1. ARV-trial.com
Switch from TDF to TAF
GS-US Study 1

2. GS-US-292-0109 Study: Switch TDF to TAF
Design
Randomisation
2 : 1
Open-label
W48
W96
N = 959
HIV+ ≥ 18 years
On E/C/F/TDF or EFV/FTC/TDF or
boosted ATV + FTC/TDF > 96 weeks
HIV RNA < 50 c/mL
eGFR (Cockroft-Gault) > 50 mL/min
Switch to E/C/F/TAF
Continue TDF-based regimen
N = 477
*Randomisation was stratified by previous treatment regimen
Endpoints
Primary: proportion of patients maintaining HIV RNA < 50 c/mL at W48 (ITT, snapshot) ; non-inferiority if lower margin of a two-sided 95% CI for the difference = -12%, 99% power
Secondary: percentage change in hip and spine bone mineral density, change in serum creatinine, and change in EFV-related symptom score at W48
GS-US
Mills A. Lancet Infec Dis 2016;16:43-52

3. GS-US-292-0109 Study: Switch TDF to TAF
ARV-trial.com
GS-US Study: Switch TDF to TAF
Baseline characteristics and patient disposition
E/C/F/TAF
N = 959
TDF-based regimens
N = 477
Median age, years 41 40
Female
11%
10%
Race: white / black / asian
68% / 18% / 6%
66% / 21% / 7%
HIV-1 RNA < 50 c/mL
98%
CD4 cell count (/mm3), median
675
662
eGFR, mL/min, median
Cockroft-Gault
CKD-EPI
105.7
92.8
107.7
93.9
Dipstick proteinuria: grade 1 / grade 2
9% / < 1%
Discontinuation by W48, N (%)
For adverse event
For lack of efficacy
Investigator discretion
Consent withdrawal
Loss to follow-up
Non-compliance
Death
32 (3.3%) 9 1 2 8 6 4
40 (8.4%) 12 3 16 7
GS-US
Mills A. Lancet Infec Dis 2016;16:43-52 3

4. GS-US-292-0109 Study: Switch TDF to TAF
Virologic outcome at W48 and W96 (ITT, snapshot)
E/C/F/TAF (N = 959)
TDF-based regimens (N = 477)
HIV RNA < 50 c/mL
Virologic failure
No virologic data
97.2
93.1 % 20 40 60 80
100
Difference (95% CI) = 4.1% (1.6 to 6.7) 1*
1.3
N=10
N=6
1.8
5.7
Superiority of E/C/F/TAF
Week 48
Week 96
≠ (95% CI) = 3.7% (0.4 to 7.0) 93 89 5 9 2
* One patient in the TAF group with virologic failure (W8) had genotypic resistance : M184I/M. The patient resuppressed 4 weeks later without a change of regimen
GS-US
Mills A. Lancet Infec Dis 2016;16:43-52 ; DeJesus E. ASM Microbe 2016, Abs. LB-087

5. GS-US-292-0109 Study: Switch TDF to TAF
HIV-1 RNA < 50 c/mL at W48 by prior treatment regimen, %
E/C/F/TAF
TDF-based regimens 97 93 96 90 92 98
100 80 60 40 20
p < 0.001
p = NS
p = 0.02
Primary Endpoint
0.5 to 12.3
0.9 to 9.2
-1.9 to 3.9
1.6 to 6.7
95% CI =
959
477
306
153
251
125
402
199
All prior regimens
Prior
EFV/FTC/TDF
Prior boosted
ATV + FTC/TDF
E/C/F/TDF
GS-US
Mills A. Lancet Infec Dis 2016;16:43-52

6. GS-US-292-0109 Study: Switch TDF to TAF
Differences in patients with HIV-1 RNA < 50 c/mL at W96
by subgroup, % (95% CI)
Overall
Age, years
Sex
Race
Adherence
< 50
> 50
Male
Female
Black
Nonblack
< 95%
> 95%
E/C/F/TAF
TDF-based regimens
-12 -6 12
GS-US
DeJesus E. ASM Microbe 2016, Abs. LB-087

