Safety, Tolerability

1
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

2
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
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
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

3
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
  well-tolerated and convenient therapies.

1DHHS Guidelines, May 2006.
4
Study Design
Phase IV, randomized (11), multicenter,
open-label, 48 week study Conducted at 46 sites
in US and Mexico
ABC/3TC/ZDV
1 tablet twice daily N139
ARV Naïve Subjects Screen HIV-1 RNA lt200,000
c/mL CD4 Count 100 cells/mm3 Stratified by
HIV-1 RNA lt or 100,000 c/mL
Atazanavir 400mg daily 3TC/ZDV 1 tablet twice
daily N140
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)
5
Study Endpoints

• Primary Endpoint
• Proportion of subjects with HIV-1 RNA lt50 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 lt50 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

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Virologic Failure Criteria

• Virologic failure was defined as any of the
  following
• Failure to have 1 log HIV-1 RNA drop by Week 12
• Failure to have HIV-1 RNA lt400 by Week 24
• Confirmed HIV-1 RNA lt50 then 400 confirmed
  prior to Week 24
• Confirmed HIV-1 RNA 400 after Week 24
• HIV-1 RNA 400 at Week 48 without confirmation
• Virologic responders could not have met any
  virologic failure criteria

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Baseline Demographics
ABC/3TC/ZDV ATV3TC/ZDV N139
N140
Median age, years
38 36

22 20
Female, n ()

Race, n ()

47 41
White Black Hispanic
32 35
19 21
Hepatitis B positive Hepatitis C
positive Hepatitis B C co-infection
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Baseline Characteristics
ABC/3TC/ZDV ATV3TC/ZDV N139
N140
CDC Class C ()
4 4

4.48 4.64

Median HIV-1 RNA log10 c/mL
HIV-1 RNA lt100,000 c/mL ()
83 82
Median CD4 (cells/mm3)
274 262
lt100
100 - lt200
200 - lt350

350
28 25
9
Subject Disposition
ABC/3TC/ZDV ATV3TC/ZDV N139
N140
Completed 48 Weeks
103 (74) 98 (70)

Premature Withdrawal

36 (26) 41 (29)
Reasons for Discontinuation Virologic
Failure Lost to Follow-Up
Adverse Event Other
Investigator Decision Subject Decision
Protocol
Violation
16 (12) 16 (11)
12 ( 9) 14 (10)
6 ( 4) 11 ( 8)
6 ( 4) 0
6 ( 4) 0
3 ( 2) 1 (lt1)
0 2 ( 1)
As reported on Study Conclusion Page. Note
subjects with VLlt1265 c/mL were allowed to stay
on study.
10
Virologic RespondersHIV-1 RNA lt50 c/mL at Week
48 Switch Failure Analysis
95CI (-7.5, 16.4)
95 CI (-6.7, 9.4)
95CI (-46.2, 15.8)
95 CI (-5.6, 19.5)
95 CI (-49.2, 27.4)
95 CI (-5.9, 10.4)
Proportion of Subjects
Overall ITT-E M/SF
Overall Observed SF
HIV-1 RNA lt100,000 c/mL
HIV-1 RNA 100,000 c/mL
HIV-1 RNA lt100,000 c/mL
HIV-1 RNA 100,000 c/mL
ABC/3TC/ZDV n 138 115
23 112
94 18
ATV3TC/ZDV
n 140 115 25
112 89
23
11
Virologic RespondersHIV-1 RNA lt50 c/mL at Week
48 Switch ? Failure
95CI (-7.4, 13.9)
95 CI (-7.8, 7)
95 CI (-5.3, 19.2)
95 CI (-50.1, 11)
95CI(-52.9, 3.1)
95 CI (-6.4, 9.5)
Proportion of Subjects
Overall ITT-E
Overall Observed S?F
HIV-1 RNA lt100,000 c/mL
HIV-1 RNA 100,000 c/mL
HIV-1 RNA lt100,000 c/mL
HIV-1 RNA 100,000 c/mL
S?F
ABC/3TC/ZDV n 138 115
23 111
93 18
n 140 115
25 110 87
23
ATV3TC/ZDV
12
Median Change from Baseline in CD4 Cell Count
147
Median 274 CD4 262
434 419
ABC/3TC/ZDV n 138 128
122 117 110
104 101
ATV3TC/ZDV
n140 125 123
118 106
98 96
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Virologic Failure Outcomes
ABC/3TC/ZDV ATV3TC/ZDV N138
N140
Virologic Failures, n ()
18 (13) 17
(12)
10 12
HIV-1 RNA lt100,000 c/mL HIV-1 RNA 100,000
c/mL
8 5
Reasons for Virologic Failure, n
1. Fail to have 1 log RNA drop by Week 12
3 3
3 4
2. Fail to have VL lt400 c/mL by Week 24
2 2
3. Two VL lt50 then confirmed 400 c/mL by Wk 24
6 11
4. Two 400 c/mL after Week 24
7 3

