Transcript Slide 1

17th Annual Canadian Conference on HIV/AIDS Research
2008)on HIV/AIDS Research
17th Annual Canadian (CAHR
Conference
Montreal, Quebec / April 24-27, 2008
(CAHR 2008)
Montreal, Quebec / April 24-27, 2008
Adapted from the Presentation
Nucleoside Analogue Spring 2008 Update
on
Friday, April 25, 2008
Is the Risk of MI Increased With HAART?
8
Incidence
(events per 1,000 person-yr)
7
6
5
4
3
2
1
0
None
<1
1–2
2–3
3–4
>4
Exposure to combination antiretroviral therapy (yr)
No of events
No of person-yr
D.A.D. N Engl J Med 2003.
3
5714
19
4140
14
4801
22
5847
31
7220
47
8477
Is the Risk of MI Increased With HAART?
Relative Risk (%)
6
5
4
3
2
1
0
Total cholesterol Exposure to
Age (per
Triglycerides Hypertension
Current or
(per 1-mmol/l combination ART additional 5 yr) (per doubling)
former smoker
increase)
(per additional yr)
Diabetes
Male sex
Relative Risk (%)
25
20
15
10
5
0
Total cholesterol Exposure to
Age (per
Triglycerides Hypertension Current or
(per 1-mmol/l combination ARTadditional 5 yr) (per doubling)
former smoker
increase) (per additional yr)
D.A.D. N Engl J Med 2003.
Diabetes
Male sex
Prior CV
disease
Is the Risk of MI Increased With PIs/NNRTIs?
D.A.D. N Engl J Med 2007.
Endpoints of the SMART Study, Including
Cardiovascular Disease
SMART N Engl J Med 2006 .
Relative Rates of MI for ABC and ddI
ABC
Cumulative use (per year)
Any recent use
Any past use
ddI
Cumulative use (per year)
Any recent use
Any past use
D:A:D
Cum use only
Cum + recent use
Cum + recent +
past use
Rel Rate [95% CI]
Rel Rate [95% CI]
Rel Rate [95% CI]
1.14 [1.08,1.21]
1.01 [0.93,1.09]
1.90 [1.47,2.45]
1.00 [0.92,1.08]
1.94 [1.48,2.55]
1.29 [0.94,1.77]
1.06 [1.01,1.12]
1.01 [0.95,1.08]
1.49 [1.14,1.95]
1.00 [0.93,1.07]
1.53 [1.10,2.13]
1.08 [0.84,1.39]
Recent use = still using or stopped within last 6 months
Past use = last used more than 6 months prior
Sabin C, et al. 15th CROI 2008 Poster 957c and Lancet 2008.
Rates of MI for Patients with Recent vs.
No Recent ABC/ddI Use
D:A:D
• Unadjusted Rates of MI per 1000 patient-years
(overall incidence/1000 PY: 3.3 [95% CI: 3.0,3.6]):
Recent Use
No Recent Use
Low Framingham CV Risk
ABC
ddI
2.9
1.8
1.0
1.3
Moderate Framingham CV Risk
ABC
ddI
7.7
7.7
5.9
6.0
High Framingham CV Risk
ABC
ddI
32.5
23.1
15.9
19.4
P>0.02 for interaction among groups
P=0.04 for interaction in Mod/High risk and ABC
Sabin C, et al. 15th CROI 2008 Poster 957c and Lancet 2008.
Event Rates in the 1993- 2003 VA Cohort
Bozzette S, et al. J Acquir Immune Defic Syndr 2007.
