ias 2015, vancouver subjects with renal impairment switching from tenofovir disoproxil fumarate to...
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IAS 2015, Vancouver
Subjects with Renal Impairment Switching from Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide Have Improved
Renal and Bone Safety through 48 Weeks
Study GS-US-292-0112
Samir K. Gupta1, Anton Pozniak2, Jose Arribas3, Frank A. Post4, Mark Bloch5, Joseph Gathe6, Paul Benson7, Joseph Custodio8, Michael Abram8, Xuelian Wei8,
Andrew Cheng8, Scott McCallister8, Marshall W Fordyce8
1Indiana University School of Medicine, Indianapolis, IN, USA; 2Chelsea and Westminster Hospital NHS Foundation Trust, London, UK; 3Hospital Universitario La Paz, IdiPAZ, Madrid, Spain; 4King’s College Hospital
NHS Foundation Trust, London, UK; 5Holdsworth House Medical Practice, Darlinghurst, NSW, AUS 6Therapeutic Concepts, Houston, TX, USA; 7Be Well Medical Center, Berkley, MI, USA;
8Gilead Sciences, Foster City, CA, USA
Abstract #TUAB0103
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Author Disclosures
Dr. Gupta has served as an advisor for Gilead Sciences and ICON/Oncolys, received unrestricted research grants from Gilead Sciences and Janssen Pharmaceuticals, received conference travel support from Gilead Sciences and Bristol-Myers Squibb, and participates as a Principal Investigator in clinical trials for Gilead Sciences, Merck & Co, Bristol-Myers Squibb, and GlaxoSmithKline.
Tenofovir Alafenamide (TAF): Novel Prodrug of Tenofovir
† T1/2 based on in vitro plasma data.1. Lee W et. Antimicr Agents Chemo 2005;49(5):1898-1906. 2. Birkus G et al. Antimicr Agents Chemo 2007;51(2):543-550. 3. Babusis D, et al. Mol Pharm 2013;10(2):459-66. 4. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449-5. 5. Sax P, et al. JAIDS 2014. 2014;67(1):52-8. 6. Sax P, et al. Lancet 2015;385:2606-15.
HIV TARGET CELL
AMIDATE
ON
NN
NH2
N
P
O
O
HN
O
O
ESTER
N
N
N
N
NH2
OP
O
OO
O
O
O
OO
O
N
N
N
N
NH2
OP
O
HOOH
DIANION
GI TRACT
Tenofovir alafenamide
(TAF)
Tenofovir disoproxil fumarate
(TDF)
Tenofovir (TFV)
ParentNucleotide
T1/2 = 90 min†
T1/2 = 0.4 min†
PLASMA
TAF25 mg
TDF 300 mg
TFV
TFV
TFV
• 91% lower plasma TFV levels minimize renal and bone effects while maintaining high potency for suppressing HIV
TFV HIV
4
Background
GS-US-292-0112 is an ongoing, single-arm, open-label Phase 3 study of HIV-1-infected participants with mild-moderate renal impairment (eGFRCG 30-69 mL/min) who switched to E/C/F/TAF
In the overall cohort, there were no changes in actual GFR, but there were reductions in total and tubular proteinuria and improvements in bone mineral density1
We present today the 48-week analysis of renal and bone safety markers in the two subgroups of participants on TDF- and non-TDF-containing regimens before switching to E/C/F/TAF
1. Pozniak A, et al. CROI 2015. Abstract 795.
Study Design
Phase 3, 96-week, multicenter, open-label study of virologically suppressed adults switching from TDF- or non-TDF–containing regimens to E/C/F/TAF
Eligibility: stable eGFRCG (30–69 mL/min)
Primary endpoint: change from baseline in eGFR at Week 24
– Actual GFR assessed with iohexol clearance in a participant subset
Week 48 data are presented here by pre-switch TDF use (within-group comparisons, not between group comparisons)
5
Primary Endpoint
E/C/F/TAF QD N=242
24 96480 12Week
Baseline Characteristics
6
TotalN=242
TDFn=158
Non-TDFn=84
Median age, years 58 59 58≥ 65 years, % 26 22 33Female, % 21 23 17Black, % 18 22 12Median CD4 count, cells/μL 632 661 585Hypertension, % 40 34 49Diabetes, % 14 13 14Median eGFRCG, mL/min 56 58 53
eGFRCG ≥60 mL/min, % 34 40 24
Dipstick proteinuria, %Grade 1 23 27 16Grade 2 10 10 10Grade 3-4 0 0 0
7
Pre-Switch Antiretroviral Treatment
*Total >100%, as some regimens included >1 third agent.
NRTI(s)
7%
TDF65%
ABC22%
5%
Third Agent(% of participants)
TotalN=242
PI 44NNRTI 42INSTI 24CCR5 antagonist 3
Other nucleoside
No nucleos(t)ide
8
0
20
40
60
80
5963
5057
62
48
5863
49
BL W2/4/8 W24
Actual GFR by Iohexol Clearance through Week 24
Actual GFR unaffected by E/C/F/TAF switch, regardless of previous regimen
aGF
R (
mL/
min
)
GLSM Ratio, % (90% CI)*
TDF (n=21)Week 2, 4, or 8 vs baseline 98 (94, 102)
Week 24 vs baseline 100 (96, 105)
Non-TDF (n=10)Week 2, 4, or 8 vs baseline 96 (86, 108)
Week 24 vs baseline 98 (87, 111)
Total Non-TDFTDF
BL W2/4/8 W24 BL W2/4/8 W24
*Lack of alteration boundary: 80–125% (GLSM).
