Up to the Minute Management of HCV Infection: Pearls, Pitfalls and Predictions FORMATTED: 05-15-2015 Chicago, IL: May 19, 2015 Michael R. Charlton, MBBS, FRCP Hepatology Director Medical Director of Liver Transplantation Intermountain Medical Center Salt Lake City, Utah ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 5 of 93 GT 1 http://www.hcvguidelines.org ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 6 of 93 Foster G, EASL, 2014, O66 SVR Rates of SOF-Based Regimens Across Genotypes and Among Patients with Multiple Negative Predictive Factors Retrospective analysis of data from Phase 2 and 3 SOF studies to identify variables associated with relapse Effect of Negative Predictors on SVR Rates Across SOF Studies SVR12 (%) Number of Negative Predictors SVR12 Rates by Number of Negative Predictors and Genotype 4/ 4 5/ 5 26/ 26 22/ 22 22/ 22 69/ 69 69/ 70 43/ 43 114/ 122 78/ 81 55/ 59 89/ 104 65/ 69 57/ 66 11/ 18 26/ 33 23/ 37 4/ 6 8/ 15 Negative predictors: Male gender, body weight ≥ 75kg, IL28B nonCC, baseline HCV RNA ≥ 800,000 IU/mL, prior treatment failure, cirrhosis 89% of patients in the Phase 3 program had ≤4 negative predictors ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Chicago, IL: May 19, 2015 1
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Up to the Minute Management of HCV Infection:
Pearls, Pitfalls and Predictions
FORMATTED: 05-15-2015
Chicago, IL: May 19, 2015
Michael R. Charlton, MBBS, FRCPHepatology Director
Medical Director of Liver Transplantation
Intermountain Medical Center
Salt Lake City, Utah
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GT 1
http://www.hcvguidelines.org
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Foster G, EASL, 2014, O66
SVR Rates of SOF-Based Regimens Across Genotypes and Among Patients with Multiple Negative Predictive Factors
Retrospective analysis of data from Phase 2 and 3 SOF studies to identify variables associated with relapse
Effect of Negative Predictors on SVR Rates Across SOF Studies
SV
R1
2 (
%)
Number of Negative Predictors
SVR12 Rates by Number of Negative Predictors and Genotype
4/4
5/5
26/26
22/22
22/22
69/69
69/70
43/43
114/122
78/81
55/59
89/104
65/69
57/66
11/18
26/33
23/37
4/6
8/15
Negative predictors: Male gender, body weight ≥ 75kg, IL28B nonCC, baseline HCV RNA ≥ 800,000 IU/mL, prior treatment failure, cirrhosis
89% of patients in the Phase 3 program had ≤4 negative predictors
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All oral therapy for HCV Genotype 1 infection
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Case 1.
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Case 1.
48 yr old man
New diagnosis of HCV infection identified during blood donation. Used intranasal cocaine as a teen.
HCV genotype 1 (not able to subtype), HCV RNA 6.48 million IU/ml
ALT 183, AST 211, normal total bilirubin
– 1:120 ASMA
– Has elevated Cr 1.74 mg/dl, GFR 45
PMH notable for gastro esophageal reflux disease and mild hypertension
Not all medications contraindicated with ritonavir and ribavirin are listed below. Refer to the most current package inserts or product labeling of ritonavir and ribavirin for a complete list of contraindicated medications
LDV/SOF Single Tablet Regimen in Treatment-Experienced GT 1 HCV
Phase 3, randomized, open-label study of LDV/SOF ± RBV for 12 or 24 weeks in HCV GT 1 treatment-experienced patients who previously failed PegIFN + RBV ± PI
ION-2 (LDV/SOF±RBV)
‡
N = 440
TE GT 1
12 24Study Weeks 36
SVR 12
SVR 12
n=109
n=111
n=109
n=111
RBV 1000-1200 mg/d
HCV RNA analyzed by COBAS® TaqMan® HCV Test v2.0 HPS, with LLOQ of 25 IU/mL
SVR 12 LDV/SOF 90/400 mg + RBV
LDV/SOF 90/400 mg
LDV/SOF 90/400 mg + RBV
SVR 12 LDV/SOF 90/400 mg
0
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SVR12 - LDV/SOF±RBV in Treatment-Experienced GT 1 HCV