VA
Median Lipid Changes from Baseline to Week 48
mg/dL
Little change in glucose tolerance
or insulin sensitivity was seen
after 96 weeks of initial ART with
ABC + Combivir, COM/NFV, or
d4T/3TC/NFV (ESS40002)
JE Hernandez, V Williams, P Wannamaker &
K Pappa, GSK R&D, RTP, NC, USA
CAHR Meeting, Montreal, April 2008
Poster # P-171
Median Change in Fasting Glucose (mg/dL)
from BL By Regimen Assignment (N=245)
ESS40002
mg/dL
*
n=
78,86,81 66,72,68 64,71,70
59,73,65 56,62,57 55,59,55 45,49,48
Study week
* P>0.8 among groups (LSMean, ANCOVA)
43,44,44
Median Change in Insulin (uIU/mL) from BL By
ESS40002
Regimen Assignment (N=245)
uIU/mL
*
n=
78,86,81
61,70,68
50,56,56
Study week
* P>0.4 among groups (LS Mean, ANCOVA)
42,47,50
41,44,45
Median Change in HOMA-IR
from BL By Regimen Assignment (N=237)
ESS40002
*
n=
76,83,78
58,69,63
50,56,53
Study week
* P>0.5 among groups (LS Mean, ANCOVA)
42,47,47
41,42,44
Markers of impaired thrombolysis and inflammation in
subjects treated with ABC+APV-based regimens for
8 weeks (N=14)
Parameter
Baseline
Week 8
P*
tPA antigen, µg/L
6.26 ± 2.98
4.67 ± 2.12
.02
PAI-1 antigen, µg/L
51.75 ± 18.17
52.64 ± 20.74
.73
CRP, ng/mL
sTNFr2, pg/mL
3.24 ± 3.88
5.54 ± 11.09
.33+
4.20 ± 1.19
3.21 ± 0.94
.003
*P-value by Wilcoxon rank-sum test BL vs wk 8
All values
means ± SE
+ One outlier with marked increase in CRP and
pneumonia; if removed: BL: 3.86 ± 3.73 ng/mL;
wk 8: 2.90 ± 2.72 (P=0.045).
Young DB, Hernandez JE, et al. Cardiovasc Toxicol 2004;4:179-86 and CAHR Meeting 2008.
BL Characteristics in Naïve Subjects
(ABC-containing CART, n=5700)
Baseline Demographic or
Disease Characteristic
Median or %
ABC in PI
Triple (N=1901)
ABC in NNRTI
Triple (N=1387)
ABC in
NRTI Triple
(N=1692)
ABC in
PI/NNRTIQuad
(N=720)
Age (years)
% Male
% Caucasian
% AA
% Hispanic
% Asian
HIV-1 RNA (Log10 C/mL)
CD4+ cell count (cells/mm3)
CDC Class A
CDC Class B
CDC Class C
CDC Class missing
37
76
50
32
14
1
4.96
192
62
23
15
<1
37
82
51
27
19
2
4.84
264
76
17
7
<1
36
73
38
31
16
14
4.58
335
81
15
4
<1
36
87
63
23
15
<1
4.97
343
50
7
3
40
Cutrell A, Hernandez J, Brothers C et al, Submitted and Lancet 2008.
BL Characteristics in naïve subjects (nonABC-containing CART, n=2406)
Baseline Demographic or
Disease Characteristic
Median or %
Non-ABC in
PI Triple
(N=1199)
Non-ABC in
NNRTI Triple
(N=829)
Non-ABC in
Other
(N=378)
Age (years)
% Male
% Caucasian
% AA
% Hispanic
% Asian
HIV-1 RNA (Log10 C/mL)
CD4+ cell count (cells/mm3)
CDC Class A
CDC Class B
CDC Class C
CDC Class missing
36
77
53
20
17
7
4.65
337
79
17
4
<1
36
79
51
25
22
1
4.69
322
79
16
5
<1
37
82
63
23
11
1
4.72
367
68
26
2
4
Cutrell A, Hernandez J, Brothers C et al, Submitted and Lancet 2008.
Proportion of Subjects on ART +/- ABC Reporting
MI or Acute MI among 14682 Subjects
Percent
3.5
S
u
b
j
e
c
t
s
3
2.5
2
Percent
High 95%CI
1.5
0.125%
0.139%
0.129%
1
0.5
n/N=
ABC
12/9639
Non-ABC
7/5043
ART Regimen
Cutrell A, Hernandez J, Brothers C et al, Submitted and Lancet 2008.
