kimberly smith, winkler weinberg, edwin dejesus, margaret fischl, qiming liao, lisa ross and tracey...
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Kimberly Smith, Winkler Weinberg, Edwin DeJesus, Margaret Fischl, Qiming Liao, Lisa Ross and Tracey Lancaster
The ALERT Study:The ALERT Study:
A Planned Week 24 Interim Analysis of A Planned Week 24 Interim Analysis of Once Daily Boosted Fosamprenavir or Once Daily Boosted Fosamprenavir or Atazanavir with Tenofovir/Emtricitabine Atazanavir with Tenofovir/Emtricitabine
BackgroundBackground
IAS Guidelines recently added boosted FPV IAS Guidelines recently added boosted FPV and ATV + 2 nucs as recommended initial and ATV + 2 nucs as recommended initial therapytherapyFPV/r dose in US product label is 1400mg FPV/r dose in US product label is 1400mg FPV + 200mg RTV once daily for naïve FPV + 200mg RTV once daily for naïve subjectssubjectsThis study used a reduced FPV/r dose of This study used a reduced FPV/r dose of 1400 mg FPV + 1400 mg FPV + 100 mg RTV100 mg RTV once daily once daily that has not been previously studiedthat has not been previously studied
ObjectiveObjective
To compare the efficacy, safety, and To compare the efficacy, safety, and tolerability of RTV-boosted FPV versus tolerability of RTV-boosted FPV versus RTV-boosted ATV, both in combination RTV-boosted ATV, both in combination with TDF/FTCwith TDF/FTC
Study DesignStudy DesignRandomized (1:1), open-label, 48 week pilot study
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/mLBaseline resistance testing was not done prior to entry
ART-naïve subjects,
n=106
FPV 1400 mg QD +
RTV 100 mg QD +
TDF/FTC QD
ATV 300 mg QD +
RTV 100 mg QD +
TDF/FTC QD
EndpointsEndpoints
PrimaryPrimary
– Proportion of patients with plasma HIV-1 Proportion of patients with plasma HIV-1 RNA <50 copies/mL at 48 weeksRNA <50 copies/mL at 48 weeks
SecondarySecondary
– Proportion of patients with plasma HIV-1 Proportion of patients with plasma HIV-1 RNA <50 copies/mL at 24 weeksRNA <50 copies/mL at 24 weeks
– Proportion of patients with plasma HIV-1 Proportion of patients with plasma HIV-1 RNA <400 copies/mL at 24 and 48 RNA <400 copies/mL at 24 and 48 weeksweeks
Endpoints cont.Endpoints cont.
SecondarySecondary
– Change from baseline in CD4 cell counts Change from baseline in CD4 cell counts at 24 and 48 weeksat 24 and 48 weeks
– HIV treatment-emergent resistance HIV treatment-emergent resistance patternspatterns
– Differences between treatment arms in Differences between treatment arms in incidence, type and severity of adverse incidence, type and severity of adverse eventsevents
Definition of Definition of Virologic FailureVirologic Failure
Confirmed plasma HIV-1 RNA ≥400 c/mL at Week 24 or later
Baseline CharacteristicsBaseline Characteristics FPV/rFPV/r ATV/r ATV/r Total Total (N=53)(N=53) (N=53) (N=53) (N=106) (N=106)
Median age, yearsMedian age, years 40 40 40 40 40 40