7. GS-US-292-0109 Study: Switch TDF to TAF
Changes in bone mineral density from baseline to W48
E/C/F/TAF
TDF-based regimens
Difference in least square means (95% CI)
Hip BMD change (N)
869
428
T-score mean change from baseline
0.11
- 0.02
0.13 (0.10 – 0.15) ; p <
Percent change from baseline
1.47%
- 0.34%
1.81 (1.49 – 2.13) ; p <
0 to 3% increase in BMD
> 3% increase
56%
21%
38% 8%
p <
Spine BMD change (N)
881
436
0.17
0.19 (0.16 – 0.23) ; p <
1.56%
- 0.44%
2.00 (1.55 – 2.45) ; p <
41%
33%
34%
13%
GS-US
Mills A. Lancet Infec Dis 2016;16:43-52

8. GS-US-292-0109 Study: Switch TDF to TAF
Changes in bone mineral density from baseline to W48
in patients previously on ATV + r + FTC/TDF
E/C/F/TAF
ATV + r + FTC/TDF
Hip BMD mean change (N) 41 13
During 144 weeks of prior ATV + r + FTC/TDF
- 4.58%
Percent change from baseline to W48
+ 1.35%
- 0.77%
Spine BMD mean change (N) 42 16
- 3.1%
+ 2.83%
- 0.74%
GS-US
Mills A. Lancet Infec Dis 2016;16:43-52

9. GS-US-292-0109 Study: Switch TDF to TAF
Median % change in BMD (Q1, Q3) on DXA
E/C/F/TAF
TDF-based regimens
Baseline
Week 24
Week 96
-2.5
-0.5
0.5
1.5
2.5
4.5
2.0
Week 48
-1.5
3.5
-0.3
p < 0,001
Spine BMD
All Patients (N=1369)
Baseline
Week 24
Week 96
-2.5
-0.5
0.5
1.5
2.5
4.5
2.1
Week 48
-1.5
3.5
-0.6
p < 0,001
Hip BMD
All Patients (N=1354)
Regardless of prior treatment regimen, differences between arms were statistically significant for spine and hip BMD
GS-US
DeJesus E. ASM Microbes 2016, Abs. LB-087

10. GS-US-292-0109 Study: Switch TDF to TAF
Change in Osteopenia/Osteoporosis Diagnosis (defined by T-Score)
Spine
Normal Osteopenia Osteoporosis
Baseline
Week 48
E/C/F/TAF N = 912
TDF-Based Regimen N = 457
Hip
E/C/F/TAF N = 902
TDF-Based Regimen N = 452 %
100 80 60 40 20
5.8
4.8
7.2
7.6
0.7
1.3
2.1 36 32 35 37 31 26 59 64 57 56 69 73 67 66
Differences between E/C/F/TAF and TDF-based regimens were statistically significant (p < 0.001)
GS-US
Mills A. IAS 2015, Abs. TUAB0102; Mills A. Lancet Infec Dis 2016;16:43-52

11. GS-US-292-0109 Study: Switch TDF to TAF
Serum creatinine and eGFR changes from baseline to W48
E/C/F/TAF
EFV/FTC/TDF
(unboosted regimen)
Other TDF-based regimens
Mean serum creatinine change, mmol/L
- 0.4 -
+ 2.9
+ 9.2
+ 1.77
Median eGFR (Cockroft-Gault), mL/min
+ 1.2
- 3.7
Median changes in markers of renal function
from baseline to W48
E/C/F/TAF
TDF-Based regimens p
Fractional excretion of phosphate
+ 0.2
+ 0.7
0.054
Fractional excretion of uric acid
- 0.8
+ 0.3
< 0.001
TmP/GFR *, mg/dL
- 0.1
0.63
* TmP/GFR: ratio of tubular maximum reabsorption of phosphate (TmP) to GFR
GS-US
Mills A. Lancet Infec Dis 2016;16:43-52

12. GS-US-292-0109 Study: Switch TDF to TAF
Renal Safety Results (Median % change in proteinuria at W48)
E/C/F/TAF
TDF-based regimens
Each difference between treatment arms was statistically significant (p < 0.001)
RBP:Cr
β-2-m:Cr
UPCR
UACR
Tubular Proteinuria 30 20 10
-10
-20
-30
-40
-50
-20.9
9.6
-17.9
8.5
-33.4
18.1
-52.3
18.7
-60
UPCR: urine protein:creatinine ratio ; UACR: urine albumin:creatinine ratio ; RBP, retinol-binding protein ; β-2-m: beta-2 microglobulin
GS-US
Mills A. Lancet Infec Dis 2016;16:43-52