• VL 400 c/mL after Week 48 without
• confirmation

Subjects could have met multiple virologic
failure criteria
14
Treatment Emergent Resistance
ABC/3TC/ZDV ATV3TC/ZDV N138
N140
18 (13) 17 (12)
Protocol-Defined Virologic Failure, n ()
17 16
Paired BL and Failure GT/ PT Results
Treatment-Emergent Mutations at VF

10 11
NRTI (M184V) (L210W, D67N,
L74V, F77L)
9 ( 90) 9 (82)
1 ( 10) 0
PI Major Minor
0 0
7 (70) 6 (55)
(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)
1 (10) 1 ( 9)
NNRTI (K103N)
15
Treatment-Related Grade 2-4 Adverse Events in gt2
of subjects
N138 N140
ABC/3TC/ZDV ATV3TC/ZDV

( Grade 3/4)
Hyperbilirubinemia
0 21 (16)
Nausea
11 (lt1) 4 (0)
Neutropenia
5 (4) 6 (4)
Fatigue
5 (0) 2 (0)
Headache
4 (lt1) 4 (0)
Suspected Abacavir HSR 5 (0)
0
Anemia
lt1 (lt1) 3 (3)
Scleral Icterus
0 4 (3)
Includes 1 Suspected ABC HSR reported as grade 1
16
Percent Change in Fasting Lipids from Baseline to
Week 48
Change in Fasting Lipids
17
Summary

• In an ITT(E) M/SF analysis, 62 vs. 59 of
  subjects achieved HIV-1 RNA lt50 copies/ml in the
  overall population (ABC/3TC/ZDV vs. ATV3TC/ZDV,
  respectively)
• Protocol-defined virologic failure occurred in
  13 of subjects and were balanced between arms
• No treatment-emergent primary PI mutations in the
  ATV3TC/ZDV arm were observed through 48 weeks
  and the majority of NRTI mutations were
  attributed to M184V

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Conclusion

• In this study, ABC/3TC/ZDV and ATV3TC/ZDV were
  well-tolerated and had comparable efficacy
• In select patients naïve to therapy with HIV-1
  RNA lt100,000 c/mL, ABC/3TC/ZDV remains a viable
  option as an initial regimen

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Back-Up Slides
20
Efficacy of ABC/3TC/ZDV Compared to Unboosted PIs
and Efavirenz
HIV-1 RNA lt50 c/mL over 48 Weeks
EFVCOM EFVTZV
Comparator ABC/3TC/ZDV ABC/3TC/ZDV
IDVCOM PBOS
NFV COM
IDV COM
IDVCOM TZV PBO
83
61
60
55
55
50
46
Proportion of Subjects
40
21
Efficacy Outcomes
TZV ATVCOM N138
N140
Week 48
n ()
HIV-1 RNAlt50 c/mL, ITT-E, M/SF
All Responders
85 (62) 83 (59)
Response by Strata,
n/N ()
76 / 115 (66) 68 / 115 (59)
HIV-1 RNA lt 100,000 c/mL
HIV-1 RNA 100,000 c/mL
9 / 23 (39) 15 / 25 (60)
HIV-1 RNA lt400 c/mL, ITT-E, MF
All Responders 93
(67) 95 (68)
Protocol-defined virologic failure was based on
multiple criteria
22
Adverse Events
N138 N140
ABC/3TC/ZDV ATV3TC/ZDV

Serious Adverse Events
14 (10) 17 (12)
Treatment-Related SAEs
7 ( 5) 3 ( 2)
ABC HSR
7 ( 5)
0 Anemia
0
3 ( 2) Abdominal Pain
0
1 (lt1)
Study Drug Discontinuation (G2-4 AE)
12 ( 9) 13 ( 9)
Drug Hypersensitivity
7 ( 5) 0 Scleral
Icterus
0 4 (
3) Hyperbilirubinemia
0 4
( 3) Jaundice
0
2 ( 1) Anemia
1 (lt1)
2 ( 1) Nausea
2 (1)
0 Abdominal Pain
2 ( 1)
0 Drug Eruption
0
2 ( 1)
Includes 1 subject with Grade 1 HSR
23
HIV-1 RNA lt50 c/mL at Week 48 Subjects without
protocol-defined virologic failureITT-E, CD4
Subgroup Analysis
Percent of Subjects
Overall MF
Overall Observed
CD4 lt200 cells/mm3
CD4 200 cells/mm3
CD4 lt200 cells/mm3
CD4 200 cells/mm3
TZV n 138 34
104 101
22 79 ATVCOM n
140 43 97
99 33
66
24
Median Fasting Lipids (mg/dL) at Baseline and
Week 48
Cholesterol
Triglycerides
NCEP III
NCEP III
162 176
160 171
113 126
117 110
Baseline n 131
137 131
137 Week 48 n 93
93
93 93
NCEP ATP III Guidelines consider TC lt200 mg/dL
and TG lt150 mg/dL as desirable
25
Median Fasting Lipids (mg/dL) at Baseline and
Week 48
LDL
HDL
NCEP III
97 102
98 99
NCEP III
36.5 44
33 44
Baseline n 127
133 130
135 Week 48 n 89
92
93 93
NCEP ATP III Guidelines consider LDL lt100 mg/dL
and HDL gt 40 mg/dL as desirable
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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

