Transcript the slides - ARV

Switch from TDF to TAF
 GS-US-292-0109 Study
 GS-US-311-1089 Study
GS-US-311-1089 Study: Switch TDF to TAF
 Design
Randomisation
1:1
Double blind
W48
W96
N = 333 F/TAF * + F/TDF placebo
HIV+ ≥ 18 years
On F/TDF + 3rd agent
HIV RNA < 50 c/ml > 6 months
eGFR (Cockroft-Gault) > 50 mL/min
+ 3rd agent unchanged
F/TDF + F/TAF * placebo
rd
N = 330 + 3 agent unchanged
Randomisation stratified on 3rd agent (boosted PI or other)
 Endpoints
* F/TAF: 200/10 mg if boosted PI, 200/25 mg if other
– 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
GS-US-311-1089
Gallant J. Lancet HIV. 2016;3:e158-65, Raffi F. HIV Drug Therapy Glasgow, 2016, Abs O125
GS-US-311-1089 Study: Switch TDF to TAF
Baseline characteristics and outcome
F/TAF
N = 333
F/TDF
N = 330
48
49
14%
16%
73% / 21% / 6%
77% / 20% / 3%
CD4/mm3, median
663
624
eGR (Cockroft-Gault), mL/min, median
99.4
100.2
47% / 53%
25% / 16% / 5%
22% / 20% / 8% / 4%
45% / 55%
25% / 15% / 5%
20% / 22% / 7% / 5%
21 (6%)
7
1
10
1/1
1/0
36 (11%)
21 (6%)
3
1
10
1/2
0/4
39 (12%)
Median age, years
Female
Race: white / black / other
3rd agent: PI/r / other
DRV/r / ATV/r / LPV/r
NVP/ RAL / DTG / other
Discontinuation by W48, N (%)
Adverse event
Investigator decision
Consent withdrawal
Lost to follow-up / Non compliance
Pregnancy / Protocol violation
Discontinuation by W96, N (%)
GS-US-311-1089
Gallant J. Lancet HIV. 2016;3:e158-65 ; Raffi F. HIV Drug Therapy Glasgow, 2016, Abs O125
GS-US-311-1089 Study: Switch TDF to TAF
Virologic outcome (ITT, snapshot)
F/TAF + 3rd agent (N = 333)
W48
W96
W48
W96
F/TDF + 3rd agent (N = 330)
%
100
94.3 93
Resistance data
88.6 89.1
F/TAF
F/TDF
(N = 333) (N = 330)
80
60
N tested for
resistance *
- D0 to W48
- W48 to W96
40
20
0.3 1.5
0
Success
HIV RNA< 50 c/mL
2.4 0.6
Virologic failure
5.4 5.5
9.0 10.3
No virologic data
Emergence of
resistance
2
2
1
2
1 (M184V
(isolated
at W36)
0
* Confirmed HIV-1 RNA ≥ 50 c/mL
at any visit or unconfirmed > 400 c/mL
at endpoint or discontinuation
Difference (95% CI)
W48 = 1.3% (-2.5 to 5.1)
W96 = -0.5% (- 5.3 to 4.4)
GS-US-311-1089
Gallant J. Lancet HIV. 2016;3:e158-65, Rafii F. HIV Drug Therapy Glasgow, 2016, Abs O125
GS-US-311-1089 Study: Switch TDF to TAF
HIV-1 RNA < 50 c/mL at W48 according to 3rd agent, %
F/TAF
%
94
100
93
F/TDF
92
93
97
93
 Virologic success was
similar between treatment
groups for the subgroups
of age, sex, race, and
study drug adherence
80
60
 Mean changes in CD4 at
W48
‒ + 20/mm3 F/TAF
‒ + 21/mm3 F/TDF
40
20
N=
333
0
GS-US-311-1089
330
All
155
151
Boosted PI
178
179
Other 3rd agent
Gallant J, CROI 2016, Abs. 29, Gallant J. Lancet HIV. 2016;3:e158-65
GS-US-311-1089 Study: Switch TDF to TAF
Adverse events, N (%)
Adverse events related to study drug (D0 to W48)
Leading to discontinuation
Adverse events leading to study discontinuation by W96
Serious adverse event (D0 to W48)
Serious adverse event related to study drug at W48
Most common adverse events (D0 to W48)
Upper respiratory tract infection
Diarrhea
Headache
Nasopharyngitis
Cough
Bronchitis
Back pain
Arthralgia
Fatigue
Sinusitis
GS-US-311-1089
F/TAF
N = 333
F/TDF
N = 330
9%
N = 2 (0.6%)
N = 8 (2%)
12%
N = 3 (0.9%)
N = 4 (1%)
18 (5%)
14 (4%)
0
1 (< 1%)
9%
9%
8%
8%
6%
6%
6%
6%
5%
4%
14%
10%
4.5%
6%
5%
5%
5%
3%
4%
7%
Gallant J, CROI 2016, Abs. 29, Gallant J. Lancet HIV. 2016;3:e158-65, Raffi F. HIV Drug Therapy 2016, Abs O125
GS-US-311-1089 Study: Switch TDF to TAF
Discontinuation for adverse event, laboratory abnormalities grade 3-4 (D0-W96)
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
F/TAF (N = 333)
F/TDF (N = 330)
8 (2.4%)
1
1
1
1
1
1
1
1
0
0
0
0
4 (1.2%)
0
0
0
0
0
0
0
0
1
1
1
1
Laboratory abnormalities grade 3-4 ≥ 2 % (no treatment discontinuation), %
LDL
Total bilirubin
CK
Total cholesterol
Gamma GT
Glycosuria
Hematuria
AST / ALT
Amylase
Lipase
GS-US-311-1089
10
7
5
4
2
3
2
2/2
2
2
5
6
6
1
3
2
<1
<1/<1
4
1
Gallant J, CROI 2016, Abs. 29, Gallant J. Lancet HIV. 2016;3:e158-65, Raffi F. HIV Drug Therapy 2016, Abs O125
GS-US-311-1089 Study: Switch TDF to TAF
Mean change in bone mineral density through W96 (%, 95% CI)
Spine
Hip
3
3
1.7
2
2.2
p < 0.001
1
2
1.2
1.9
1
p < 0.001
-0.1
0
0
-1
-0.3
-0.1
-0.2
-1
0
24
48
72
96
0
24
Week
48
72
96
Week
FTC/TAF, N 321
310
300
294
287
321
309
300
293
288
FTC/TDF, N 320
310
306
297
292
317
305
303
296
289
GS-US-311-1089
Rafii F. HIV Drug Therapy Glasgow, 2016, Abs O125
GS-US-311-1089 Study: Switch TDF to TAF
Bone mineral density status changes through W48

