Transcript Safety, Tolerability, & Efficacy of Abacavir / Lamivudine

Safety, Tolerability & Efficacy of
Abacavir/Lamivudine/Zidovudine
vs.
Atazanavir & Lamivudine/Zidovudine
in Antiretroviral Naïve Subjects
ESS100327: ACTION Study
No. H-1058
Kumar PN, Salvato P, DeJesus E, LaMarca A, Patel P,
Sutherland-Phillips D, McClernon D, Florance A, Sall J,
Wannamaker P, and Shaefer M for the ACTION study group
Acknowledgements
Investigators:
C Aneziokoro
N Bellos
J Boghossian
J Brand
G Coodley
P Cook
E DeJesus
R Dretler
F Felizarta
T File
F Garcia
E Godofsky
S Green
P Greiger-Zanlungo
J Hernandez
M Hill
M Hoffman-Terry
J Horvath
A Huang
R Jones
P Kumar
P Lackey
A LaMarca
H Lampiris
F Lutz
A Mills
J Morales-Reyes
R Nahass
D Parks
R Peskind
D Pitrak
R Poblete
J Ramos-Jimenez
A Rodriguez
J Rodriguez
P Salvato
J Schrank
R Schwartz
R Scott
CB Small
D Sweet
E Tedaldi
J Torres
M Tribble
W Weinberg
R Wilcox
D Wright
Study
Coordinators
Patients
GlaxoSmithKline
J Royall
J Weidner
K Frusciante
D Sutherland-Phillips
J Sall
P Wannamaker
D McClernon
A Florance
M Moore
M Watson
B Matthews
C Brothers
S Chriscoe
M Shaefer
P Patel
Background
•
Abacavir/Lamivudine/Zidovudine (ABC/3TC/ZDV,
Trizivir) & Atazanavir (ATV, Reyataz) are
alternative options in ARV-naïve patients
•
•
•
ABC/3TC/ZDV should be reserved for those who cannot
receive an NNRTI or PI-based regimen1
ATV without ritonavir is an alternative to the preferred
PI-based regimen, Lopinavir/ritonavir
Both regimens are used in clinical practice in
select patient populations as they are welltolerated and convenient therapies.
1DHHS
Guidelines, May 2006.
Study Design
Phase IV, randomized (1:1), multicenter, open-label, 48 week study
Conducted at 46 sites in US and Mexico
ABC/3TC/ZDV
1 tablet twice daily
N=139
ARV Naïve Subjects
Screen HIV-1 RNA <200,000 c/mL
CD4+ Count ≥ 100 cells/mm3
Stratified by HIV-1 RNA
< or ≥ 100,000 c/mL
Atazanavir 400mg daily +
3TC/ZDV 1 tablet twice daily
N=140
Non-Inferiority established if the lower limit of the two-sided 95% CI was ≥ -0.12
Switch allowed for ABC HSR (TDF) or jaundice or scleral icterus (FPV)
Study Endpoints
Primary Endpoint
– Proportion of subjects with HIV-1 RNA <50 c/mL at Week 48
• Subjects must not have met any definition of virologic failure
• ITT-E, Missing/Switch = Failure Analysis
Key Secondary Endpoints
 Efficacy
 Proportion of subjects with HIV-1 RNA <50 c/mL, switch ≠ failure
 Change in HIV-1 RNA and CD4 cell counts from BL
 Treatment-emergent genotype mutations
 Safety
 Drug-related adverse events (Grade 2-4) and serious adverse
events
 Changes in lipid parameters, insulin sensitivity and resistance
Virologic Failure Criteria
Virologic failure was defined as any of the following:
1. Failure to have ≥ 1 log HIV-1 RNA drop by Week 12
2. Failure to have HIV-1 RNA <400 by Week 24
3. Confirmed HIV-1 RNA <50 then ≥ 400 confirmed prior
to Week 24
4. Confirmed HIV-1 RNA ≥ 400 after Week 24
5. HIV-1 RNA ≥ 400 at Week 48 without confirmation
*Virologic responders could not have met any virologic failure criteria
Baseline Demographics
ABC/3TC/ZDV
N=139
Median age, years
Female, n (%)
ATV+3TC/ZDV
N=140
38
36
22%
20%
47%
32%
19%
41%
35%
21%
Race, n (%)
White
Black
Hispanic
Hepatitis B positive
Hepatitis C positive
Hepatitis B & C co-infection
1%
6%
0
4%
7%
<1%
Baseline Characteristics
ABC/3TC/ZDV
N=139
ATV+3TC/ZDV
N=140
4%
4%
Median HIV-1 RNA log10 c/mL
4.48
4.64
HIV-1 RNA <100,000 c/mL (%)
83%
82%
Median CD4+ (cells/mm3)
274
262
0%
24%
47%
28%
5%
26%
44%
25%
CDC Class C (%)
<100
100 - <200
200 - <350
≥ 350
Subject Disposition
Completed 48 Weeks
Premature Withdrawal
Reasons for Discontinuation
Virologic Failure*
Lost to Follow-Up
Adverse Event
Other
Investigator Decision
Subject Decision
Protocol Violation
ABC/3TC/ZDV
N=139
ATV+3TC/ZDV
N=140
103 (74%)
36 (26%)
98 (70%)
41 (29%)
16 (12%)
12 ( 9%)
6 ( 4%)
6 ( 4%)
6 ( 4%)
3 ( 2%)
0
16 (11%)
14 (10%)
11 ( 8%)
0
0
1 (<1%)
2 ( 1%)
*As reported on Study Conclusion Page.
