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from TDF to TAF GSUS2920109 Study GSUS3111089 Study Design Endpoints Primary proportion of patients maintaining HIV RNA lt 50 cmL at W48 ITT snapshot noninferiority if lower margin of a twosided 95 CI for the difference 10 gt 95 power ID: 541817 Download Presentation
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Presentation on theme: "Switch"— Presentation transcript
Slide1
Switch from TDF to TAF
GS-US-292-0109 Study
GS-US-311-1089 Study
Slide2
Design
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 = -10%, > 95% power
Secondary with multiple adjustments: percentage change in hip and spine bone mineral density
F/TAF * + F/TDF placebo + 3rd agent unchanged
F/TDF + F/TAF * placebo + 3rd agent unchanged
GS-US-311-1089
Randomisation
1 : 1Double blind
HIV+ ≥ 18 yearsOn F/TDF + 3rd agent HIV RNA < 50 c/ml > 6 monthseGFR (Cockroft-Gault) > 50 mL/min
N = 330
N = 333
W48
GS-US-311-1089
Study
: Switch TDF to TAF
W96
Randomisation stratified on 3
rd
agent (boosted PI or other)
* F/TAF: 200/10 mg if boosted PI, 200/25 mg if other
Gallant J. Lancet HIV. 2016;3:e158-65,
Raffi
F. J
Acquir
Immune
Defic
Syndr
. 2017;75:226-31Slide3
F/TAF
N = 333
F/TDF
N = 330
Median age, years
4849
Female14%16%
Race: white / black / other
73% / 21% / 6%77% / 20% / 3%
CD4/mm3, median663624
eGR
(Cockroft-Gault
), mL/min, median99.4100.2
3rd agent: PI/r / otherDRV/r / ATV/r / LPV/rNVP/ RAL / DTG / other
47% / 53%
25% / 16% / 5%
22% / 20% / 8% / 4%
45% / 55%
25% / 15% / 5%
20% / 22% / 7% / 5%
Discontinuation by W48, N (%)
Adverse eventInvestigator decisionConsent withdrawalLost to follow-up / Non compliance
Pregnancy / Protocol violation
Discontinuation by W96, N (%)
21 (6%)71101 / 11 / 036 (11%)21 (6%)31101 / 20 / 439 (12%)
Baseline characteristics and outcome
GS-US-311-1089
GS-US-311-1089 Study: Switch TDF to TAF
Gallant J. Lancet HIV. 2016;3:e158-65,
Raffi
F. J
Acquir
Immune
Defic
Syndr
. 2017;75:226-31Slide4
F/TAF
(N = 333)
F/TDF
(N = 330)
N tested for resistance *
- D0 to W48
- W48 to W962212
Emergence of resistance
1 (M184V (isolated at W36)0Resistance data* Confirmed HIV-1 RNA ≥ 50 c/mL at any visit or unconfirmed > 400 c/mL at endpoint or discontinuation
Virologic outcome (ITT, snapshot)
GS-US-311-1089
GS-US-311-1089
Study: Switch TDF to TAF
F/TAF + 3rd agent (N = 333)
F/TDF + 3
rd
agent (N = 330)
W48
W48
W96
Difference (95% CI)
W48 = 1.3% (-2.5 to 5.1)
W96 = -0.5% (- 5.3 to 4.4)
Success
HIV RNA< 50 c/mLVirologic failureNo virologic data
W96%94.30.35.4931.5
