Transcript Document

Ledipasvir/Sofosbuvir for 12 Weeks in
Patients Coinfected With HCV and HIV-1:
ION-4
Susanna Naggie1, Curtis Cooper2, Michael Saag3, Luisa M. Stamm4, Jenny C. Yang4,
Phillip S. Pang4, John G. McHutchison4, Douglas Dieterich5, Mark Sulkowski6
1Duke
Clinical Research Institute, Durham, NC; 2University of Ottawa, The Ottawa
Hospital, Ottawa, ON; 3University of Alabama at Birmingham, Birmingham, AL;
4Gilead Sciences, Inc., Foster City, CA; 5Icahn School of Medicine at Mount Sinai,
New York, NY; 6Johns Hopkins University School of Medicine, Baltimore, MD
CROI 2015, Seattle
Background
 Ledipasvir
– Once-daily, oral, 90-mg
NS5A inhibitor
LDV
NS5A
inhibitor
 Sofosbuvir
SOF
nucleotide
polymerase
inhibitor
‒ Once-daily, oral, 400-mg
NS5B inhibitor
 Ledipasvir/Sofosbuvir FDC
– Once-daily, oral, fixed-dose
(90/400 mg) combination tablet
– Single-tablet regimen for
hepatitis C
FDC, fixed-dose combination.
LDV
NS5A
LDV
inhibitor
NS5A
inhibitor
SOF
SOF
SOFnucleotide
nucleotide
SOF
nucleotide
polymerase
polymerase
nucleotide
polymerase
inhibitor
inhibitor
polymerase
inhibitor
inhibitor
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Background and Aims
HIV-HCV (ION-4)
 Liver-related complications remain a leading cause of
death among HIV/HCV-coinfected patients.1
 Safe and effective oral treatments compatible with
multiple antiretrovirals are needed for the eradication of
HCV in HIV/HCV-coinfected patients.
 Aim of this study was to evaluate the efficacy and safety
of LDV/SOF for the treatment of HCV in patients
coinfected with HIV-1, currently on antiretroviral therapy.
1Smith,
CJ et al. Lancet 2014; 384:241-8.
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Study Design
HIV-HCV (ION-4)
Wk 0
Wk 12
Wk 24
SVR12
N=335
LDV/SOF
 Phase 3, multicenter, open-label study (NCT02073656)
 HCV GT 1 or 4 patients in US, Canada, and New Zealand
 Broad inclusion criteria
– HCV treatment-naïve or treatment-experienced
– 20% with compensated cirrhosis
– Platelets ≥50,000/mm3; hemoglobin ≥10 mg/dL, CrCl ≥60 mL/min
– HIV-1 positive, HIV RNA <50 copies/mL; CD4 cell count >100 cells/mm3
 ART regimens included emtricitabine and tenofovir disoproxil fumarate
plus efavirenz, raltegravir, or rilpivirine
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Endpoints
HIV-HCV (ION-4)
 Primary efficacy endpoint: SVR12
– HCV RNA <LLOQ at post-treatment Week 12
• HCV RNA analyzed by COBAS TaqMan HCV Test v2.0 HPS,
with LLOQ of 25 IU/mL
 Safety
– Adverse events and discontinuations
– Maintenance of HIV-1 RNA <50 copies/mL
– Serum creatinine
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Results: Demographics and Baseline Characteristics
HIV-HCV (ION-4)
LDV/SOF 12 weeks
N=335
Mean age, y (range)
52 (26-72)
Male, n (%)
276 (82)
Black, n (%)
115 (34)
Hispanic or Latino, n (%)
56 (17)
Mean BMI, kg/m2 (range)
27 (18-66)
IL28B CC, n (%)
81 (24)
GT 1
327 (98)
HCV treatment experienced, n (%)
185 (55)
Cirrhosis, n (%)
67 (20)
Mean HCV RNA, log10 IU/mL ± SD
Median CD4 cell count, cells/µL (range)
6.7 ± 0.6
628 (106-2069)
HIV ARV Regimen
Efavirenz + FTC + TDF
160 (48)
Raltegravir + FTC + TDF
146 (44)
Rilpivirine + FTC + TDF
29 (9)
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Results: SVR12
HIV-HCV (ION-4)
Overall
100
Naïve vs Experienced
Cirrhosis Status
96
95
97
96
94
321/335
142/150
179/185
258/268
63/67
Naïve
Experienced
No Cirrhosis
Cirrhosis
SVR12 (%)
80
60
40
20
0
LDV/SOF
12 Weeks
Error bars represent 95% confidence intervals.
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Results: SVR12
HIV-HCV (ION-4)
Overall
Overall
100
96
Naïve vs Experienced
95
97
Cirrhosis Status
96
94
SVR12 (%)
80
60
40
•
•
•
•
10 relapses
2 on-treatment failures (noncompliance, per investigators)
1 lost to follow-up
1 death (IVDU-related endocarditis/sepsis)
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321/335
142/150
179/185
258/268
63/67
Naïve
Experienced
No Cirrhosis
Cirrhosis
0
LDV/SOF
12 Weeks
Error bars represent 95% confidence intervals.
