Ledipasvir/Sofosbuvir for 12 Weeks in
Patients Coinfected With HCV and HIV-1:
ION-4
Curtis Cooper1, Susanna Naggie2,Michael Saag3, Luisa M. Stamm4, Jenny C.
Yang4, Phillip S. Pang4, John G. McHutchison4, Douglas Dieterich5, Mark
Sulkowski6
1 University
of Ottawa, 2Duke Clinical Research Institute, Durham, NC; The Ottawa Hospital, Ottawa,
ON;
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
3University
IAS 2015, Vancouver
Disclosures
Dr. Cooper received funding as a :
 Speaker for Gilead Sciences, Abbvie
 Consultant for Gilead Sciences, Abbvie, MK, BMS
 Program Funding for Gilead Sciences, Abbvie. MK, Roche
2
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
3
Background and Aims
HIV-HCV (ION-4)
 Liver-related complications remain a leading cause of death
among HIV/HCV-coinfected patients1
 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.
4
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
5
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
6
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)
7
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.
8
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)
20
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.
9
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.
10
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.
11
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
12
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
13
ION-4 – LDV/SOF in HIV/HCV
SVR12 by ARV Regimen and Race
Non-Black
100
100
99
90
Black
98
100
95
90
85
% SVR12
80
60
40
20
215/217 103/115
97/97
52/61
13/13 100/102 42/44
49/50
18/18
9/10
0
Overall
EFV/FTC/TDF
RAL+FTC/TDF
RPV/FTC/TDF
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
15
Results: HCV Sequence Analysis
HIV-HCV (ION-4)
 Deep sequencing of NS5A at baseline identified 59 (18%) patients with
NS5A variants (RAVs)
– 55 (93%) 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
16
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.
17
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)
18
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
19
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
20
Acknowledgments
We extend our thanks to:
The patients and their families
All participating investigators throughout the US, Canada,
and New Zealand
UNITED STATES: David Asmuth, Rachel Baden, Meena Bansal, Maurizio Bonacini,
Norbert Brau, U. Fritz Bredeek, Raymond Chung, Calvin J. Cohen, Eric Daar, Craig Dietz,
Robin Henry Dretler, Richard Elion, W.J. Fessel, Jason Flamm, Timonthy Friel, Joel E.
Gallant, Joseph C. Gathe, Eliot Godofsky, Philip M. Grant, Federico Hinestrosa, Gregory
Huhn, Mamta Jain, Dushyantha Jayaweera, Donald Kotler, Jay Lalezari, Charles Landis,
Annie Luetkemeyer, Kristen Marks, Cynthia Mayer, Anthony Mills, Karam Mounzer,
Susanna Naggie, Bruce S. Rashbaum, Jorge E. Rodriguez, Peter J. Ruane, Paul Edward
Sax, Michael Saag, Kenneth Sherman, Marc Siegel, Richard Sterling, Mark Sulkowski,
Karen T. Tashima, Pablo Tebas, Melanie A. Thompson, William J. Towner, Chia Wang,
David A. Wheeler, David A. Wohl, Kimberly Workowski, David Wyles, Benjamin Young
CANADA: Curtis Cooper, Emmanuelle Huchet, Mark Hull, Marina Klein, David Wong
PUERTO RICO: Javier O. Morales-Ramirez, Jorge L. Santana-Bagur NEW ZEALAND:
Edward Gane, Catherine Stedman
 This study was funded by Gilead Sciences, Inc.
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