-10
0
10
Estimated GFR: Change from Baseline to Week 48M
edia
n Δ
fro
m B
asel
ine
eGFRCG
mL/min
eGFRCKD-EPI Cr
mL/min/1.73m2
9
eGFRCKD-EPI cys C
mL/min/1.73m2
TDF Non-TDFTotal
Baseline: 56 58 53 54 56 50 70 75 60
-0.6
+0.2
-1.8 -1.8* -1.5-2.7*
+1.6*
-1.4
+2.7*
*p<0.05 by two-sided Wilcoxon signed-rank test.
Proteinuria: Change From Baseline to Week 48
10
85
100
20
40
60
80
100
120
140
160
180
200
78
10
110
14
Med
ian
(mg/
g)
105
160
188
166 2140
500
1000
1500
2000
2500
3000
3500
151 207197 221
Med
ian
(µg/
g)
228
801
1525 1563
3477
399
Tubular Proteins
b-2-m:CrUPCR UACR RBP:Cr
*All Total and TDF changes statistically significant; †all non-TDF changes not statistically significant.
2941
18
Total* TDF* Non-TDF†
Baseline
Week 48
Clinically Significant Proteinuria: Baseline to Week 48
11
0
20
40
60
80
100
5984
53
8771 78
4116
47
1329 22
≤200 mg/g >200 mg/g
Par
ticip
ants
(%
)
Total* TDF* Non-TDF
BL Wk 48 BL Wk 48 BL Wk 48
Proteinuria (UPCR)
*Total and TDF changes statistically significant.
Clinically Significant Albuminuria: Baseline to Week 48
12
0
20
40
60
80
100
5174
45
7863 66
4926
55
2237 34
≤30 mg/g >30 mg/g
Par
ticip
ants
(%
)
Total* TDF* Non-TDF
BL Wk 48 BL Wk 48 BL Wk 48
Albuminuria (UACR)
*Total and TDF changes statistically significant.
13
BMD: Mean Change from Baseline to Week 48
*p<0.05 by two-sided Wilcoxon signed-rank test.
Spine Hip
2
4
-2
0
Me
an
(S
D)
% Δ
Sp
ine
BM
D
2
4
-2
0
2.95*
2.29*
0.99
1.85*
1.47*
0.70
Me
an
(S
D)
% Δ
Hip
BM
D
Week 24n=226
Baselinen=236
Week 48n=214
Week 24n=225
Baselinen=236
Week 48n=216
TDF Non-TDFTotal
-15
-10
-5
0
5
10
15
20 19
7
1
12
-11
-5 -4-1
Fasting Lipids at Week 48
14*Wilcoxon signed-rank test.
Me
dia
n C
ha
ng
e F
rom
Ba
selin
e (
mg
/dL
)
00.05
0.10.15
0.20.25
0.30.35
0.40.45
0.5
0.3
0.2
Me
dia
n C
ha
ng
e
Fro
m B
ase
line
<0.001 0.028 0.002 0.011 0.36 <0.001 0.028 0.73 <0.001 0.010p-value*
TDF Non-TDF
Total Cholesterol LDL HDL Triglycerides Total: HDL Ratio
Baseline: 194 205 122 126 54 55 122 165 3.6 3.7
15
Conclusions
Participants on TDF at time of switch had
– No change in actual GFR
– Significant improvements in urinary markers of renal function
– Significant improvements in BMD
– Significant increases in lipids Consistent with independent effect of circulating TFV on reducing
cholesterol levels
Participants not on TDF at time of switch had
– No changes in actual GFR
– Stable urinary markers of renal function and BMD
– Significant decreases in cholesterol fractions
These 48 week data support the renal and bone safety of once daily, single-tablet E/C/F/TAF for adults with HIV and renal impairment (eGFRCG 30–69 mL/min)
Acknowledgments
The authors gratefully acknowledge the investigators, the study staff, and all the study participants of GS-US-292-0112.
Study 0112 investigators
J Andrade-Villanueva, J Arribas, A Avihingsanon, J Bartczak, P Benson, M Bloch, R Bolan,I Brar, F Bredeek, T Campbell, K Casey, P Chetchotisakd, A Clarke, C Cohen, L Cotte,G Crofoot, D Cunningham, C Dietz, R Dretler, C Fichtenbaum, D Fish, J Flamm,S Follansbee, F Garcia, J Gathe, R Grossberg, S Gupta, T Hawkins, K Henry, T Jefferson, R Kalayjian, C Katlama, S Kerkar, A Khalsa, S Kiertiburanakul, D Klein, E Koenig, S Lewis, K Lichtenstein, C Martorell, C McDonald, J McGowan, J McMahon, A Mills, T Mudrikova,E Negredo, O Osiyemi, P Palmieri, D Podzamczer, F Post, A Pozniak, D Prelutsky,M Ramagopal, W Ratanasuwan, G Richmond, W Robbins, N Roth, P Ruane, A Scarsella, G Schembri, S Schneider, P Shalit, W Short, J Slim, L Sloan, D Stein, J Stephens, P Tebas, D Ward, T Wills
This study was funded by Gilead Sciences, Inc.
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