Switching From a Tenofovir Disoproxil Fumarate
(TDF)-Based Regimen to a Tenofovir Alafenamide (TAF)-Based Regimen:
Data in Virologically Suppressed Adults Through 48 Weeks of Treatment
Anthony Mills, Jaime Andrade-Villanueva, Giovanni DiPerri, Jan Van Lunzen, Ellen Koenig, Richard Elion, Matthias Cavassini, Jose
Valdez-Madruga, Jason Brunetta, David Shamblaw, Edwin DeJesus, Andrew Plummer, YaPei Liu, and Scott McCallister
Abstract TUAB0102
Switch to E/C/F/TAF in Virologically Suppressed Adults
™
All patients
Š HIV-1 RNA <50 copies/mL for ≥96 weeks on stable TDF-based regimen
Š Estimated GFR >50 mL/min
E/C/F/TAF = EVG 150 mg, COBI 150 mg, FTC 200 mg, TAF 10 mg
™ E/C/F/TDF = EVG 150 mg, COBI 150 mg, FTC 200 mg, TDF 300 mg
™
Primary Endpoint
HIV-1 RNA <50 c/mL
Randomized (2:1),
active-controlled,
open-label study
Virologically
Suppressed
Adults
Week 0
E/C/F/TDF
(n=459)
n=959
EFV/FTC/TDF
(n=376)
Boosted ATV +
FTC/TDF
(n=601)
*Boosted by RTV or COBI
Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.
n=477
48
Switch to E/C/F/TAF
Continue TDF-Based
Regimen
96
Switch to E/C/F/TAF in Suppressed Adults: Results
Treatment Difference (95% CI)
Virologic Outcome
E/C/F/TAF n=959
HIV-1 RNA <50 c/mL, %
100
97
TDF-Based Regimen n=477
93
TDF Based
E/C/F/TAF
80
60
4.1
40
1.6
20
Success
n=
1
1
0
932
Failure
444
10
6.7
6
2
No Virologic Data
6
17
27
‒12%
+12%
0
Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.
Switch to E/C/F/TAF in Suppressed Adults:
Virologic Outcome by Prior Treatment
Patients With HIV-1 RNA <50 c/mL, %
Primary Endpoint
100
E/C/F/TAF
p <0.001
p=0.02
97
96
93
p=0.02
97
90
92
TDF-Based Regimen
p=NS
98
97
301
306
149
153
80
60
40
20
0
95% CI =
932
959
444
477
241
251
112
125
390
402
183
199
All Prior Regimens
Prior
EFV/FTC/TDF
Prior
Boosted
ATV + FTC/TDF
Prior
E/C/F/TDF
1.6—6.7
0.5—12.3
0.9—9.2
-1.9—3.9
Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.
GS-US-292-0109
Virologic Outcome, Differences by Subgroup
TDF-Based Regimen
E/C/F/TAF
Overall*
Age, y
Sex
Race
Adherence
<50*
≥50
Male*
Female
Black
Non-Black*
<95%
≥95%*
-12
-6
0
6
12
Treatment Difference in
Participants with HIV-1 RNA <50 c/mL, % (95% CI)
*Statistically significant difference favoring E/C/F/TAF treatment.
Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.
GS-US-292-0109
AEs Leading to Discontinuation
E/C/F/TAF
n=959
TDF-Based Regimen
n=477
0.9
2.5
Participants %
Renal Events
All Other
Events
• Acute renal failure†
• Interstitial nephritisǂ
•
•
•
•
•
Chronic kidney disease
Elevated serum creatinine
Fanconi syndrome, mild jaundice
Increased creatinine
Nephretic colic (nephrolithiasis)
• Depression
• Leg swelling, impaired concentration
• Memory loss, speech disturbance,
lack of motivation
• Nausea, vomiting, headache
• Panic attack
• Reiter syndrome
• Suicide attempt
•
•
•
•
•
•
Abnormal dreams
Depression, insomnia, irritability
Depression, insomnia, nightmares
Elevated bilirubin
Icterus (n=2)
Increased forgetfulness
†After cancer chemotherapy, participant hospitalized with neutropenia, sepsis, and multi-system organ failure
ǂRecurrent hematuria on treatment, subsequent off-treatment diagnosis of Hodgkin’s Lymphoma
Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.