Note: subjects with VL<1265 c/mL were allowed to stay on study.
Virologic Responders
HIV-1 RNA <50 c/mL at Week 48
Switch = Failure Analysis
Proportion of Subjects
100
80
60
95% CI
(-5.9, 10.4)
62
95% CI
(-5.6, 19.5)
95% CI
(-49.2, 27.4)
95% CI
(-6.7, 9.4)
95%CI
(-7.5, 16.4)
95%CI
(-46.2, 15.8)
81
76
76
74
66
59
65
60
59
50
40
39
20
0
Overall
ITT-E
M/S=F
HIV-1 RNA
HIV-1 RNA
<100,000 c/mL ≥100,000 c/mL
ABC/3TC/ZDV
ABC/3TC/ZDV n = 138
ATV+3TC/ZDV n = 140
115
115
23
25
Overall
Observed
S=F
HIV-1 RNA
HIV-1 RNA
<100,000 c/mL ≥100,000 c/mL
ATV+3TC/ZDV
112
112
94
89
18
23
Virologic Responders
HIV-1 RNA <50 c/mL at Week 48
Switch ≠ Failure
Proportion of Subjects
100
80
60
95% CI
(-6.4, 9.5)
95% CI
(-5.3, 19.2)
95%CI
(-52.9, 3.1)
95%CI
(-7.4, 13.9)
95% CI
(-7.8, 7)
86
80
80
83
95% CI
(-50.1, 11)
70
70
64
63
64
63
50
40
39
20
0
Overall
ITT-E
S≠F
HIV-1 RNA
HIV-1 RNA
<100,000 c/mL ≥100,000 c/mL
ABC/3TC/ZDV
ABC/3TC/ZDV n = 138
ATV+3TC/ZDV n = 140
115
115
23
25
Overall
Observed
S≠F
HIV-1 RNA
HIV-1 RNA
<100,000 c/mL ≥100,000 c/mL
ATV+3TC/ZDV
111
110
93
87
18
23
Median Change from Baseline in
CD4+ Cell Count
Median CD4+ Cell Count
(cells/mm3)
200
150
+ 147
100
50
TZV
ATV+COM
0
0
8
16
24
32
40
Study Week
Median 274
CD4+
262
48
434
419
ABC/3TC/ZDV n= 138
128
122
117
110
104
101
ATV+3TC/ZDV n=140
125
123
118
106
98
96
Virologic Failure Outcomes
ABC/3TC/ZDV
N=138
Virologic Failures, n (%)
HIV-1 RNA <100,000 c/mL
HIV-1 RNA ≥ 100,000 c/mL
ATV+3TC/ZDV
N=140
18 (13%)
17 (12%)
10
8
12
5
3
3
3
4
2
6
2
11
7
3
Reasons for Virologic Failure*, n
1. Fail to have ≥1 log RNA drop by Week 12
2. Fail to have VL <400 c/mL by Week 24
3. Two VL <50 then confirmed ≥400 c/mL by Wk 24
4. Two ≥400 c/mL after Week 24
5. VL ≥400 c/mL after Week 48 without
confirmation
* Subjects could have met multiple virologic failure criteria
Treatment Emergent Resistance
ABC/3TC/ZDV ATV+3TC/ZDV
N=138
N=140
Protocol-Defined Virologic Failure, n (%)
18 (13%)
17 (12%)
Paired BL and Failure GT/ PT Results
17
16
Treatment-Emergent Mutations at VF
10
11
NRTI*
(M184V)
(L210W, D67N, L74V, F77L)
9 ( 90%)
1 ( 10%)
9 (82%)
0
PI
Major
Minor
0
7 (70%)
0
6 (55%)
1 (10%)
1 ( 9%)
(L10I, I13V, I13L/V, G16E,K20M, L24I,
I31L/V, L33V, E35G, I54I/L, I62I/V,
L63L/P, A71A/V, V77I/V, I85I/V, I93I,
I93L)
NNRTI
(K103N)
Treatment-Related Grade 2-4
Adverse Events in >2% of subjects
ABC/3TC/ZDV ATV+3TC/ZDV
% (% Grade 3/4)
Hyperbilirubinemia
Nausea
N=138
0
11% (<1%)
N=140
21% (16%)
4% (0)
Neutropenia
5% (4%)
6% (4%)
Fatigue
5% (0)
2% (0)
Headache
4% (<1%)
4% (0)
Suspected Abacavir HSR*
5% (0)
0
Anemia
<1% (<1%)