5.5020406080100
88.6
89.1
2.4
0.6
9.0
10.3
Gallant J. Lancet HIV. 2016;3:e158-65,
Raffi
F. J
Acquir
Immune
Defic
Syndr
. 2017;75:226-31Slide5
HIV-1 RNA < 50 c/mL at W48 according to 3
rd
agent, %
Virologic success was similar between treatment groups for the subgroups of age, sex, race, and study drug adherence
Mean changes in CD4 at W48+ 20/mm3 F/TAF+ 21/mm3 F/TDF
GS-US-311-1089GS-US-311-1089 Study: Switch TDF to TAF
Gallant J, CROI 2016, Abs. 29, Gallant J. Lancet HIV. 2016;3:e158-65AllBoosted PIOther 3rd agent
0
20
406080100949392
93
97
93333330155151178179% N =
F/TDF
F/TAFSlide6
Adverse events, N (%)
F/TAF
N = 333
F/TDF
N = 330
Adverse events related to study drug (D0 to W48)Leading to discontinuation
Adverse events leading to study discontinuation by W969%N = 2 (0.6%)N = 8 (2%)
12%
N = 3 (0.9%)N = 4 (1%)Serious adverse event (D0 to W48)18 (5%)
14 (4%)Serious adverse event related to study drug at W4801 (< 1%)
Most common adverse events (D0 to W48)
Upper respiratory tract infection
DiarrheaHeadacheNasopharyngitisCoughBronchitis
Back painArthralgiaFatigueSinusitis
9%9%
8%
8%6%
6%
6%
6%
5%
4%14%10%4.5%
6%
5%
5%5%3%4%7%GS-US-311-1089GS-US-311-1089 Study: Switch TDF to TAFGallant J, CROI 2016, Abs. 29, Gallant J. Lancet HIV. 2016;3:e158-65,Raffi F. J Acquir Immune Defic Syndr. 2017;75:226-31Slide7
F/TAF (N = 333)
F/TDF (N = 330)
Discontinuation for adverse event
Insomnia / Mood altered
Dysphagia Atrial fibrillation
Diarrhea Peripheral edema Overdose Lymphoma Acquired lipodystrophy
/affective disorder Increased serum creatinine Rectal tenesmus Feeling abnormal / Headache Renal tubular disorder
8 (2.4%)
11111111
00004 (1.2%)000
0
0
000111
1Laboratory abnormalities grade 3-4 ≥ 2 % (no treatment discontinuation), %
LDL
Total bilirubin
CK
Total cholesterol
Gamma GT
Glycosuria
Hematuria
AST / ALTAmylaseLipase107
5
4
2322 / 222566132< 1< 1 / < 141Discontinuation for adverse event, laboratory abnormalities grade 3-4 (D0-W96)
GS-US-311-1089GS-US-311-1089
Study: Switch TDF to TAFGallant J, CROI 2016, Abs. 29, Gallant J. Lancet HIV. 2016;3:e158-65,Raffi F. J Acquir Immune Defic Syndr. 2017;75:226-31Slide8
321
310
300
320
310
306
294
297
287
292
321
309
300
317
305
303
293
296
288
289
FTC/TAF, N
FTC/TDF, N
Spine
Hip
-1
0
1
2
3
0
24
48
72
96
Week
2.2
-0.2
p < 0.001
1.7
-0.1
-1
0
1
2
3
0
24
48
72
96
Week
1.9
-0.3
p < 0.001
1.2
-0.1
GS-US-311-1089
Study
: Switch TDF to TAF
GS-US-311-1089
Mean
change
in
bone
mineral
density
through
W96 (%, 95% CI)
Gallant J, CROI 2016, Abs. 29,
Gallant J. Lancet HIV.