GS-US-292-0109
DXA Scan Results: Spine BMD
Regardless of prior treatment regimen, differences between arms were
statistically significant
™ More than 2% difference between the arms at Week 48
™
Median % Change in BMD (Q1, Q3)
Change From Baseline to Week 48
All Participants (N=1,369)
4
3
2
E/C/F/TAF
TDF-Based Regimen
1.79
1
0
-0.28
p
<0.001
-1
-2
-3
Baseline
Week 24
Week 48
Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.
GS-US-292-0109
DXA Scan Results: Hip BMD
Regardless of prior treatment regimen, differences between arms were
statistically significant
™ More than 1.6% difference between arms at Week 48
™
Median % Change in BMD (Q1, Q3)
Change From Baseline to Week 48
All Participants (N=1,354)
3
E/C/F/TAF
2
TDF-Based Regimen
1.37
1
p <0.001
0
-0.26
-1
-2
Baseline
Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.
Week 24
Week 48
GS-US-292-0109 Change in Diagnosis of Osteopenia
or Osteoporosis (Defined by T-Score)
™
Differences between E/C/F/TAF and TDF-based regimens were statistically
significant (p <0.001)
Normal
Osteopenia
Osteoporosis
Spine
80
Patients, %
4.8
5.8
100
32
36
Hip
7.2
7.6
35
37
100
80
0.7
31
26
69
73
1.3
2.1
32
32
67
66
Baseline
Week 48
60
60
40
40
64
59
57
56
20
20
0
0.7
Baseline
Baseline
Week 48
E/C/F/TAF
n=912
0
Week 48
Baseline
TDF-Based Regimen
n=457
Week 48
E/C/F/TAF
n=902
TDF-Based Regimen
n=452
Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.
Switch to E/C/F/TAF in Suppressed Adults:
Effect on Tubular Proteinuria
Median % Change
30
Urine
Protein:Creatinine
Urine
Albumin:Creatinine
Urine Beta 2
Urine Retinol
Binding Protein:Creat Microglobulin:Creatinine
19
18
20
10
10
9
0
-10
-20
-30
E/C/F/TAF
-21
-40
-18
TDF-Based Regimen
-33
-50
-60
™
-52
Statistically significant improvements for participants who switched from either
E/C/F/TDF or from boosted ATV + FTC/TDF
Š Serum creatinine (p <0.001); eGFR (p <0.001)
Š Fractional excretion of phosphate, FEPO4 (p=0.05); fractional excretion of uric acid, FEUA (p <0.001)
™
Changes began by Week 2 and persisted to Week 48
Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.
Week 48 Conclusions
™
Study GS-292-0109 is the largest randomized switch study conducted in HIV-positive
virologically suppressed adults
™
Participants who switched to E/C/F/TAF were significantly more likely to maintain
virologic success
Š Had significant improvements in spine and hip BMD
Š Had significant reductions in osteopenia/osteoporosis
Š Had significant improvements in proteinuria and other markers of renal function
Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.
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. Gupta, Anton Pozniak, Jose Arribas, Frank A. Post, Mark Bloch, Joseph Gathe, Paul Benson,
Joseph Custodio, Michael Abram, Xuelian Wei, Andrew Cheng, Scott McCallister, Marshall W Fordyce
Abstract TUAB0103
Tenofovir Alafenamide (TAF):
Novel Prodrug of Tenofovir
™
91% lower plasma TFV levels minimize renal and bone effects while maintaining
high potency for suppressing HIV
GI TRACT PLASMA
Tenofovir
(TFV)
Parent
Nucleotide
Tenofovir
disoproxil
fumarate
(TDF)
DIANION
TFV
HIV
TARGET CELL
TFV
TDF
300 mg
ESTER
T1/2 = 0.4 min†
TFV
TAF
Tenofovir
alafenamide
(TAF)
HIV
†
T1/2 = 90 min
25 mg
TFV
AMIDATE
† 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.
Gupta S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0103.
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
Gupta S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0103.
Study GS-US-292-0112 – Switch to FTC/TAF in Subjects with
Renal Dysfunction (Stable eGFR CG 30–69 mL/min): Design
Primary Endpoint
Week
0
N=242
12
24
48
96
E/C/F/TAF QD
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
™
Š 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)
Gupta S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0103.