3% (3%)
Scleral Icterus
* Includes 1 Suspected ABC HSR reported as grade 1
0
4% (3%)
Percent Change in Fasting Lipids
from Baseline to Week 48
% Change in Fasting Lipids
100
Total Cholesterol
Triglycerides
80
LDL-Cholesterol
60
HDL-Cholesterol
40
20
5
11
21
16
-5
2
5
-6
0
-20
TZV
ATV+COM
Summary
•
•
•
In an ITT(E) M/S=F analysis, 62% vs. 59% of
subjects achieved HIV-1 RNA <50 copies/ml
in the overall population (ABC/3TC/ZDV vs.
ATV+3TC/ZDV, respectively)
Protocol-defined virologic failure occurred in
13% of subjects and were balanced between
arms
No treatment-emergent primary PI mutations
in the ATV+3TC/ZDV arm were observed
through 48 weeks and the majority of NRTI
mutations were attributed to M184V
Conclusion
• In this study, ABC/3TC/ZDV and
ATV+3TC/ZDV were well-tolerated
and had comparable efficacy
• In select patients naïve to therapy
with HIV-1 RNA <100,000 c/mL,
ABC/3TC/ZDV remains a viable
option as an initial regimen
Back-Up Slides
Efficacy of ABC/3TC/ZDV Compared to
Unboosted PIs and Efavirenz
HIV-1 RNA <50 c/mL over 48 Weeks
Proportion of Subjects
100
80
Comparator:
ABC/3TC/ZDV
ABC/3TC/ZDV
+ IDV+COM
PBOS
60%
55%
IDV+COM IDV+
+ TZV PBO COM
NFV+
COM
EFV+COM
EFV+TZV
83%
61%
60
46%
40%
50%
55%
40
20
0
ABC/3TC/ZDV
CNAAB3005
CNA3014
Comparator Arms
CNAF3007
ACTG5095
Efficacy Outcomes
n (%)
Week 48
TZV
ATV+COM
N=138
N=140
HIV-1 RNA<50 c/mL, ITT-E, M/S=F
All Responders
85 (62%)
83 (59%)
Response by Strata, n/N (%)
HIV-1 RNA < 100,000 c/mL
76 / 115 (66%)
68 / 115 (59%)
HIV-1 RNA ≥ 100,000 c/mL
9 / 23 (39%)
15 / 25 (60%)
93 (67%)
95 (68%)
HIV-1 RNA <400 c/mL, ITT-E, M=F
All Responders
* Protocol-defined virologic failure was based on multiple criteria
Adverse Events
ABC/3TC/ZDV ATV+3TC/ZDV
Serious Adverse Events
Treatment-Related SAEs
ABC HSR
Anemia
Abdominal Pain
Study Drug Discontinuation (G2-4 AE)
Drug Hypersensitivity*
Scleral Icterus
Hyperbilirubinemia
Jaundice
Anemia
Nausea
Abdominal Pain
Drug Eruption
*Includes 1 subject with Grade 1 HSR
N=138
N=140
14 (10%)
17 (12%)
7 ( 5%)
7 ( 5%)
0
0
3 ( 2%)
0
3 ( 2%)
1 (<1%)
12 ( 9%)
13 ( 9%)
7 ( 5%)
0
0
0
1 (<1%)
2 (1%)
2 ( 1%)
0
0
4(
4(
2(
2(
0
0
2(
3%)
3%)
1%)
1%)
1%)
HIV-1 RNA <50 c/mL at Week 48
Subjects without protocol-defined virologic failure
ITT-E, CD4 Subgroup Analysis
Percent of Subjects
100
88
80
94
91
86
89
89
72
60
64
67
64
61
56
40
20
0
Overall
M=F
CD4+ <200
cells/mm3
CD4+ ≥ 200
cells/mm3
Overall
Observed
TZV
ATV+COM
CD4+ <200
cells/mm3
CD4+ ≥ 200
cells/mm3
TZV
n = 138
34
104
101
22
79
ATV+COM
n = 140
43
97
99
33
66
Median Fasting Lipids (mg/dL)
at Baseline and Week 48