MaleMale 79% 79% 89% 89% 84% 84%Race-African AmericanRace-African American 34% 45% 40% 34% 45% 40% -Causasian-Causasian 64% 49% 56% 64% 49% 56% -Other-Other 2% 6% 4% 2% 6% 4%Ethnicity- HispanicEthnicity- Hispanic 23% 23% 23% 23% 23% 23%
CDC Class CCDC Class C 9 (17%) 9 (17%) 11 (21%) 20 (19%) 11 (21%) 20 (19%)
Median HIV-1 RNA, logMedian HIV-1 RNA, log1010 c/mL 4.88 c/mL 4.88 4.88 4.88 4.88 4.88HIV-1 RNA <100,000 c/mLHIV-1 RNA <100,000 c/mL 37 (70%) 37 (70%) 36 (68%) 73 (69%) 36 (68%) 73 (69%)HIV-1 RNA HIV-1 RNA 100,000 c/mL100,000 c/mL 16 (30%) 16 (30%) 17 (32%) 33 (31%) 17 (32%) 33 (31%)
Median CD4 count, cells/mmMedian CD4 count, cells/mm3 3 161161 188 188 172 172<50 cells/mm<50 cells/mm33 14 (26%) 14 (26%) 9 (17%) 23 (22%) 9 (17%) 23 (22%)50 - <200 cells/mm50 - <200 cells/mm33 21 (40%) 21 (40%) 19 (36%) 19 (36%) 40 (38%)40 (38%) 200 cells/mm200 cells/mm33 18 (34%) 18 (34%) 25 (47%) 43 (41%) 25 (47%) 43 (41%)
Completion Status at 24 WeeksCompletion Status at 24 WeeksFPV/rFPV/r ATV/rATV/r TotalTotal
CompletedCompleted 49 (92%)49 (92%) 50 (94%)50 (94%) 99 (93%)99 (93%)
Prematurely Prematurely withdrawnwithdrawn
4 (8%)4 (8%) 3 (6%)3 (6%) 7 (7%)7 (7%)
Primary Reason for Primary Reason for Withdrawal:Withdrawal:
Non-ResponseNon-Response 1 (2%)1 (2%) 00 1 (<1%)1 (<1%)
Adverse EventAdverse Event 1 (2%) 1 (2%) 1 (2%)1 (2%) 2 (2%)2 (2%)
Lost to follow upLost to follow up 1 (2%) 1 (2%) 2 (4%)2 (4%) 3 (3%)3 (3%)
Protocol ViolationProtocol Violation 1 (2%)1 (2%) 00 1 (<1%)1 (<1%)
0
20
40
60
80
100
0 4 8 12 16 20 24
Study Week
% o
f S
ub
ject
s
FPV/r, MD=FATV/r, MD=FFPV/r, ObservedATV/r, Observed
HIV-1 RNA <400 c/mLHIV-1 RNA <400 c/mL
= 89%= 89%= 94%= 94%
0
20
40
60
80
100
0 4 8 12 16 20 24
Study Week
% o
f S
ub
ject
s
FPV/r, MD=FATV/r, MD=FFPV/r, ObservedATV/r, Observed
HIV-1 RNA <50 c/mLHIV-1 RNA <50 c/mL
= 79%= 83%= 84%= 88%
Mean CD4+ Cell Count with 95% Mean CD4+ Cell Count with 95% Confidence Intervals Confidence Intervals
FPV/r ATV/r
361342
205
W0 W12 W24
302276
176
100
150
200
250
300
350
400
450
W0 W12 W24
Cells
/ mm3
160
177
153
180
116
160
127 133
0
50
100
150
200
250
m g
/d L
FPV/r ATV/r FPV/r ATV/r
Baseline
Week 24
Cholesterol Triglycerides
Baseline n= 48 46 48 46
Week 24 n= 38 39 38 39
Median Fasting LipidsMedian Fasting Lipidsat Baseline and Week 24at Baseline and Week 24
95 99 97103
38 41 3845
0
50
100
150
m g
/d L
FPV/r ATV/r FPV/r ATV/r
Baseline
Week 24
LDL HDL
Median Fasting LipidsMedian Fasting Lipidsat Baseline and Week 24at Baseline and Week 24
Baseline n= 48 45 48 46
Week 24 n= 36 39 38 39
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (week)
HIV
-1 R
NA
Lo
g10
cp
/mL
Subject 1: TDF/FTC+FPV/rSubject 1: TDF/FTC+FPV/rRT: S68G, K70T, V118I, L210W, T215CPRO: K20I, M46I, L63P, A71V, V77I
TDF FC=0.95; APV FC= 3.8 FTC FC=1.5
RT: S68G, K70T, V118I, L210W, T215C, M184V PRO: K20I, M46I, I54I/L/M L63P, A71V, V77I
TDF FC= 0.61; APV FC= 13FTC FC > 112.8
Clade B
Week 0
Week 20
