Comparison of NRTI combinations
 ZDV/3TC vs TDF + FTC
– Study 934
 ABC/3TC vs TDF/FTC
– HEAT Study
– ACTG A5202 Study
– ASSERT Study
 FTC/TDF vs FTC/TAF
– Studies GS-US-292-0104 and GS-US-292-0111
Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
 Design
Randomisation*
1:1
Double-blind
Adults
ARV-naïve
HIV RNA > 1,000 c/mL
Any CD4 cell count
eGFR ≥ 50 mL/min
W48
W96
W144
N = 866 E/C/F/TAF QD
E/C/F/TDF placebo
N = 867 E/C/F/TDF QD
E/C/F/TAF placebo
* Randomisation was stratified by HIV RNA (< or > 100,000 c/mL), CD4 cell count at screening,
and geographic region
 Objective
– Non inferiority of E/C/F/TAF at W48: % HIV RNA < 50 c/mL by intention to
treat, snapshot analysis (lower margin of the 95% CI for the difference = -12%)
– Safety: serum creatinine, proteinuria, hip BMD, spine BMD
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Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
Baseline characteristics and patient disposition
E/C/F/TAF
N = 866
E/C/F/TDF
N = 867
33
35
Female
15%
15%
HIV RNA (log10 c/mL), median
4.58
4.58
HIV RNA > 100,000 c/mL
23%
23%
CD4 cell count (/mm3), median
404
406
CD4 < 200 per mm3
13%
14%
eGFR (Cockroft-Gault), mL/min, median
117
114
Discontinuation by W48, n (%)
45 (5%)
71 (8%)
For lack of efficacy
2
3
For adverse event
8
13
15 / 12
18 / 16
2
1
Median age, years
Lost to follow-up / Withdrew consent
Non-compliance
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Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
Plasma TFV and intracellular TFV-DP levels
– Intensive PK substudy :
– E/C/F/TAF, N = 36 (PBMC substudy : 21/36)
– E/C/F/TDF, N = 29 (PBMC substudy : 14/29)
Intracellular TFV-DP
Mean plasma TFV concentration, ng/mL (SD)
E/C/F/TDF (N = 29)
E/C/F/TAF (N = 36)
500
20
TFV Exposure (µM*h),
Geometric mean (95% CI)
15
100
4.1 X
10
10
5
5
0
6
12
Time (h)
18
0
24
X
E/C/F/TDF
(N = 14)
E/C/F/TAF
(N = 21)
Steady State TFV PK
E/C/F/TDF
N = 29
E/C/F/TAF
N = 36
% reduction
Mean AUCtau ng*h/mL (% CV)
3,410 (25)
297 (20)
91
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Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
Response to treatment at week 48
HIV RNA < 50 c/mL, ITT, snapshot analysis
E/C/F/TAF
E/C/F/TDF
%
100
Primary analysis
(Overall)
92
90
By baseline HIV RNA (c/mL)
94
91
By baseline CD4 count(/mm3)
93
87
89
86
89
171/
196
174/
195
96/
112
104/
117
91
75
50
25
0
800/
866
784/
867
Adjusted difference
(95% CI) =
2.0% (- 0.7 ; 4.7)
GS-US-292-0104/0111
629/
670
610/
672
< 100,000
> 100,000
< 200
703
/753
680/
750
≥ 200
Sax PE. Lancet 2015; 385:2606-15
Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
Response to treatment at week 48
%
E/C/F/TAF
E/C/F/TDF
Secondary endpoints
HIV RNA < 20 c/mL,
ITT, snapshot
Per-protocol
98
100
84.4
97
HIV RNA < 50 c/mL
Missing=Failure
analysis
93.0
Missing=Excluded
analysis
97.5
97.0
92.3
84.0
75
50
25
781/
801
0
Adjusted difference
(95% CI) =
0.4% (- 3.0 ; 3.8)
GS-US-292-0104/0111
763/
789
Adjusted difference
(95% CI) =
0.8% (- 1.0 ; 2.5)
Adjusted difference
(95% CI) =
0.8% (- 1.8 ; -3.3)
Adjusted difference
(95% CI) =
0.5% (- 1.2 ; -2.1)
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Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
 Criteria for resistance testing
– 2 consecutive HIV RNA > 50 c/mL (with the second ≥ 400 c/mL) after
achieving < 50 c/mL, or HIV RNA > 400 c/mL at W48 or last study visit
Resistance data at week 48
E/C/F/TAF, N = 866
E/C/F/TDF, N = 867
16 (1.8%)
19 (2.2%)
Emergent primary genotypic resistance
7 (0.8%)
5 (0.6%)
Emergent reverse transcriptase inhibitor
resistance
7
5
6
1
3
2
5
3
1
2
0
1
0
1
0
1
1
0
1
0
Analysed for the development of resistance
M184V/I
M184V/I + K65R
Emergent integrase inhibitor resistance
T66A
E92Q
Q148R
Q148R + T66I/A
Q148R + E92Q
N155H
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Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
 Adverse events (all grades) occurring in ≥ 5% of patients in either
group (W48)
E/C/F/TAF
E/C/F/TDF
Diarrhoea
17%
19%
Nausea
15%
17%
Headache
14%
13%
Upper respiratory tract infection
11%
13%
Nasopharyngitis
9%
9%
Fatigue
8%
8%
Cough
8%
7%
Vomiting
7%
6%
Arthralgia
7%
5%
Back pain
7%
7%
Insomnia
7%
6%
Rash
6%
6%
Pyrexia
5%
5%
Dizziness
5%
4%
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Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
 Adverse events leading to study drug discontinuation
E/C/F/TAF
