Phase 2 of new ARVs
 Fostemsavir, prodrug of temsavir (attachment inhibitor)
– AI438011 Study
 TAF (TFV prodrug)
– Study 292-0102
– Study 299-0102
 Doravirine (non nucleoside reverse transcriptase inhibitor)
– MK1439007 Study
 Cabotegravir (integrase inhibitor)
– LATTE Study
 BMS-955176 (maturation inhibitor)
– AI468002 Study
Study GS-US-299-0102: D/C/F/TAF QD STR
vs DRV + COBI + F/TDF QD
 Design
Randomisation*
2:1
Double-blind
Adults ≥ 18 years
ARV-naïve
HIV RNA > 5,000 c/mL
CD4 cell count > 50/mm3
eGFR ≥ 70 mL/min
Sensitive to DRV,
FTC and TDF
W24
W48
N = 100 D/C/F/TAF STR 800/150/200/10 mg QD
DRV 400 mg x 2 + COBI + F/TDF placebos QD
DRV 400 mg x 2 + COBI 150 mg + F/TDF 200/300 mg QD
N = 50
D/C/F/TAF STR QD placebo
D = darunavir ; C = cobicistat ; F = FTC
* Randomisation was stratified by HIV RNA (< or > 100,000 c/mL) and race (black or nonblack)
 Objective
– Primary endpoint : non inferiority of D/C/F/TAF at W24: % HIV RNA < 50 c/mL
by intention to treat, snapshot analysis (lower margin of the 2 sided 95% CI for
the difference = -12%)
– Secondary endpoints : HIV RNA < 50 c/mL at W48, safety, tolerability
GS-US-299-0102
Mills A, JAIDS 2015; 69: 439-45
Study GS-US-299-0102: D/C/F/TAF QD
vs DRV + COBI + F/TDF QD
Baseline characteristics and patient disposition
D/C/F/TAF
N = 103
DRV + COBI
+ F/TDF
N = 50
Median age, years
31
36
Female
8%
6%
Black
35%
34%
HIV RNA (log10 c/mL), median
4.7
4.6
HIV RNA > 100,000 c/mL
22%
14%
CD4 cell count (/mm3), median
368
433
10.7%
20%
116
110
19 (18%)
8 (16%)
For investigator’s discretion
1
0
For adverse event
2
2
10 / 4
4/2
2
0
CD4 < 200 per mm3
eGFR (Cockroft-Gault), mL/min, median
Discontinuation by W48
Lost to follow-up / Withdrew consent
Non-compliance
GS-US-299-0102
Mills A, JAIDS 2015; 69: 439-45
Study GS-US-299-0102: D/C/F/TAF QD
vs DRV + COBI + F/TDF QD
Response to treatment
HIV RNA < 50 c/mL, ITT, snapshot analysis
D/C/F/TAF
DRV + COBI + F/TDF
Outcome at W48
%
100
75
Primary analysis, W24
(Overall)
74.8
W48
84.0
76.7
74.0
D/C/F/TAF
DRV + COBI
+ F/TDF
Virologic failure
16%
12%
No data
8%
4%
CD4/mm3 response
50
D/C/F/TAF
25
171/
196
0
Adjusted difference Adjusted difference
(95% CI) =
(95% CI) =
3.3% (- 11.4 ; 18.1) -6.2% (- 19.9 ; 7.4)
GS-US-299-0102
W24
174/
195
W48
96/
112
+ 104/
186
117
+ 231
DRV + COBI
+ F/TDF
703 +
/753
139
680/
750
+ 212
p : not significant
Mills A, JAIDS 2015; 69: 439-45
Study GS-US-299-0102: D/C/F/TAF QD
vs DRV + COBI + F/TDF QD
 Criteria for resistance testing
– Confirmed virologic failure : 2 consecutive HIV RNA > 50 c/mL and an HIV
RNA > 400 c/mL at or after W8
– Second, confirmatory, sample, tested for resistance
Resistance data at week 48
Virologic failure
D/C/F/TAF
N = 103
DRV + COBI + F/TDF
N = 50
6 (5.8%)
2 (4%)
No emergence of resistance to TDF, FTC or DRV
GS-US-299-0102
Mills A, JAIDS 2015; 69: 439-45
Study GS-US-299-0102: D/C/F/TAF QD
vs DRV + COBI + F/TDF QD
Adverse events by W48
D/C/F/TAF
DRV + COBI + F/TDF
6.8%
8.0%
Diarrhea
21.4%
26%
Upper respiratory tract infection
15.5%
14%
Fatigue
13.6%