94 96 99 99
0
20
40
60
80
100
107/111
12 Weeks 24 Weeks
LDV/SOF + RBV
102/109 108/109
SV
R1
2 (
%)
110/111
LDV/SOF + RBVLDV/SOF LDV/SOF
Error bars represent 95% confidence intervals
Afdhal N, EASL, 2014, O109
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
ION-2 (LDV/SOF±RBV)
‡
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Reasons for Not Achieving SVR
Afdhal N, EASL, 2014, O109
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
12 Weeks 24 Weeks
Patients, n (%)
LDV/SOF
n=109
LDV/SOF+RB
V
n=111
LDV/SOF
n=109
LDV/SOF+RB
V
n=111
SVR12 102 (94) 107 (96) 108 (99) 110 (99)
Breakthrough 0 0 0 1 (<1)
Relapse 7 (7) 4 (4) 0 0
Lost to Follow-
Up0 0 1 (<1) 0
Single on-treatment breakthrough was due to non-compliance
– Patient had no detectable levels of LDV or SOF at multiple time points prior to and at the time of virologic failure
ION-2 (LDV/SOF±RBV)
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93 96 100 9894 97 98 100
0
20
40
60
80
100
Failed PegIFN+RBV Failed Protease Inhibitor
SV
R1
2 (
%)
40/43 62/66 45/47 62/64 58/58 49/50 58/59 51/51
12 Weeks 24 Weeks
LDV/SOF + RBV LDV/SOF + RBVLDV/SOF LDV/SOF
SVR12 in PegIFN+RBV vs. PI+PegIFN+RBV Failures
Error bars represent 95% confidence intervalsAfdhal N, EASL, 2014, O109
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
ION-2 (LDV/SOF±RBV)
‡
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95 100 99 9986 82100 100
0
20
40
60
80
100
Absence of Cirrhosis Cirrhosis
SV
R1
2 (
%)
83/87 19/22 89/89 18/22 86/87 22/22 88/89 22/22
12 Weeks 24 Weeks
LDV/SOF + RBV LDV/SOF + RBVLDV/SOF LDV/SOF
SVR12: Absence of Cirrhosis vs. Cirrhosis
Error bars represent 95% confidence intervalsAfdhal N, EASL, 2014, O109
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
ION-2 (LDV/SOF±RBV)
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Conclusions
LDV/SOF RBV for 12 weeks resulted in SVR12 rates of
94–96% in treatment-experienced GT 1 patients–Adding RBV and/or extending LDV/SOF treatment duration to 24
weeks did not significantly increase SVR12 rates
24 weeks is needed in treatment experienced patients with
cirrhosis
Afdhal N, EASL, 2014, O109
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
ION-2 (LDV/SOF±RBV)
‡
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Gane E, EASL, 2014, O6
LDV/SOF±RBV in Difficult-to-Treat HCV Populations
ELECTRON-2 (LDV/SOF±RBV)
Wk 0 Wk 12 Wk 24
SVR12
LDV/SOF, n=20GT 1
CPT class B
LDV/SOF + RBV, n=19GT 1
Prior SOF exposure
LDV/SOF + RBV, n=26
LDV/SOF, n=25GT 3
Treatment naïve
Ran
do
miz
ed
Prior treatment history of SOF relapsers included SOF + RBV ± DAA
Cirrhosis was present in all CPT class B and 16% of GT 3 patients
Phase 2, open-label study of LDV/SOF RBV for 12 weeks in HCV GT 1 prior SOF relapsers, GT 1 patients with decompensated cirrhosis, and treatment-naïve GT 3 patients
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100
65 64
100
0
20
40
60
80
100
GT1 Retreatment GT1 CPT Class B GT3 Naïve GT3 Naïve
SV
R12 (
%)
19/19 13/20 16/25 26/26
LDV/SOF + RBV LDV/SOF LDV/SOF LDV/SOF + RBV
SVR12 Results with LDV/SOF±RBV for 12 Weeks
13/20 16/25 26/2619/19
Gane E, EASL, 2014, O6
ELECTRON-2 (LDV/SOF±RBV)
‡
LDV/SOF+RBV for 12 weeks achieved 100% SVR12 (19/19) in HCV GT 1 patients who previously relapsed after SOF-based regimens, including short-
duration LDV/SOF
LDV/SOF without RBV for 12 weeks achieved 65% SVR12 (13/20) in HCV GT 1 patients with CPT B cirrhosis who currently have no treatment options
LDV/SOF + RBV for 12 weeks achieved 100% SVR12 (26/26) in HCV GT 3 naive patients
LDV/SOF without RBV for 12 weeks achieved 64% SVR12 (16/25) in HCV GT 3 naïve patients
The regimens were safe and well tolerated
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Are responses durable?