8
Results: SVR12 by Prior Treatment Experience
HIV-HCV (ION-4)
Overall
Overall
100
Naïve vs Experienced
Cirrhosis Status
96
95
97
96
94
321/335
142/150
179/185
258/268
63/67
Naïve
Experienced
No Cirrhosis
Cirrhosis
SVR12 (%)
80
60
40
20
0
LDV/SOF
12 Weeks
Error bars represent 95% confidence intervals.
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Results: SVR12 by Prior Treatment Experience
and Cirrhosis Status
HIV-HCV (ION-4)
Overall
Overall
100
Naïve vs Experienced
Cirrhosis Status
96
95
97
96
94
321/335
142/150
179/185
258/268
63/67
Naïve
Experienced
No Cirrhosis
Cirrhosis
SVR12 (%)
80
60
40
20
0
LDV/SOF
12 Weeks
Error bars represent 95% confidence intervals.
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Results: SVR12 in Subgroups
HIV-HCV (ION-4)
LDV/SOF 12 Weeks, N=335
Overall
Sex
Race
HCV Genotype
Baseline HCV RNA (IU/mL)
Baseline BMI (kg/m2)
IL28B
Cirrhosis
Prior HCV Treatment
ARV Regimen
Baseline CD4 (cells/μL)
Male
Female
Black
Non-Black
1a
1b
4
<800,000
≥800,000
<30
≥30
CC
CT
TT
No
Yes
No
Yes
EFV + FTC + TDF
RAL + FTC + TDF
RPV + FTC + TDF
<350
≥350
60
70
80
90
SVR12, % (95% CI)
100
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Results: SVR12 in Subgroups
HIV-HCV (ION-4)
LDV/SOF 12 Weeks, N=335
Overall
Sex
Race
HCV Genotype
Baseline HCV RNA (IU/mL)
Baseline BMI (kg/m2)
IL28B
Cirrhosis
Prior HCV Treatment
ARV Regimen
Baseline CD4 (cells/μL)
Male
Female
Black
Non-Black
1a
1b
4
<800,000
≥800,000
<30
≥30
CC
CT
TT
No
Yes
No
Yes
EFV + FTC + TDF
RAL + FTC + TDF
RPV + FTC + TDF
<350
≥350
60
Statistically significant
in multivariate analysis
70
80
90
SVR12, % (95% CI)
100
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PK and Other Exploratory Analyses
HIV-HCV (ION-4)
 No difference in SVR in HCV mono-infected ION
program (12 weeks) for black (89/90, 99%) versus
non-black (431/448, 96%)2
 LDV and SOF population PK levels
– Similar across the different ARV regimens
– Similar between black and non-black patients
– Similar between patients who relapsed and those who
achieved SVR
 GWAS and whole genome sequencing analysis
underway
2Lennox
et al. AASLD 2014 Oral abstract #237
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Results: HCV Sequence Analysis
HIV-HCV (ION-4)
 Deep sequencing of NS5A at baseline identified 67
(20%) patients with NS5A variants (RAVs)
– 63 (94%) of patients with NS5A RAVs achieved
SVR12
 Post-treatment NS5A RAVs were observed in 10 of
the 12 patients with virologic failure
 No NS5B S282T was observed in any patient at
baseline or virologic failure
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Results: Safety Summary
HIV-HCV (ION-4)
Patients, n (%)
AEs
Overall
safety
LDV/SOF 12 Weeks
N=335
257 (77)
Grade 3‒4 AE
14 (4)
Serious AE
8 (2)*
Treatment D/C due to AE
0
Death
1 (<1)†
Grade 3‒4 laboratory abnormality
36 (11)
 Stable CD4 counts through treatment and follow-up phase
 No patient had confirmed HIV virologic rebound
*Serious AEs in >1 patient were hepatocellular carcinoma (n=2) and portal vein thrombosis (n=2) in patients with cirrhosis.
†Confirmed IV drug user developed Staphylococcus aureus sepsis, endocarditis with associated embolic brain abscesses,
and multi-organ system failure.
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Results: Adverse Events (≥5%)
HIV-HCV (ION-4)
Patients, n (%)
LDV/SOF 12 Weeks
N=335
Headache
83 (25)
Fatigue
71 (21)
Diarrhea
36 (11)
Nausea
33 (10)
Arthralgia
22 (7)
Upper respiratory tract infection
18 (5)
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Results: Renal Function
HIV-HCV (ION-4)
Creatinine Clearance
(mL/min), mean ± SD
LDV/SOF +
EFV+FTC+TDF (n=160)
150
RAL+FTC+TDF (n=146)
140
RPV+FTC+TDF (n=29)
130
120
110
100
90
80
70
60
BL
1
2
4
6
8
10
12
FU-4
Week
 4 patients (1%) had change in creatinine ≥ 0.4 mg/dL
– 2 completed treatment with no ART change
– 1 had dose reduction of TDF, 1 discontinued TDF
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Conclusions
HIV-HCV (ION-4)
 In this Phase 3 study of 335 HIV/HCV-coinfected patients,
96% achieved SVR12 after 12 weeks of a once-daily,
single-tablet regimen of LDV/SOF
– Prior HCV treatment status or the presence or absence of
cirrhosis did not impact outcome
– In contrast to larger studies among monoinfected patients, a
lower response rate was observed among coinfected black
patients treated with LDV/SOF (SVR12 90%)
 LDV/SOF was well tolerated, with no treatment
discontinuations due to adverse events and no adverse
impact on HIV disease or its treatment
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