Cholesterol
250
Triglycerides
Baseline
Week 48
NCEP III
mg/dL
200
150
NCEP III
162 176
160 171
100
113 126
117 110
ATV+COM
50
0
Baseline n=
Week 48 n=
TZV
ATV+COM
TZV
131
93
137
93
131
93
137
93
NCEP ATP III Guidelines consider TC <200 mg/dL and TG <150 mg/dL as desirable
Median Fasting Lipids (mg/dL)
at Baseline and Week 48
LDL
150
HDL
Baseline
Week 48
NCEP III
mg/dL
100
98
99
97 102
NCEP III
50
36.5 44
33
44
0
Baseline n=
Week 48 n=
TZV
ATV+COM
TZV
ATV+COM
127
89
133
92
130
93
135
93
NCEP ATP III Guidelines consider LDL <100 mg/dL and HDL > 40 mg/dL as desirable
The ACTION Study
•
•
Phase IV, randomized, multicenter, open-label
study evaluating the safety and efficacy of
ABC/3TC/ZDV vs. ATV + 3TC/ZDV in ART-naïve
subjects over 48 weeks
279 subjects were enrolled from 46 sites in the
U.S. & Mexico between May 2004 – March 2005.
• 95% from U.S. sites.
•
Subjects experiencing toxicity from randomized
treatment were permitted to switch medications
• Suspected ABC HSR reaction  3TC/ZDV +
Tenofovir
• Atazanavir-related jaundice or scleral icterus 
Fosamprenavir + 3TC/ZDV
•
Virologic failure was based on multiple criteria
Study Discontinuation Due to
Grade 2-4 Adverse Events
TZV
ATV+COM
N=138
N=140
6 (4%)
8 (6%)
Rash
0
3 (2%)
Anemia
1 (<1%)
2 (1%)
Abdominal pain
2 (1%)
0
Nausea
2 (1%)
0
Dyspepsia
0
1 (<1%)
Enteritis
0
1 (<1%)
Vomiting
Fatigue
Headache
1 (<1%)
1 (<1%)
1 (<1%)
0
0
0
Hyperbilirubinemia
0
1 (<1%)
Jaundice
0
1 (<1%)
Study Discontinuation from AEs, n (%)
Toxicity Switches
TZV
N=138
Toxicity Switches
ATV+COM
N=140
7 (5%)
9 (6%)
7 (5%)
0
0
0
0
2 (1%)
4 (3%)
3 (2%)
3
Abacavir – Related
Suspected Abacavir HSR
Atazanavir - Related
Jaundice
Scleral Icterus
Hyperbilirubinemia**
Grade 3 (>2.5-5x ULN)
**Although hyperbilirubinemia was not a protocol allowable toxicity switch reason,
3 subjects switched off ATV+COM due to ATV-related hyperbilirubinemia
HIV-1 RNA <400 c/mL at Week 48
100
Proportion of Subjects
92
96
92
87
80
78
74
67
60
68
40
20
0
Week 24
Week 48
Week 24
M=F
Week 48
Obs
TZV
ATV+COM
Virologic Response
HIV-1 RNA <50 c/mL
Proportion of Subjects
100
84
86
80
62
61
60
40
ITT-E, M/S=F
20
ITT-E, S=F
TZV
ATV+COM
TZV, Observed
ATV+COM, Observed
0
0
8
16
24
32
40
48
Study Week
n (obs)
TZV = 138
130
122
117
111
104
101
ATV+CO M = 140
128
123
118
109
100
99
Virologic Response
HIV-1 RNA <50 c/mL
Proportion of Subjects
100
88
91
80
65
64
60
40
ITT-E, M=F,S≠F
20
ITT-E, S≠F
TZV
ATV+COM
TZV, Observed
ATV+COM, Observed
0
0
8
16
24
32
40
48
Study Week
n (obs)
TZV = 138
130
122
117
111
104
101
ATV+CO M = 140
128
123
118
109
100
