Transcript The ALERT Study: A Planned Week 24 Interim Analysis of Once Daily Boosted Fosamprenavir or Atazanavir with Tenofovir/Emtricitabine Kimberly Smith, Winkler Weinberg, Edwin DeJesus, Margaret.

The ALERT Study:
A Planned Week 24 Interim Analysis of
Once Daily Boosted Fosamprenavir or
Atazanavir with Tenofovir/Emtricitabine
Kimberly Smith, Winkler Weinberg, Edwin DeJesus,
Margaret Fischl, Qiming Liao, Lisa Ross and
Tracey Lancaster
Background
IAS Guidelines recently added boosted FPV
and ATV + 2 nucs as recommended initial
therapy
FPV/r dose in US product label is 1400mg
FPV + 200mg RTV once daily for naïve
subjects
This study used a reduced FPV/r dose of
1400 mg FPV + 100 mg RTV once daily
that has not been previously studied
Objective
To compare the efficacy, safety, and
tolerability of RTV-boosted FPV versus
RTV-boosted ATV, both in combination with
TDF/FTC
Study Design
Randomized (1:1), open-label, 48 week pilot study
FPV 1400 mg QD +
RTV 100 mg QD +
ART-naïve
subjects,
n=106
TDF/FTC QD
ATV 300 mg QD +
RTV 100 mg QD +
TDF/FTC QD
Entry criteria:
HIV-1 RNA >1000 c/mL
No CD4 cell count restrictions
Stratified by entry HIV-1 RNA <100,000 c/mL or 100,000 c/mL
Baseline resistance testing was not done prior to entry
Endpoints
Primary
– Proportion of patients with plasma HIV-1
RNA <50 copies/mL at 48 weeks
Secondary
– Proportion of patients with plasma HIV-1
RNA <50 copies/mL at 24 weeks
– Proportion of patients with plasma HIV-1
RNA <400 copies/mL at 24 and 48
weeks
Endpoints cont.
Secondary
– Change from baseline in CD4 cell counts
at 24 and 48 weeks
– HIV treatment-emergent resistance
patterns
– Differences between treatment arms in
incidence, type and severity of adverse
events
Definition of
Virologic Failure
Confirmed plasma HIV-1 RNA ≥400
c/mL at Week 24 or later
Baseline Characteristics
FPV/r
ATV/r
Total
(N=53)
(N=53)
Median age, years
40
40
40
Male
Race-African American
-Causasian
-Other
Ethnicity- Hispanic
79%
34%
64%
2%
23%
89%
45%
49%
6%
23%
84%
40%
56%
4%
23%
9 (17%)
11 (21%)
20 (19%)
Median HIV-1 RNA, log10 c/mL
4.88
HIV-1 RNA <100,000 c/mL 37 (70%)
HIV-1 RNA 100,000 c/mL 16 (30%)
4.88
36 (68%)
17 (32%)
4.88
73 (69%)
33 (31%)
Median CD4 count, cells/mm3
<50 cells/mm3
50 - <200 cells/mm3
200 cells/mm3
188
9 (17%)
19 (36%)
25 (47%)
172
23 (22%)
40 (38%)
43 (41%)
CDC Class C
161
14 (26%)
21 (40%)
18 (34%)
(N=106)
Completion Status at 24 Weeks
FPV/r
ATV/r
Total
Completed
49 (92%)
50 (94%)
99 (93%)
Prematurely
withdrawn
4 (8%)
3 (6%)
7 (7%)
Non-Response
1 (2%)
0
1 (<1%)
Adverse Event
1 (2%)
1 (2%)
2 (2%)
Lost to follow up
1 (2%)
2 (4%)
3 (3%)
Protocol Violation
1 (2%)
0
1 (<1%)
Primary Reason for
Withdrawal:
HIV-1 RNA <400 c/mL
100
% of Subjects
80
60
40
FPV/r,
ATV/r,
FPV/r,
ATV/r,
20
MD=F
MD=F
Observed
Observed
=
=
=
=
89%
89%
94%
94%
0
0
4
8
12
Study Week
16
20
24
HIV-1 RNA <50 c/mL
100
% of Subjects
80
60
40
FPV/r,
ATV/r,
FPV/r,
ATV/r,
20
MD=F
MD=F
Observed
Observed
=
=
=
=
79%
83%
84%
88%
0
0
4
8
12
Study Week
16
20
24
Mean CD4+ Cell Count with 95%