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (week)
HIV
-1 R
NA
Lo
g10
cp
/mL
Subject 2: TDF/FTC+FPV/rSubject 2: TDF/FTC+FPV/r
RT: WTPRO: L10V, L63L/P, V77V/INo phenotypic resistance
RT: K65RPRO: L10V, V32I, M46M/I, I47V
TDF FC= 2.2 APV FC= 8.6FTC FC= 5.6
RT: K65RPRO: L10V, L63L/P, V77V/INo phenotypic resistance
Clade B
Week 0
Week 12
Week 24
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (week)
HIV
-1 R
NA
Lo
g10
cp
/mL
Subject 3: TDF/FTC+ATV/rSubject 3: TDF/FTC+ATV/r
RT: WTPRO: M36I, L63A
TDF FC= 1.1 ATV FC= 0.9FTC FC= 1.04
WD
RT: WTPRO: M36I, L63A
TDF FC= 1.08 ATV FC= 2.07FTC FC= 1.08
Clade B
Week 0
Week 24
Adverse Event Related Adverse Event Related Study DiscontinuationsStudy Discontinuations
One pt. DC’d FPV/r due to AE- Grade 3 Rash
One pt. DC’d ATV/r due to SAE- new onset Kaposi’s Sarcoma
Adverse Event Related Adverse Event Related Study Drug DiscontinuationsStudy 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 Treatment-Related AEs by Overall Frequency >4%AEs by Overall Frequency >4%
Grades 2-4Grades 2-4
FPV/rFPV/r
n=53n=53
ATV/rATV/r
n=53n=53
Any EventAny Event 6 (11%)6 (11%) 28 (53%)28 (53%)
Bilirubin Bilirubin ↑↑ 00 22 (41%)22 (41%)
DiarrheaDiarrhea 3 (6%)3 (6%) 1 (2%)1 (2%)
NauseaNausea 2 (4%)2 (4%) 1 (2%)1 (2%)
Scleral IcterusScleral Icterus 00 2 (4%)2 (4%)
ConclusionsConclusions
Both arms provided similar rates of Both arms provided similar rates of virologic suppression and immunologic virologic suppression and immunologic improvement at Week 24improvement at Week 24
Lipid changes were similarLipid changes were similar
Overall, fewer severe adverse effects Overall, fewer severe adverse effects occurred with FPV/r than with ATV/r; occurred with FPV/r than with ATV/r; differences due primarily to bilirubin- differences due primarily to bilirubin- associated AEsassociated AEs
AcknowledgementsAcknowledgements
Cynthia Brinson- Austin, TXCynthia Brinson- Austin, TXCal Cohen- Boston, MACal Cohen- Boston, MAEdwin DeJesus- Orlando, FLEdwin DeJesus- Orlando, FLMargaret Fischl- Miami, FLMargaret Fischl- Miami, FLJoseph Horvath- Columbia, SCJoseph Horvath- Columbia, SCRicky Hsu- New York, NYRicky Hsu- New York, NYLewis McCurdy- Charlotte, NCLewis McCurdy- Charlotte, NCCheryl McDonald- Ft. Worth, TXCheryl McDonald- Ft. Worth, TX
Support was provided by GlaxoSmithKlineSupport was provided by GlaxoSmithKline
Bruce Rashbaum- Wash., DCBruce Rashbaum- Wash., DCRobert Scott- Oakland, CARobert Scott- Oakland, CAKimberly Smith- Chicago, ILKimberly Smith- Chicago, ILFord Kinder- Miami, FLFord Kinder- Miami, FLWinkler Weinberg- Atlanta, GAWinkler Weinberg- Atlanta, GABen Young- Denver, COBen Young- Denver, CO
ALERT was made possible by the contributionsALERT was made possible by the contributionsof patients and staff at the following US sites*:of patients and staff at the following US sites*:
*Also wish to thank the CRO, MediStaf Research, for their contributions.