18%
Nausea
12.6%
10%
Rash
11.7%
8%
Flatulence
4.9%
12%
Pain in extremity
7.8%
10%
Vitamin D deficiency
1.9%
10%
Vomiting
3.9%
10%
4.9%
4.0%
N=2
Rash;
Substance dependance
N=2
Worsening of diarrhea ;
Proximal renal tubulopathy
Grade 3-4 AE
AEs (all grades) in ≥ 10% of patients in
either group
Serious AEs
AE leading to discontinuation
GS-US-299-0102
Mills A, JAIDS 2015; 69: 439-45
Study GS-US-299-0102: D/C/F/TAF QD
vs DRV + COBI + F/TDF QD
Renal outcome at W48
D/C/F/TAF
DRV + COBI + F/TDF
P
+ 0.06 (0.04 - 0.08)
+ 0.09 (0.05 - 0.14)
0.053
Median decrease in eGFR
(Cockroft-Gault), mL/min
-2.9
-10.6
0.017
Median change in urine retinol binding
protein/creatinine ratio, mg/g
+ 9%
+ 54%
0.003
Median change in urine beta-2
microglobulin/creatinine ratio, mg/g
-42%
+2.3%
0.002
Mean (95% CI) change from baseline
in creatinine, mg/dL
Median change in urine albumin/creatinine
ratio, mg/g
Median change in urine protein/creatinine
ratio, mg/g
Median change in fractional excretion
of phosphates
Emergent dipstick proteinuria
GS-US-299-0102
-13.1%
-22.6%
0.17
-8.22%
-27.52%
+ 2.4%
+ 1.8%
ns
32%
34%
ns
0.19
Mills A, JAIDS 2015; 69: 439-45
Study GS-US-299-0102: D/C/F/TAF QD
vs DRV + COBI + F/TDF QD
Mean percentage change from baseline in bone mineral density (DEXA)
0
Total hip
-0,53
0
-0,84
-1
Lumbar spine
-1,09
-1
-2,09
-2
-3
-3,82
D/C/F/TAF
DRV + COBI + F/TDF
-1,57
-2
-3
-3,82
-3,62
-4
P < 0,001
P < 0,001
-4
P < 0,001
P = 0,003
-5
W24
W48
-5
W24
W48
Bone sub-study outcome at W48
D/C/F/TAF
DRV + COBI + F/TDF
P
BMD decline > 3% in hip
18.3%
61.7%
< 0.001
BMD decline > 3% in lumbar spine
32.5%
55.3%
0.002
P1NP (bone formation) increase
+ 4.7%
+ 52.5%
< 0.001
CTx (bone resorption) increase
+ 23.2%
+ 74.4%
< 0.001
P1NP : pro-collagen Type 1 N-terminal propeptide ; CTx : C-terminal telopeptide
GS-US-299-0102
Mills A, JAIDS 2015; 69: 439-45
Study GS-US-299-0102: D/C/F/TAF QD
vs DRV + COBI + F/TDF QD
Median change in fasting metabolic parameters at Week 48
D/C/F/TAF
DRV + COBI + F/TDF
P
Total cholesterol, mg/dL
+ 40
+5
< 0.001
LDL-cholesterol, mg/dL
+ 26
+4
< 0.001
HDL-cholesterol, mg/dL
+7
+3
0.009
Total cholesterol:HDL-cholesterol ratio
0.0
-0.2
0.15
Triglycerides, mg/dL
+ 29
-5
0.007
Serum glucose, mg/dL
+5
+7
0.33
Initiation of lipid lowering agent by W48
6.8%
8%
GS-US-299-0102
Mills A, JAIDS 2015; 69: 439-45
Study GS-US-299-0102: D/C/F/TAF QD
vs DRV + COBI + F/TDF QD
 Conclusion
– D/C/F/TAF had significantly improved renal and bone safety
parameters than DRV + COBI + F/TDF in antiretroviral-naïve, HIV-1
infected subjects :
• Less proteinuria
• Less change in hip and spine BMD
– Study limitations
• Small sample size
• Each participant had to take 5 tablets (double-blind) not optimal for
patient’s adherence and retention in the study
• Few women enrolled
– This D/C/F/TAF STR offers a promising option for initial HIV
treatment, with
• The high barrier to resistance of DRV
• And the potential for improved long-term renal and bone safety with TAF
GS-US-299-0102
Mills A, JAIDS 2015; 69: 439-45