Confidence Intervals
450
Cells / mm3
400
342
350
361
302
300
276
250
200
205
176
150
100
W0
W12
FPV/r
W24
W0
W12
ATV/r
W24
Median Fasting Lipids
at Baseline and Week 24
250
Cholesterol
Triglycerides
Baseline
m g /d L
200
160
Week 24
180
177
160
153
150
127 133
116
100
50
0
Baseline n=
Week 24 n=
FPV/r
ATV/r
48
38
46
39
FPV/r
48
38
ATV/r
46
39
Median Fasting Lipids
at Baseline and Week 24
LDL
150
m g /d L
100
95
99
HDL
97
Baseline
Week 24
103
50
38
41
38
45
0
FPV/r
Baseline n=
Week 24 n=
48
36
ATV/r
45
39
FPV/r
ATV/r
48
38
46
39
Subject 1: TDF/FTC+FPV/r
RT: S68G, K70T, V118I,
L210W, T215C
PRO: K20I, M46I, L63P, A71V, V77I
6
HIV-1 RNA Log10 cp/mL
5.5
5
4.5
TDF FC=0.95; APV FC= 3.8
FTC FC=1.5
Week 0
4
3.5
RT: S68G, K70T, V118I,
L210W, T215C, M184V
PRO: K20I, M46I, I54I/L/M L63P,
A71V, V77I
3
2.5
2
TDF FC= 0.61; APV FC= 13
Week 20 FTC FC > 112.8
1.5
Clade B
1
0
4
8
12
16
20
24
28
Time (week)
32
36
40
44
48
Subject 2: TDF/FTC+FPV/r
Week 0
6
RT: WT
PRO: L10V, L63L/P, V77V/I
No phenotypic resistance
HIV-1 RNA Log10 cp/mL
5.5
5
Week 24
RT: K65R
PRO: L10V, V32I, M46M/I, I47V
4.5
TDF FC= 2.2
APV FC= 8.6
FTC FC= 5.6
4
3.5
3
Week 12
RT: K65R
PRO: L10V, L63L/P, V77V/I
No phenotypic resistance
2.5
2
1.5
Clade B
1
0
4
8
12
16
20
24
28
Time (week)
32
36
40
44
48
Subject 3: TDF/FTC+ATV/r
6
HIV-1 RNA Log10 cp/mL
5.5
Week 0
5
RT: WT
PRO: M36I, L63A
4.5
TDF FC= 1.1
ATV FC= 0.9
FTC FC= 1.04
4
3.5
Week 24
RT: WT
PRO: M36I, L63A
3
2.5
TDF FC= 1.08
ATV FC= 2.07
FTC FC= 1.08
WD
2
1.5
Clade B
1
0
4
8
12
16
20
24
28
Time (week)
32
36
40
44
48
Adverse Event Related
Study Discontinuations
One pt. DC’d FPV/r due to AEGrade 3 Rash
One pt. DC’d ATV/r due to SAEnew onset Kaposi’s Sarcoma
Adverse Event Related
Study Drug Discontinuations
Two pts.* DC’d TDF/FTC (then switched
to individual components of ABC/3TC)
due to declining renal function, defined in
protocol as:
eGFR change >25% below baseline, or
eGFR <50mL/min (confirmed)
*61% of subjects had baseline GFR >50 and <90 mL/min by MDRD
Treatment-Related
AEs by Overall Frequency >4%
Grades 2-4
FPV/r
n=53
ATV/r
n=53
Any Event
6 (11%)
28 (53%)
Bilirubin ↑
0
22 (41%)
Diarrhea
3 (6%)
1 (2%)
Nausea
2 (4%)
1 (2%)
0
2 (4%)
Scleral Icterus
Conclusions
Both arms provided similar rates of
virologic suppression and immunologic
improvement at Week 24
Lipid changes were similar
Overall, fewer severe adverse effects
occurred with FPV/r than with ATV/r;
differences due primarily to bilirubinassociated AEs
Acknowledgements
ALERT was made possible by the contributions
of patients and staff at the following US sites*:
Cynthia Brinson- Austin, TX
Cal Cohen- Boston, MA
Edwin DeJesus- Orlando, FL
Margaret Fischl- Miami, FL
Joseph Horvath- Columbia, SC
Ricky Hsu- New York, NY
Lewis McCurdy- Charlotte, NC
Cheryl McDonald- Ft. Worth, TX
Bruce Rashbaum- Wash., DC
Robert Scott- Oakland, CA
Kimberly Smith- Chicago, IL
Ford Kinder- Miami, FL
Winkler Weinberg- Atlanta, GA
Ben Young- Denver, CO
*Also wish to thank the CRO, MediStaf Research, for their contributions.