99
Virologic Response
HIV-1 RNA <400 c/mL
Proportion of Subjects
100
88
91
80
65
64
60
40
ITT-E, M/S=F
20
ITT-E, S=F
TZV
ATV+COM
TZV, Observed
ATV+COM, Observed
0
0
8
16
24
32
40
48
Study Week
n (obs)
TZV = 138
130
122
117
111
104
101
ATV+CO M = 140
128
123
118
109
100
99
Virologic Response
HIV-1 RNA <400 c/mL
Proportion of Subjects
100
92
96
80
67
68
60
40
ITT-E, M=F,S≠F
20
ITT-E, S≠F
TZV
ATV+COM
TZV, Observed
ATV+COM, Observed
0
0
8
16
24
32
40
48
Study Week
n (obs)
TZV = 138
130
122
117
111
104
101
ATV+CO M = 140
128
123
118
109
100
99
Time to Loss of Virologic Response
HIV-1 RNA<50 c/mL (TLOVR)
Time to Loss of Virologic Response
HIV-1 RNA<50 c/mL (TLOVR)
M/S=F
Median Changes in Metabolic
Parameters at Baseline & Week 48
HOMA-IR
5
QUICK1
Baseline
Week 48
Calculation
4
3
2.9
3
2.4
2.2
2
0.59
1
0.54
0.58 0.54
0
TZV
Baseline n=
Week 48 n=
110
83
ATV+COM
112
87
TZV
110
83
ATV+COM
112
87
Subject 855: TZV
RT: L74V, F77L, V118I
PRO: D30N, L63P, N88D
ABC FC= 1.19
ATV FC = 4.79
3TC FC= 1.33
ZDV FC= 0.85
5
HIV-1 RNA Log10 .
4.5
4
WD
3.5
RT: L74V, F77L, V118I, L210W
PRO: D30N, M36I, L63P, N88D
ABC FC= 5.90 ATV FC = 11
3TC FC= 8.59
ZDV FC = 115
3
2.5
2
1.5 0
4
8
12
16
20
24
28
Time (week)
32
36
40
44
48
Subject 573: TZV
5
HIV-1 RNA Log10 .
4.5
4
3.5
3
RT: WT
PRO: L63P
ABC FC= 0.95
3TC FC= 1.27
ZDV FC= 0.65
RT: WT
PRO: L63P
ABC FC= 0.82
3TC FC= 1.22
ZDV FC= 0.59
ATV FC = 0.72
ATV FC = 0.58
2.5
2
1.5 0
4
8
12
16
20
24
28
Time (week)
32
36
40
44
48
5
Subject 668: TZV
HIV-1 RNA Log10 .
4.5
RT: WT
PRO: L63P
ABC FC= 0.72
3TC FC= 1.03
ZDV FC= 1.10
4
ATV FC = 0.92
RT: M184V
PRO: L63P
ABC FC= 3.00
3TC FC= 104
ZDV FC= 0.48
3.5
ATV FC = 0.80
3
2.5
2
1.5 0
4
8
12
16
20
24
28
Time (week)
32
36
40
44
48
Subject 852: ATV/COM
5.5
5
RT: WT
PRO: L63P
ABC FC= 0.76
3TC FC= 1.05
ZDV FC= 0.63
HIV-1 RNA Log10 .
4.5
RT: K103N
PRO: L63P
ABC FC= 0.84
3TC FC= 1.21
ZDV FC= 0.60
ATV F = 0.83
ATV FC = 1.05
4
3.2 log
3.5
3
3log
2.5
2
1.5
0
4
8
12
16
20
24
28
Time (week)
32
36
40
44
48
Subject 918: ATV/COM
5
RT: K103N
PRO: L63P
ABC FC= 0.57
3TC FC= 1.01
ZDV FC= 0.22
HIV-1 RNA Log10 .
4.5
4
ATV FC = 0.95
RT: K103N, M184V
PRO: K20M, L24I, L63P
ABC FC= 2.99
ATV FC = 0.58
3TC FC= 104
ZDV FC= 0.43
3.5
3
2.5
2
1.5 0
4
8
12
16
20
24
28
Time (week)
32
36
40
44
48
5
Subject 592: ATV/COM
HIV-1 RNA Log10 .
4.5
RT: L74V, M184V, P225H
PRO: L10I, K20I, I54L, A71V, L90M
ABC FC= 2.85
ATV FC = 1.83
3TC FC= 87
ZDV FC= 0.91
RT: L74V, P225H
PRO: L10I, K20I, A71V, L90M
ABC FC= 0.99
ATV FC = 1.59
3TC FC= 1.06
ZDV FC= 1.27
4
3.5
3
2.5
2
1.5 0
4
8
12
16
20
24
28
Time (week)
32
36
40
44
48