Naggie S. И др. (докладчик Cooper.) «Ledipasvir/sofosbuvir for 12 weeks in patients co-infected with HCV and HIV-1» 8th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, Vancouver, 2015. TUAB0202.

1. 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; 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
IAS 2015, Vancouver

2. 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

3. Background
 Ledipasvir
– Once-daily, oral, 90-mg
NS5A inhibitor
 Sofosbuvir
‒ 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
3
FDC, fixed-dose combination.
SOF
nucleotide
polymerase
inhibitor
LDV
NS5A
inhibitor
SOF
nucleotide
polymerase
inhibitor
SOF
nucleotide
polymerase
inhibitor
LDV
NS5A
inhibitor
SOF
nucleotide
polymerase
inhibitor
LDV
NS5A
inhibitor
SOF
nucleotide
polymerase
inhibitor

4. 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
4
1Smith, CJ et al. Lancet 2014; 384:241-8.

5. Study Design
HIV-HCV (ION-4))
 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
Wk 0 Wk 12 Wk 24
SVR12
LDV/SOFN=335

6. 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

7. Results: Demographics and Baseline Characteristics
HIV-HCV (ION-4)
7
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 6.7 ± 0.6
Median CD4 cell count, cells/µL (range) 628 (106-2069)
HIV ARV Regimen
Efavirenz + FTC + TDF 160 (48)
Raltegravir + FTC + TDF 146 (44)
Rilpivirine + FTC + TDF 29 (9)

8. 96 95 97 96 94
0
20
40
60
80
100
Naïve vs ExperiencedOverall Cirrhosis Status
LDV/SOF
12 Weeks
ExperiencedNaïve No Cirrhosis Cirrhosis
321/335 142/150 179/185 63/67258/268
SVR12(%)
Results: SVR12
HIV-HCV (ION-4)
8Error bars represent 95% confidence intervals.

9. 96 95 97 96 94
0
20
40
60
80
100
Naïve vs ExperiencedOverall Cirrhosis Status
LDV/SOF
12 Weeks
ExperiencedNaïve No Cirrhosis Cirrhosis
321/335 142/150 179/185 63/67258/268
SVR12(%)
Results: SVR12
HIV-HCV (ION-4)
9
• 10 relapses
• 2 on-treatment failures (noncompliance, per investigators)
• 1 lost to follow-up
• 1 death (IVDU-related endocarditis/sepsis)
Overall
Error bars represent 95% confidence intervals.

10. 96 95 97 96 94
0
20
40
60
80
100
Naïve vs ExperiencedOverall Cirrhosis Status
LDV/SOF
12 Weeks
ExperiencedNaïve No Cirrhosis Cirrhosis
321/335 142/150 179/185 63/67258/268
SVR12(%)
Results: SVR12 by Prior Treatment Experience
HIV-HCV (ION-4)
10
Overall
Error bars represent 95% confidence intervals.

11. 96 95 97 96 94
0
20
40
60
80
100
Naïve vs ExperiencedOverall Cirrhosis Status
LDV/SOF
12 Weeks
ExperiencedNaïve No Cirrhosis Cirrhosis
321/335 142/150 179/185 63/67258/268
SVR12(%)
Results: SVR12 by Prior Treatment Experience and
Cirrhosis Status
HIV-HCV (ION-4)
11
Overall
Error bars represent 95% confidence intervals.

12. Results: SVR12 in Subgroups
HIV-HCV (ION-4)
12
LDV/SOF 12 Weeks, N=335
Overall
Sex
Male
Female
Race
Black
Non-Black
HCV Genotype
1a
1b
4
Baseline HCV RNA (IU/mL)
<800,000
≥800,000
Baseline BMI (kg/m2)
<30
≥30
IL28B
CC
CT
TT
Cirrhosis
No
Yes
Prior HCV Treatment
No
Yes
ARV Regimen
EFV + FTC + TDF
RAL + FTC + TDF
RPV + FTC + TDF
Baseline CD4 (cells/μL)
<350
≥350
60 70 80 90 100
SVR12, % (95% CI)

13. Results: SVR12 in Subgroups
HIV-HCV (ION-4)
13
LDV/SOF 12 Weeks, N=335
Overall
Sex
Male
Female
Race
Black
Non-Black
HCV Genotype
1a
1b
4
Baseline HCV RNA (IU/mL)
<800,000
≥800,000
Baseline BMI (kg/m2)
<30
≥30
IL28B
CC
CT
TT
Cirrhosis
No
Yes
Prior HCV Treatment
No
Yes
ARV Regimen
EFV + FTC + TDF
RAL + FTC + TDF
RPV + FTC + TDF
Baseline CD4 (cells/μL)
<350
≥350
60 70 80 90 100
SVR12, % (95% CI)
Statistically significant
in multivariate analysis

14. 99 100 98 100
90
85
95
90
0
20
40
60
80
100
Overall EFV/FTC/TDF RAL+FTC/TDF RPV/FTC/TDF
%SVR12
Non-Black Black
103/115215/217 52/6197/97 13/13 49/5042/44100/102 9/1018/18
ION-4 – LDV/SOF in HIV/HCV
SVR12 by ARV Regimen and Race

15. 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
15
2Lennox et al. AASLD 2014 Oral abstract #237

16. 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

17. Results: Safety Summary
HIV-HCV (ION-4)
17
*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.
Patients, n (%)
LDV/SOF 12 Weeks
N=335
Overall
safety
AEs 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

18. Results: Adverse Events (≥5%)
HIV-HCV (ION-4)
18
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)

19. Results: Renal Function
HIV-HCV (ION-4)
19
EFV+FTC+TDF (n=160)
RAL+FTC+TDF (n=146)
RPV+FTC+TDF (n=29)
LDV/SOF +
60
70
80
90
100
110
120
130
140
150
CreatinineClearance
(mL/min),mean±SD
Week
BL 1 2 4 6 8 10 12 FU-4
 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

20. 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

22. Acknowledgments
22
We extend our thanks to:
The patients and their families
All participating investigators throughout the US, Canada,
and New Zealand
 This study was funded by Gilead Sciences, Inc.
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