E/C/F/TDF
All adverse events
8 (0.9%)
13 (1.5%
Adverse events related to study drug
7 (0.8%)
11 (1.3%)
 Death
N
Reason
Related to study drugs
GS-US-292-0104/0111
E/C/F/TAF
E/C/F/TDF
2
3
Embolic stroke
Alochol poisoning
Cardiac arrest
Multiple drug overdose
Myocardial infarction
0
0
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Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
 Grade 3 or 4 laboratory abnormalities in ≥ 1% of patients in either
group (W48)
E/C/F/TAF
E/C/F/TDF
Any
20%
20%
CK elevation
7%
6%
LDL elevation (fasting)
5%
2%
Hypercholesterolemia (fasting)
2%
1%
Hematuria (quantitative)
2%
2%
AST elevation
2%
2%
Serum amylase elevation
2%
3%
Neutropenia, < 1000 neutrophils/mL
2%
2%
ALT elevation
1%
1%
 Discontinuation for renal event


E/C/F/TAF = 0
E/C/F/TDF = 4 : renal failure = 2, decreased GFR = 1, nephropathy = 1
GS-US-292-0104/0111
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Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
Mean (SD) change in eGFR (Cockcroft-Gault), mL/min, from baseline
10
0
-6.6
-10
p<0.001
-11.2
-20
0
12
24
36
48 Weeks
Patients with ≥ 25% Decrease in eGFR
p < 0,001
35
30
25
20
15
10
5
0
p < 0,001
E/C/F/TAF
E/C/F/TDF
31
26
17
12
Cockroft-Gault
CKD-EPI-serumCreatinine
eGFR Equation
GS-US-292-0104/0111
Sax PE. Lancet 2015; 385:2606-15
Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
Renal laboratory abnormalities at week 48, n (%)
E/C/F/TAF
E/C/F/TDF
0
1 (0.1)
Serum creatinine (≥ 0.4 mg/dL increase)
0
0
Hypophosphatemia (≥ 1 grade decrease)
3 (0.3)
4 (0.5)
0
2 (0.2)
2 (0.2)
2 (0.2)
Subclinical tubulopathy (> 2 confirmed abnormalities)
Normoglycemic glycosuria (≥ 1 grade increase urine
glucose; serum glucose ≤ 100 mg/dL)
Proteinuria (≥ 2 grade increase)
Changes in Quantitative proteinuria/creatininuria ratio at week 48
Baseline
E/C/F/TAF
E/C/F/TDF
Median % change at W48*
E/C/F/TAF
E/C/F/TDF
Protein : creatinine (mg/g)
44
44
-3
+20
Albumin : creatinine (mg/g)
5
5
-5
+7
Retinol binding protein : creatinine (mg/g)
64
67
+9
+51
Beta2-microglobulin : creatinine (mg/g)
101
103
-32
+24
* p<0.001 for all
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Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
Spine BMD Change at W48
Mean (SD) % change in Spine BMD
through Week 48
≥ 3% gain
Gain or loss < 3%
≥ 3% loss
E/C/F/TAF
E/C/F/TDF
2
E/C/F/TAF
E/C/F/TDF
0
‒1.30
p <0.001
-2
3%
7%
26%
‒2.86
45%
-4
68%
-6
0
24
51%
48
Week
845
797
784
850
816
773
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Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
Hip BMD Change at W48
Mean (SD) % change in Hip BMD through
Week 48
≥ 3% gain
Gain or loss < 3%
≥ 3% loss
E/C/F/TAF
E/C/F/TDF
2
E/C/F/TAF
0
E/C/F/TDF
‒0.66
p <0.001
-2
‒2.95
3%
7%
-4
17%
50%
-6
46%
0
24
48
76%
Week
836
789
780
848
815
767
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Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
Fasting Lipids at Week 48
200
E/C/F/TAF
Baseline
Week 48
189
E/C/F/TDF
Baseline
Week 48
5
Median Values (mg/dL)
177
150
160
4
163
115
114
109
100
101
104
95
51
50
44
3.6
108
100
p <0.001
p <0.001
3.6
3
2
1
44
0
LDL
3.7
48
0
Total Cholesterol
3.7
HDL
p <0.001
Triglycerides
p=0.027
TC:HDL Ratio
p=0.84
Patients initiating lipid-modifying medications: 3.6% E/C/F/TAF vs 2.9% E/C/F/TDF (p=0.42)
GS-US-292-0104/0111
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Studies GS-US-292-0104 and GS-US-292-0111:
E/C/F/TAF QD vs E/C/F/TDF QD
 Summary of week 48 results
– E/C/F/TAF QD is virologically non inferior to E/C/F/TDF QD
– 92% of patients treated with E/C/F/TAF achieved virologic suppression through
week 48
– High and similar response rates, irrespective of baseline HIV RNA and CD4 cell
count, age, sex, race
– Low rates of virologic failure, with resistance emergence < 1% in both arms
– CD4 response from baseline significantly higher with E/C/F/TAF
– Discontinuation because of adverse events : 0.9 % vs 1.5 %
• Discontinuation due to renal events : 0 vs 4
– Common adverse events occurred at similar frequency in both arms
– No case of proximal tubulopathy
– Compared with E/C/F/TDF, E/C/F/TAF demonstrated
•
•
•
•
Significantly smaller decreases in eGFR
Significantly less proteinuria, albuminuria, and tubular proteinuria
Significantly less impact on spine and hip BMD
Greater increases in fasting lipids
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