Support was provided by GlaxoSmithKline
Backup Slides (Additional Data)
Fasting Cholesterol
158
165
173
182
Fasting Triglycerides
141
144
192
145
Fasting LDL
94
101
98
105
Fasting HDL
47
37
36
40
Mean CD4+ Cell Count Change
from Baseline with 95% CI
190
Baseline mean: 176
Cells / mm3
170
Baseline mean: 205
150
148
132
130
110
124
105
90
FPV/r
70
ATV/r
50
Week 12
Week 24
Fasting Lipids
Median Change from Baseline at
Week 24
m g/d L Change
25
FPV/r
ATV/r
20
17
15
10
7
8
6
4
5
-3
-5
Chol
n=
36
37
Trig
36
37
LDL
34
36
HDL
36
37
Treatment Emergent Fasting Lipid
Toxicities by Intensity Grading
% of Subjects
30%
Cholesterol
Triglycerides
g3
LDL
g2
3%
g1
3%
20%
3%
8%
5%
5%
10%
20%
10%
11%
11%
FPV/r
ATV/r
38
38
3%
0%
FPV/r
n=
40
ATV/r
39
FPV/r
40
ATV/r
39
eGFR by MDRD (FPV/r)
Wk 0 to Wk 24
Wk 0
Week 24
58
60
60
50
40
% of
30
Subjects
20
10
0
36
30
2
0
<30
4
10
30-<60
60-<90
>/=90
eGFR by MDRD (ATV/r)
Wk 0 to Wk 24
Wk 0
70
60
50
% of
40
Subjects 30
20
10
0
Week 24
66
58
40
24
10
0
<30
0
2
30-<60
60-<90
>/=90
eGFR by MDRD (All Subjects)
Wk 0 to Wk 24
Wk 0
70
60
50
% of
40
Subjects 30
20
10
0
Week 24
58
63
38
27
1
<30
0
3
10
30-<60
60-<90
>/=90
Two pts. DC’d Truvada due to declining renal function, defined as
eGFR change >25% below baseline or eGFR <50mL/min (confirmed)
Subject 1: TDF/FTC+FPV/r
RT: S68G, K70T, V118I, 210W,T215C
PRO: K20I, M46I, L63P, A71V, V77I
6
Week 0
HIV-1 RNA Log10 cp/mL
5.5
TDF FC=0.95
FTC FC=1.5
APV FC= 3.8
5
4.5
Week 12
4
RT: S68G, K70T, V118I, M184V, L210W, 215C,
K219K/Q
PRO: K20I, M46I, I47I/V, F53F/L, I54I/L, L63P,
A71V, V77I
TDF FC= 0.61
FTC FC > 78.3
3.5
3
APV FC= 2.98
RT: S68G, K70T, V118I, M184V, L210W, 215C,
PRO: K20I, M46I, I54I/L/M L63P, A71V, V77I
2.5
Week 20
2
TDF FC= 0.61
FTC FC > 112.8
APV FC= 13
1.5
Clade B
1
0
4
8
12
16
20
24
28
Time (week)
32
36
40
44
48
Subject 2: TDF/FTC+FPV/r
6
HIV-1 RNA Log10 cp/mL
5.5
Week 0
Week 24
RT: WT
PRO: L10V, L63L/P, V77V/I
No phenotypic resistance
RT: K65R
PRO: L10V, V32I, M46M/I, I47V
5
TDF FC= 2.2
FTC FC= 5.6
Week 4
RT: WT
PRO: L10V, L63L/P, V77V/I
No phenotypic resistance
4.5
APV FC= 8.6
Week 28
4
RT: K65R, D67D/N,
PRO: L10V, V32I, M46I, I47V
3.5
TDF FC= 1.8
FTC FC= 8.5
3
APV FC= 19
2.5
Week 12
2
RT: K65R
PRO: L10V, L63L/P, V77V/I
No phenotypic resistance
1.5
Clade B
1
0
4
8
12
16
20
24
28
Time (week)
32
36
40
44
48
Subject 3: TDF/FTC+ATV/r
6
HIV-1 RNA Log10 cp/mL
5.5
Week 0
5
RT: WT
PRO: M36I, L63A
4.5
TDF FC= 1.1
FTC FC= 1.04
4
ATV FC= 0.9
Week 12
RT: WT
PRO: M36I, L63A
3.5
3
TDF FC= 1.08
FTC FC= 1.08
2.5
ATV FC= 2.07
WD
2
1.5
Clade B
1
0
4
8
12
16
20
24
28
Time (week)
32
36
40
44
48