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Gordon S, EASL, 2014, P1171SOF 400 mg/d; PegIFN 180 μg/wk; RBV 1000-1200 mg/d for SOF+RBV arms and 800 mg/d for PegIFN+RBV arm
Integrated Safety Analysis of SOF-Based HCV Treatment Regimens from Phase 3 Studies
Safety data from patients enrolled in 5 Phase 3 studies (NEUTRINO, VALENCE, FISSION, POSITRON, and FUSION)
0 12 16 24Week 48
Historical Control: TVR or BOC + PegIFN + RBV
PegIFN-Unable: POSITRON
PBO, n=71
SOF + RBV, n=207 SVR12
Treatment-Naïve: FISSION
SOF + RBV, n=256 SVR12
No response-guided therapy
PegIFN + RBV, n=243 SVR12
Treatment-Naïve: NEUTRINO
GT 1,4,5,6
GT 2,3
GT 2,3
IFN-
LIMITING
Treatment-Experienced: FUSION
SOF + RBV, n=103 PBO SVR12
SOF + RBV, n=98 SVR12GT 2,3
ALL
ORAL
THERAPY
Treatment-Naïve and Treatment-Experienced: VALENCE
SVR12SOF + RBV, n=73
SVR12SOF + RBV, n=250GT 3
GT 2
SVR12
SOF + PegIFN + RBV, n=327 SVR12
36
Integrated Safety Analysis of SOF Phase 3 Studies
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Cheng W, EASL, 2014, P1112
• SVR24 was durable in 100% of 480 patients with available data from Phase 3 trials
• 435 (91%) and 90 (19%) had available Week 24 and 48 data, respectively
Durability of SVR24Long-Term Follow-Up of SOF Phase 3 Studies
ConclusionsLong-Term Follow-Up of SOF Phase 3 Studies
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Cheng W, EASL, 2014, P1112
–Patient starts SOF/LDV for 12 weeks.
–HCV RNA negative at 4-12 weeks.
–Arthralgias and rash 6 weeks after end of treatment
–HCV RNA 4.5 million IU/ml
–What happened??
Case 1.
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Genotype 4
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Wk 0 Wk 24Wk 12
SOF+RBV
(n=31)*
SOF+RBV (n=29)*
SVR12
Wk 36 Wk 48
SVR24SVR4
SVR24
*SOF 400 mg/d; RBV 1000–1200 mg/d
SOF+RBV for GT 4 HCV
Randomized, open-label, single-center study conducted in the US of the safety and efficacy of all-oral SOF + RBV in patients of Egyptian ancestry with HCV GT 4
79
100
59
87
0
20
40
60
80
100
13/15
Treatment Naïve Treatment Experienced
12 Weeks
SOF+RBV
24 Weeks
SOF+RBV
SV
R1
2 (
%)
11/14 10/17
12 Weeks
SOF+RBV
24 Weeks
SOF+RBV
14/14
‡
Ruane P, EASL, 2014, P1243 *1 patient had RBV D/C after Day 35 due to AE of dyspnea, and completed SOF 24 wk
An Alternative View of Cirrhosis in Genotypes 1 and 4
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Ledipasvir/Sofosbuvir With Ribavirin for the Treatment of HCV in Patients With Decompensated
Cirrhosis: Preliminary Results of a Prospective, Multicenter Study
Michael R. Charlton3, Steven L. Flamm1, Gregory T. Everson2, Jill M. Denning4, Sarah Arterburn4, Theo Brandt-Sarif4, Phillip S. Pang4, John
G. McHutchison4, K. Rajender Reddy5, Nezam H. Afdhal6
1Northwestern Feinberg School of Medicine, Chicago, IL; 2University of Colorado Denver, Aurora, CO; 3Intermountain Medical Center, Murray, UT; 4Gilead Sciences, Inc., Foster City,
CA; 5University of Pennsylvania School of Medicine, Philadelphia, PA; 6Beth Israel Deaconess Medical Center, Boston, MA
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Study DesignGT 1 and 4, CPT Class B and C
108 patients randomized 1:1 to 12 or 24 Weeks of Treatment
GT 1 or 4 treatment-naïve or -experienced patients with decompensated cirrhosis (CPT class B [7-9] or C [score 10–12])
Broad inclusion criteria
– No history of major organ transplant, including liver