Study GS-US-292-0112 - Switch to FTC/TAF in Subjects with Renal
Dysfunction (Stable eGFR CG 30–69 mL/min):Baseline Characteristics
Primary Endpoint
Week
12
0
N=242
24
48
96
E/C/F/TAF QD
Total
N=242
TDF
n=158
Non-TDF
n=84
Median age, years
58
59
58
≥ 65 years, %
26
22
33
Female, %
21
23
17
Black or African descent, %
18
22
12
Median CD4 count, cells/μL
632
661
585
Hypertension, %
40
34
49
Diabetes, %
14
13
14
Median eGFRCG, mL/min
56
58
53
eGFRCG ≥60 mL/min, %
34
40
24
Grade 1
23
27
16
Grade 2
10
10
10
Grade 3-4
0
0
0
Dipstick proteinuria, %
Gupta S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0103.
Switch to FTC/TAF in Pts with Renal Dysfunction:
Actual GFR by Iohexol Clearance (1º Endpoint)
Total
aGFR (mL/min)
80
59
60
TDF
63
58
57
62
Non-TDF
63
50
49
48
40
20
0
BL
W2/4/8
BL
W24
W2/4/8 W24
BL
W2/4/8 W24
GLSM Ratio, % (90% CI)*
TDF (n=21)
Non-TDF (n=10)
Week 2, 4, or 8 vs baseline
98 (94, 102)
Week 24 vs baseline
100 (96, 105)
Week 2, 4, or 8 vs baseline
96 (86, 108)
Week 24 vs baseline
98 (87, 111)
*Lack of alteration boundary: 80–125% (GLSM).
Actual GFR unaffected by E/C/F/TAF switch, regardless of previous regimen
Gupta S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0103.
Estimated GFR: Change from Baseline to Week 48
TDF
Total
Non-TDF
Median Δ from Baseline
10
+0.2
0
-10
Baseline:
+1.6*
-0.6
56
-1.8
58
eGFRCG
mL/min
*p<0.05 by two-sided Wilcoxon signed-rank test.
Gupta S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0103.
53
-1.8* -1.5
54
56
+2.7*
-1.4
-2.7*
50
eGFRCKD-EPI Cr
mL/min/1.73m2
70
75
60
eGFRCKD-EPI cys C
mL/min/1.73m2
Switch to FTC/TAF in Pts with Renal Dysfunction:
Proteinuria From Baseline to Week 48
Tubular Proteins
200
180
Median (µg/g)
Median (mg/g)
3000
160
160
140
120
105
100
105
80
85
60
78
40
18
20
10
Urine
Protein:Creatinine
2500
2000
14
10
Total*
801
500
0
Urine
Albumin:Creatinine
TDF*
1563
1525
1500
1000
41
29
0
3477
3500
188
399
228
166
151
214
197
Urine Retinol
Binding Protein:Creat
207
221
Urine Beta 2
Microglobulin:Creatinine
Non-TDF†
Baseline
Week 48
*All Total and TDF changes statistically significant; †all non-TDF changes not statistically significant.
Gupta S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0103.
Switch to FTC/TAF in Pts with Renal Dysfunction:
Change in BMD from Baseline to Week 48
Hip
Mean (SD) % Δ Hip BMD
Mean (SD) % Δ Spine BMD
Spine
4
2.95*
2
2.29*
0.99
0
-2
Baseline
n=236
Week 24
n=226
Week 48
n=214
*p<0.05 by two-sided Wilcoxon signed-rank test.
Gupta S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0103.
Total
TDF
Non-TDF
4
1.85*
2
1.47*
0.70
0
-2
Baseline
n=236
Week 24
n=225
Week 48
n=216
Total
Cholesterol
20
LDL
HDL
Median Change From Baseline
Median Change From Baseline (mg/dL)
Switch to FTC/TAF in Pts with Renal Dysfunction:
Fasting Lipids at Week 48
Triglycerides
19
15
12
10
7
5
1
0
-1
-5
-4
-5
Total: HDL Ratio
0.5
0.3
0.2
0
-10
-11
-15
Baseline
P-value*
194
205
0.001
0.028
TDF
122
126
0.002 0.011
Non-TDF
54
55
122
165
3.6
3.7
0.36
<0.001
0.028
0.73
<0.001
0.010
*Wilcoxon signed-rank test.
Gupta S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0103.
Conclusions
™
Participants on TDF at time of switch had
Š
Š
Š
Š
No change in actual GFR
Significant improvements in urinary markers of renal function
Significant improvements in BMD
Significant increases in lipids
Š Consistent with independent effect of circulating TFV on reducing cholesterol levels
™
Participants not on TDF at time of switch had
Š No changes in actual GFR
Š Stable urinary markers of renal function and BMD
Š 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)
Gupta S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0103.