Backup Slides (Additional Data)Backup Slides (Additional Data)
Fasting CholesterolFasting Cholesterol
158165 173 182
Fasting TriglyceridesFasting Triglycerides
141 144 192145
Fasting LDLFasting LDL
94101 98 105
Fasting HDLFasting HDL
37 3640
47
Mean CD4+ Cell Count Change Mean CD4+ Cell Count Change from Baseline with 95% CI from Baseline with 95% CI
Baseline mean: 176
Baseline mean: 205
Week 12 Week 24
148
105
124132
50
70
90
110
130
150
170
190
Cel
ls /
mm
3
FPV/r
ATV/r
17
10
20
7 6
-3
4
8
-5
5
15
25
m
g /
d
L
C h
a n
g e
Chol Trig LDL HDL
FPV/r
ATV/r
n= 36 37 36 37 34 36 36 37
Fasting LipidsFasting LipidsMedian Change from Baseline at Median Change from Baseline at
Week 24Week 24
20%
3%
3%
10%
5%
3%
11%
5%
3%
11%
8%
0%
10%
20%
30%
%
o f
S u
b j
e c
t s
FPV/r ATV/r FPV/r ATV/r FPV/r ATV/r
g3
g2
g1
n= 40 39 40 39 38 38
Treatment Emergent Fasting LipidTreatment Emergent Fasting LipidToxicities by Intensity GradingToxicities by Intensity Grading
Cholesterol Triglycerides LDL
eGFR by MDRD (FPV/r) eGFR by MDRD (FPV/r) Wk 0 to Wk 24 Wk 0 to Wk 24
2 04
10
58 60
3630
0
10
20
30
40
50
60
% of Subjects
<30 30-<60 60-<90 >/=90
Wk 0 Week 24
eGFR by MDRD (ATV/r) eGFR by MDRD (ATV/r) Wk 0 to Wk 24Wk 0 to Wk 24
0 0 210
5866
40
24
010203040506070
% of Subjects
<30 30-<60 60-<90 >/=90
Wk 0 Week 24
eGFR by MDRD (All Subjects) eGFR by MDRD (All Subjects) Wk 0 to Wk 24Wk 0 to Wk 24
1 03
10
58 63
38
27
010203040506070
% of Subjects
<30 30-<60 60-<90 >/=90
Wk 0 Week 24
Two pts. DC’d Truvada due to declining renal function, defined as eGFR change >25% below baseline or eGFR <50mL/min (confirmed)
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (week)
HIV
-1 R
NA
Lo
g10
cp
/mL
Subject 1: TDF/FTC+FPV/rSubject 1: TDF/FTC+FPV/rRT: S68G, K70T, V118I, 210W,T215CPRO: K20I, M46I, L63P, A71V, V77I
TDF FC=0.95 APV FC= 3.8 FTC FC=1.5
RT: S68G, K70T, V118I, M184V, L210W, 215C, K219K/QPRO: K20I, M46I, I47I/V, F53F/L, I54I/L, L63P, A71V, V77I
TDF FC= 0.61 APV FC= 2.98FTC FC > 78.3
RT: S68G, K70T, V118I, M184V, L210W, 215C, PRO: K20I, M46I, I54I/L/M L63P, A71V, V77I
TDF FC= 0.61 APV FC= 13FTC FC > 112.8
Clade B
Week 0
Week 12
Week 20
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (week)
HIV
-1 R
NA
Lo
g10
cp
/mL
Subject 2: TDF/FTC+FPV/rSubject 2: TDF/FTC+FPV/r
RT: WTPRO: L10V, L63L/P, V77V/INo phenotypic resistance
RT: WTPRO: L10V, L63L/P, V77V/INo phenotypic resistance
RT: K65RPRO: L10V, V32I, M46M/I, I47V
TDF FC= 2.2 APV FC= 8.6FTC FC= 5.6
RT: K65R, D67D/N,PRO: L10V, V32I, M46I, I47V
TDF FC= 1.8 APV FC= 19FTC FC= 8.5
RT: K65RPRO: L10V, L63L/P, V77V/INo phenotypic resistance
Clade B
Week 0
Week 4
Week 12
Week 24
Week 28
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (week)
HIV
-1 R
NA
Lo
g10
cp
/mL
Subject 3: TDF/FTC+ATV/rSubject 3: TDF/FTC+ATV/r
RT: WTPRO: M36I, L63A
TDF FC= 1.1 ATV FC= 0.9FTC FC= 1.04
WD
RT: WTPRO: M36I, L63A
TDF FC= 1.08 ATV FC= 2.07FTC FC= 1.08
Clade B
Week 0
Week 12