2016;3:e158-65,
Raffi
F. J
Acquir
Immune
Defic
Syndr
. 2017;75:226-31Slide9
The distribution of the bone mineral density status (normal, osteopenia, osteoporosis) adjusted for baseline status was significantly different between treatment groups at W48 at the hip (p = 0.012)
and at the spine (p = 0.037)
Driven by a higher percentage of subjects in the F/TAF group with an improvement in BMD status (i.e. osteopenia to normal, osteoporosis to normal or osteopenia), and correspondingly, a lower percentage of subjects in the F/TAF with worsening BMD status (i.e. normal to osteopenia or osteoporosis, or osteopenia to osteoporosis)
GS-US-311-1089
Bone mineral density status changes through W48
Gallant J. Lancet HIV. 2016;3:e158-65
0
20
40
60
80
100
Normal
Osteopenia
Osteoporosis
6.2
4.0
5.6
5.6
0.9
0.7
0.9
1.3
39.5
38.7
34.0
35.0
33.030.3
33.8
35.3
54.2
57.3
60.3
59.5
66.0
69.0
65.3
63.4
BL
W48
BL
W48
BL
W48
BL
W48
F/TAF
N = 321
F/TDF
N = 320
F/TAF
N = 321
F/TDF
N = 317
Patients (%)
Spine
Hip
GS-US-311-1089
Study
: Switch TDF to TAFSlide10
Change in renal biomarkers at W96
GS-US-311-1089
Discontinuation for renal adverse event
F/TAF = 0F/TDF = 2 (creatinine increase = 1, renal tubular disorder = 1)
Urine protein to creatinine ratio (% median change)eGFRMedian Change (mL/min)*10.04.0
* p < 0.001
- 26.0
3.4
- 4.1
- 29.7
2.7
27.0
42.6
46.8-30-20-10010
2030
P/Cr
Alb/CrRBP/Cr
b2MG/Cr
Cr: creatininuria*
*
*
*4050GS-US-311-1089 Study: Switch TDF to TAF
F/TAF
F/TDF
Raffi F. J Acquir Immune Defic Syndr. 2017;75:226-31Slide11
Safety by 3
rd
Agent
GS-US-311-1089 Study: Switch TDF to TAF
GS-US-311-1089
Boosted PI
Other 3rd Agent
FTC/TAF
N = 155FTC/TDFN = 151
FTC/TAFN = 178FTC/TDFN = 179Renal safety (Changes at W96)
eGFR
(mL/min)
+ 9.3
+ 4.2
+ 10.6
+ 3.3
Urine protein/Cr (%)
- 27.2
- 1.8
-25.6
+ 7.8
Urine albumin/Cr (%)
- 1.3
+ 21.7+ 5.0+ 29.2 Urine RBP/Cr (%)- 5.5
+ 36.5- 2.0+ 49.9
Urine β2MG/Cr (%)- 28.2
+ 41.8
- 31.9
+
51.5
Bone safety (Changes at W96)
Spine BMD (%)
+ 2.03
- 0.49
+ 2.26
+ 0.10
Hip BMD (%)
+ 1.82
- 0.28
+ 1.88
- 0.38
Raffi
F. J
Acquir
Immune
Defic
Syndr
. 2017;75:226-31Slide12
Median fasting lipids W48 versus baseline (mg/
dL
)
F/TAF
F/TDF
Patients initiating lipid-lowering agents
4%
4%
F/TAF
F/TDF
Week 48
Baseline
GS-US-311-1089
GS-US-311-1089
Study
: Switch TDF to TAF
Gallant J. Lancet HIV. 2016;3:e158-65
Total
Cholesterol
LDL
HDL
Triglycerides
p = 0.073
128
118
112
110
p = 0.02
51
49
50
49
p < 0.001
125
112
114
110
p < 0.001
201
187
183
182
0
50
100
150
200
250
TC: HDL Ratio
p = 0.094
3.7
3.6
3.6
3.6
0
1
2
3
4Slide13
Conclusion
In this
randomised
double-blind study, switch of patients on F/TDF + 3rd agent with suppressed viral load for F/TAF + continuation of 3rd agent Is non-inferior at W48 and W96 for maintaining virologic suppression (HIV-1 RNA < 50 c/mL)in rare cases of virologic failure, the risk of resistance emergence is low (1 case of M184V on F/TAF), none after W48Is associated with a similar clinical and biological toleranceLeads to improvement of renal parameters: increase in eGFR and decrease in proteinuria, no renal discontinuations or renal tubulopathy in F/TAF group Improves bone mineral density: increase on F/TAF with significant difference of changes at W48 vs F/TDF and continuing increase in hip and spine BMD after W48Increases lipid parameters, with no change in the total cholesterol total: HDL-cholesterol ratio
Similar safety findings by 3rd agent
GS-US-311-1089GS-US-311-1089 Study: Switch TDF to TAF
Gallant J. Lancet HIV. 2016;3:e158-65; Raffi F. J Acquir Immune Defic Syndr. 2017;75:226-31