13. GS-US-292-0109 Study: Switch TDF to TAF
Adverse events, N (%) (W48)
E/C/F/TAF
N = 959
TDF-based regimens
N = 477
Study-drug related adverse event
21%
16%
Grade 3 or 4 adverse event 9%
11%
Serious adverse event
65 (7%)
35 (7%)
Study drug-related serious adverse event
2 (< 1%)
Premature study drug discontinuation
for kidney-related adverse event
for jaundice
9 (0.94%) * 2
12 (2.52%) **
5 (1 Fanconi)
3 (all on boosted ATV)
* Panic attack; apathy, amnesia, speech disorder; Reiter’s syndrome; nausea, vomiting, and headache; suicide attempt; leg swelling and impaired concentration; depression; acute renal failure (after cancer chemotherapy: sepsis and multisystem organ failure); tubulo-interstitial nephritis (recurrent hematuria with subsequent diagnosis of Hodgkin lymphoma)
** Abnormal dreams; depression, insomnia, and irritability; depression, insomnia, and nightmares; elevated bilirubin; jaundice (N = 2); memory impairment; chronic kidney disease; elevated serum creatinine (N = 2); Fanconi’s syndrome and mild jaundice; renal colic
No discontinuation for adverse event in both groups between W48 and W96
GS-US
Mills A. Lancet Infec Dis 2016;16:43-52

14. GS-US-292-0109 Study: Switch TDF to TAF
Most-common drug-related adverse event, % (W48)
E/C/F/TAF
N = 959
TDF-based regimens
N = 477
Upper respiratory tract infection 16 11
Diarrhea 10 9
Nasopharyngitis 8
Headache 7 4
Cough 5
Syphilis 6
Insomnia
Arthralgia
Bronchitis
Depression
Osteopenia
Back pain
Nausea 3
Sinusitis
GS-US
Mills A. Lancet Infec Dis 2016;16:43-52

15. GS-US-292-0109 Study: Switch TDF to TAF
Grade 2-4 laboratory abnormalities (W48)
E/C/F/TAF
N = 959
TDF-based regimens
N = 477
Any abnormality
25%
31%
Creatine kinase
10%
AST 5% 7%
ALT
Neutropenia 4% 3%
Hypophosphatemia 2%
Hyperuricemia 1%
Alkaline phosphatase
< 1%
Leukopenia
Platelets
Total bilirubin
24%
Hemoglobin
Creatinine
GS-US
Mills A. Lancet Infec Dis 2016;16:43-52

16. GS-US-292-0109 Study: Switch TDF to TAF
Fasting Lipids (mg/dL, median), baseline and W48
Total Cholesterol
LDL
HDL
Triglycerides
TC:HDL Ratio
p < p < p = p < p = 0.004
E/C/F/TAF
Baseline
Week 48
TDF-Based Regimens
202
183
125
114 52
112
3.6
131
3.8
181
116 49
120 50
100
150
200
250 1 2 3 4 5
Participants initiating lipid-modifying medications: E/C/F/TAF: 8% ; TDF-based regimens: 6%
GS-US
Mills A. Lancet Infec Dis 2016;16:43-52

17. GS-US-292-0109 Study: Switch TDF to TAF
ARV-trial.com
GS-US Study: Switch TDF to TAF
Conclusion
Switching virologically suppressed patients to TAF regimen (EVG 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and TAF 10 mg) was non inferior to the to 3 TDF-containing regimens at week 48 and week 96
It was also superior to continuing with the TDF-containing regimens.
Switching to the TAF group showed several important safety advantages of TAF over any of the TDF-containing regimens :
Improvements in hip and spine bone mineral density
Improvements in renal function
Decreases in serum creatinine in patients switched from a boosted regimen
Decreases in dipstick proteinuria, in quantitative tests of total urine protein, and total urine albumin, in specific proximal tubular proteins
Improvements in proximal renal tubular function (fractional excretion of uric acid, fractional excretion of phosphate, and renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate
Slightly higher lipid concentrations with TAF than with TDF-based regimens
GS-US
Mills A. Lancet Infec Dis 2016;16:43-52 17