The distribution of the bone mineral
density status (normal, osteopenia,
osteoporosis) adjusted for baseline
status was significantly different
between treatment groups at W48
Normal
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
Hip
6.2
4.0
5.6
5.6
0.9
0.7
0.9
39.5
38.7
34.0
35.0
33.0
30.3
33.8
54.2
57.3
60.3
59.5
66.0
69.0
65.3
63.4
BL
W48
BL
W48
BL
W48
BL
W48
100
80
Patients (%)

Osteoporosis
Spine
– at the hip (p = 0.012)
– and at the spine (p = 0.037)
Osteopenia
1.3
35.3
60
40
20
0
F/TAF
N = 321
F/TDF
N = 320
F/TAF
N = 321
F/TDF
N = 317
Gallant J. Lancet HIV. 2016;3:e158-65
GS-US-311-1089 Study: Switch TDF to TAF
Change in renal biomarkers at W96
eGFR
Median Change (mL/min)
Urine protein to creatinine ratio (% median change)
P/Cr
F/TAF
F/TDF
10
-10
*
40
*
20
10
42.6
b2MG/Cr
*
27.0
*
2.7
3.4
0
- 4.1
-10
-20
-20

46.8
*
30
4.0
0
RBP/Cr
50
20
10.0
Alb/Cr
-30
* p < 0.001
- 26.0
- 29.7
Cr: creatininuria
Discontinuation for renal adverse event
– F/TAF = 0
– F/TDF = 2 (creatinine increase = 1, renal tubular disorder = 1)
GS-US-311-1089
Raffi F, HIV Drug Therapy Glasgow, 2016, Abs O125
GS-US-311-1089 Study: Switch TDF to TAF
Safety by 3rd Agent
Boosted PI
Other 3rd Agent
FTC/TAF
N = 155
FTC/TDF
N = 151
FTC/TAF
N = 178
FTC/TDF
N = 179
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
Spine BMD (%)
+ 2.03
- 0.49
+ 2.26
+ 0.10
Hip BMD (%)
+ 1.82
- 0.28
+ 1.88
- 0.38
Renal safety (Changes at W96)
Bone safety (Changes at W96)
GS-US-311-1089
Raffi F, HIV Drug Therapy Glasgow, 2016, Abs O125
GS-US-311-1089 Study: Switch TDF to TAF
Median fasting lipids W48 versus baseline (mg/dL)
F/TAF
p = 0.094
Week 48
p < 0.001
250
F/TDF
4
Baseline
201
200
187
150
183
p < 0.001
p = 0.073
125
114
112 110
p = 0.02
51
49
50
Total
Cholesterol
LDL
128
112
118 110
3
HDL
2
1
50
49
Patients initiating lipid-lowering agents
GS-US-311-1089
3.6
3.6 3.6
182
100
0
3.7
Triglycerides
F/TAF
F/TDF
4%
4%
0
TC: HDL Ratio
Gallant J. Lancet HIV. 2016;3:e158-65
GS-US-311-1089 Study: Switch TDF to TAF
 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 W48
• Is associated with a similar clinical and biological tolerance
• Leads 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 W48
• Increases lipid parameters, with no change in the total cholesterol total:
HDL-cholesterol ratio
• Similar safety findings by 3rd agent
GS-US-311-1089
Gallant J. Lancet HIV. 2016;3:e158-65; Rafii F. HIV Drug Therapy Glasgow, 2016, Abs O125