOF/RBV failures achieved SVR12 with SOF/LDV for 12 weeks.Osinusi A. EASL 2014.
Slide 28 of 50
Case 262 WM with cirrhosis who was treated in the ION-2 study. Received 12 weeks of SOF/LDV (no RBV). CPT A5.
• Week 4: HCV RNA <25 IU/mL (detected)
• All subsequent HCV RNA TND
• SVR4 f/u: AST/ALT: 45/67….
–HCV RNA: 253,000 IU/mL
Slide 29 of 50
Case 2He returns to clinic to discuss treatment options. Now about 4 months post relapse.
• Updated labs:
– PLT 61, Hgb 13.8 g/dL
– AST/ALT: 59/59, TB 0.7, DB 0.3, ALB 4.1, INR 1.0
– Cr 1.29 (prior 1.08)
– HCV RNA 1.2 million
• U/S: Nodular liver, no lesions. 12mm PV, 15cm spleen. No ascites. Non-occlusive R PVT.
• EGD: grade 1 esophageal varices
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Slide 31 of 50
NS5A Inhibitor Resistance
• Similar resistance pattern for 1st gen NS5A with respect to GT 1a and 1b
Kitrinos KM. #1949 AASLD 2014. Wang C. AAC 2013
Slide 32 of 50
Not all NS5A inhibitors are created equalEC50 (pM) 1a 2a 3 4 6
LDV 34 21000 35000 110 120
DCV 50 71 150 12 --
GS-5816 12 9 12 9 6
Elbasvir 4 3 20 3 --
ACH-3102 26 <10x FC in EC50
ABT-530 2 2 2 2 3
Wang C. AAC 2012. Zhao Y. #A845 EASL 2012. Ng T. #639 CROI 2014.
Later generation compounds retain activity against variants at polymorphic site (Q30, L31) and those associated with resistance (28, 30, 31, 58, and 93).
16% (12/76)Patients with NS5ARAVs
84% (64/76) Patients without NS5A RAVs
Before LDV Treatment
At Virologic Failure
99% (72/73)
Patients with NS5A RAVs
NS5A RAVs in Patients Treated With LDV Regimens Without SOF
Wyles D. EASL 2015.
4/30/2015
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Parent Study
Durability of treatment emergent RAVs
98 100 98 10095
86
0
20
40
60
80
100
VF Baseline FU-12 FU-24 FU-48 FU-96
Pati
ents
Wit
h N
S5A
RA
Vs
(%)
Registry Study
62/63 58/58 42/43 45/45 52/55 50/58
NS5A RAVs persisted in majority of patients for 96 weeksWyles D. EASL 2015.
14%
19%
33%
34%
16%
22%62%
Number of NS5A RAVs at Baseline and Follow-Up
Baseline Registry Follow-Up Week 96
No RAVs
1 RAV
2 RAVs
≥3 RAVs
Number of RAVs per patient declined over the 96-week observation period
Wyles D. EASL 2015.
Slide 36 of 50
RAV persistence after 3D treatment
NS3 NS5A NS5B
Krishnan P. EASL 2015.
4/30/2015
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Slide 38 of 50
Baseline NS5A resistance and SOF/LDV
• Deep sequencing analysis of baseline samples (n=1904) in phase 2/3 SOF/LDV studies
– ELECTRON, LONESTAR and ION studies
Sarrazin C. #1926 AASLD 2014.
97%
93%
GT 1 (n=2137)
98%95%
GT 1b (n=529)
96%
92%
GT 1a (n=1602)
NS5A RAVsNo NS5A RAVs
SVR12 (%)
Slide 39 of 50
Baseline NS5A resistance and SOF/LDV
Sarrazin C. #1926 AASLD 2014.
<100X
>100X
No RAVs
Slide 40 of 50
We got our hopes up…based on the “infamous” SOF LDV patient.
LONESTAR Lawitz E. #215 AASLD 2013.
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Slide 41 of 50
Retreatment of SOF failure with SOF/LDV + RBV: GS-US-342-1118
Lawitz E. EASL 2015.
Wk 0 Wk 12 Wk 36Wk 24
LDV/SOF + RBV SVR12SOF failures (n=51)
LDV/SOF SVR12LDV/SOF failures(n=41)
LDV/SOF + RBV SVR12SOF failures (advanced
liver disease)
Slide 42 of 50
Retreatment of SOF failure with SOF/LDV + RBV: GS-US-342-1118
Lawitxz E. EASL 2015.
LDV/SOF 24 WeeksN=41
Mean age, y (range) 58 (35–71)
Male, n (%) 34 (83)
Black/African American, n (%) 10 (24)
IL28B non-CC, n (%) 38 (93)
GT 1a, n (%) 34 (83)
Mean HCV RNA, log10 IU/mL (range) 6.2 (4.5–7.4)
Cirrhosis, n (%) 19 (46)
Prior HCV treatment, n (%)
LDV/SOF ± RBV 33 (80)
LDV/SOF + GS-9669 8 (20)
Prior HCV treatment duration, n (%)
8 weeks 30 (73)
Presence of NS5A RAVs 19 (63)
12 weeks 11 (27)
Presence of NS5A RAVs 11 (100)
Slide 43 of 50
SVR12 with retreatment
32
95 100 100
7371
0
20
40
60
80
100
Wk 1 Wk 4 Wk 8 EOT SVR4 SVR12
Lawitz E. EASL 2015.
Retreatment of SOF failure with SOF/LDV + RBV
4/30/2015
13
44
Results: SVR12 by Subgroup
68
80
100
74
46
60
0
20
40
60
80
100
No Yes 8 wks 12 wks No Yes
22/34 7/7 15/22 14/19 11/11 18/30
Cirrhosis Prior Treatment
Duration
Baseline NS5A
RAVs
All 11 patients without NS5A RAVs received 8 weeks of prior treatment
SV
R12 (
%)
Lawitz E. EASL 2015.
Retreatment of SOF failure with SOF/LDV + RBV
Results: SVR12 by Baseline NS5A RAVs
70
58
42
50
0
20
40
60
80
100
Q30 L31 Y93 Other*
9/13 7/12 2/45/12
*Other: M28T (n=2), S38F, H58D and A92T (n=1 each)
100
69
50
0
20
40
60
80
100
None 1 ≥2
11/11 11/16 7/14
Number of NS5A RAVs
SV
R12 (
%)
NS5A RAVs
(H/R/T/Y/N/K) (M/I/V) (H/N)
Lawitz E. EASL 2015.
Retreatment of SOF failure with SOF/LDV + RBV
Slide 46 of 50
The optimal re-treatment approach for this patient is unknown.
• What does the addition of RBV do?
• Triple therapy studies are being designed.
–Nuc/NS5A/PI
• Are failures of 3D + RBV any different?
• Do we need to go back to adding PEG?
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Slide 47 of 50
Conclusions• Interferon plus DAA (PI) treated
patients respond well to DAA retreatment.
• SOF failure + IFN respond similarly well
• IFN-free DAA failures do not have an established retreatment approach.
• Resistance to NS5As appear to impact re-treatment responses