27
Study Discontinuation Due to Grade 2-4 Adverse
Events
N138 N140
TZV ATVCOM

Study Discontinuation from AEs, n ()
6 (4) 8 (6)
Rash
0 3
(2)
Anemia
1 (lt1) 2 (1)
Abdominal pain
2 (1) 0
Nausea
2 (1) 0
Dyspepsia
0 1
(lt1)
Enteritis
0
1 (lt1)
Vomiting
1 (lt1) 0

Fatigue
1 (lt1) 0
Headache
1 (lt1) 0
Hyperbilirubinemia
0 1 (lt1)
Jaundice
0 1
(lt1)
28
Toxicity Switches
N138 N140
TZV ATVCOM
7 (5) 9 (6)
Toxicity Switches
Abacavir Related
Suspected Abacavir HSR

7 (5) 0
Atazanavir - Related
Jaundice Scleral Icterus Hyperbilirubinemia
0 2 (1)
0 4 (3)
0 3 (2)
Grade 3 (gt2.5-5x ULN)
3
Although hyperbilirubinemia was not a protocol
allowable toxicity switch reason, 3 subjects
switched off ATVCOM due to ATV-related
hyperbilirubinemia
29
HIV-1 RNA lt400 c/mL at Week 48
Proportion of Subjects
Week 24
Week 24
Week 48
Week 48
MF
Obs
30
Virologic Response HIV-1 RNA lt50
c/mL
62
61
ITT-E, M/SF
ITT-E, SF
n (obs) TZV 138
130 122 117
111 104
101 ATVCO M 140 128
123 118 109
100 99
31
Virologic Response HIV-1 RNA lt50
c/mL
65
64
ITT-E, MF,S?F
ITT-E, S?F
n (obs) TZV 138
130 122 117
111 104
101 ATVCO M 140 128
123 118 109
100 99
32
Virologic Response HIV-1 RNA lt400
c/mL
65
64
ITT-E, M/SF
ITT-E, SF
n (obs) TZV 138
130 122 117
111 104
101 ATVCO M 140 128
123 118 109
100 99
33
Virologic Response HIV-1 RNA lt400
c/mL
67
68
ITT-E, MF,S?F
ITT-E, S?F
n (obs) TZV 138
130 122 117
111 104
101 ATVCO M 140 128
123 118 109
100 99
34
Time to Loss of Virologic Response HIV-1 RNAlt50
c/mL (TLOVR)
35
Time to Loss of Virologic Response HIV-1 RNAlt50
c/mL (TLOVR)M/SF
36
Median Changes in Metabolic Parameters at
Baseline Week 48
HOMA-IR
QUICK1
3
2.9
2.4
2.2
0.59
0.54
0.58
0.54
Baseline n 110
112 110
112 Week 48 n 83
87
83 87
37
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
WD
RT L74V, F77L, V118I, L210W PRO D30N, M36I,
L63P, N88D ABC FC 5.90 ATV FC 11 3TC
FC 8.59 ZDV FC 115


38
Subject 573 TZV
RT WT PRO L63P ABC FC 0.82 ATV FC
0.72 3TC FC 1.22 ZDV FC 0.59
RT WT PRO L63P ABC FC 0.95 ATV FC
0.58 3TC FC 1.27 ZDV FC 0.65


39
Subject 668 TZV
RT WT PRO L63P ABC FC 0.72 ATV FC
0.92 3TC FC 1.03 ZDV FC 1.10
RT M184V PRO L63P ABC FC 3.00 ATV FC
0.80 3TC FC 104 ZDV FC 0.48


40
Subject 852 ATV/COM
RT WT PRO L63P ABC FC 0.76 ATV F
0.83 3TC FC 1.05 ZDV FC 0.63
RT K103N PRO L63P ABC FC 0.84 ATV FC
1.05 3TC FC 1.21 ZDV FC 0.60
3.2 log

3log

41
Subject 918 ATV/COM
RT K103N PRO L63P ABC FC 0.57 ATV FC
0.95 3TC FC 1.01 ZDV FC 0.22
RT K103N, M184V PRO K20M, L24I, L63P ABC FC
2.99 ATV FC 0.58 3TC FC 104 ZDV FC
0.43


42
Subject 592 ATV/COM
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