Total
19/14682
0
Low 95%CI
Relative Rate of Events Per 1000 Person Years of
Exposure to ABC Compared with No Exposure to ABC
Exposure to
ABC
Person/
Years
Number of
events
Rate /1000
Person/Years
Relative rate
(95% CI)
p-value
0.593 (0.348 ,1.010)
0.055
Any ischemic coronary artery disease or disorder:
None
4641.873
27
5.817
ABC CART
7831.88
27
3.447
Any Myocardial Infarction or Acute Myocardial Infarction:
None
4652.945
11
2.363
ABC CART
7845.185
13
2.039
Cutrell A, Hernandez J, Brothers C et al, Submitted and Lancet 2008.
0.863 (0.400,1.860)
0.706
Incidence of Serious CV Events D:A:D Study,
VA Study & GSK Data Repository
D:A:D
1999-2006
VA
1993-2003
GSK DR
1995-2007
Patient numbers
33,000
41,213
14,680
Total patient f/u, PY
156,667
168,213
22,023
Average patient f/u,
yrs
4.7
4.1
~1.5
Mortality
7.7%
42.6%
< 1%
Incidence of serious
CV events/MI
1.6%
4.2%
0.31%
0.129%
3.3
10
4.39/1.92
Incidence 1000/PY
Sabin C, et al. 15th CROI 2008 Poster 957c and Lancet 2008.
Bozzette S, et al. J Acquir Immune Defic Syndr 2007;0:1-4.
Cutrell A, et al. Submitted and Lancet 2008.
Rates of MI, stratified by predicted 10 year risk of
CAD & recent use of ddI or ABC
D.A.D. Study Group. The Lancet.
Published online April 2, 2008 DOI:10.1016/S0140-6736(08)60423-7.
ACTG5202 Study Design
Phase IV, randomized (1:1:1:1), double blind, 96-week study
conducted at US ACTG sites
ART-naïve
subjects,
n=1858
Kivexa QD +
Truvada placebo +
Efavirenz QD (n=~450) or
Atazanavir/r QD (n=~450)
Truvada QD +
Kivexa placebo +
Efavirenz QD (n=~450) or
Atazanavir/r QD (n=~450)
Entry criteria:
No CD4 cell count restrictions
HIV-1 RNA >1000 c/mL
Stratified by entry HIV-1 RNA <100,000 c/mL or 100,000 c/mL
Clinical Trials with Third Drugs (N>100)
ABC+3TC
(BID, QD, or Kivexa)
NNRTI
PI
EFV
908
CNA30021
CNA30024
CLASS
ABCDE
ESS30008
ESS30009
CAL30001
ACTG5202
ASSERT
NEAT
SOLO
CLASS
ESS30008
KLEAN
LPV/r NFV
KLEAN
HEAT
NRTI
ATV
d4T
NEAT
ARIES
CLASS
SOLO
SHARE
ESS30008 ACTG5202 ZDV
MERIT CNA3005
CNA3014
NZTA4006
ACTG5095
etc.
Completed trials
Trials in progress
Trials with same arms as in ACTG5202
Subject Disposition by Week 48
HEAT
KIVEXA
(n=343)
Truvada
(n=345)
Total
(n=688)
275 (80%)
262 (76%)
537 (78%)
68 (20%)
83 (24%)
151 (22%)
13 (19%)
20 (24%)
33 (22%)
2 ( 3%)
0
2 ( 1%)
4 ( 6%)
27 (40%)
4 ( 5%)
30 (36%)
8 ( 5%)
57 (38%)
Subject decision
9 (13%)
14 (17%)
23 (15%)
Non-compliance
7 (10%)
9 (11%)
16 (11%)
Other
6 ( 9%)
6 ( 7%)
12 ( 8%)
Completion Status
Completed 48 weeks
Prematurely withdrawn
Primary Reason for withdrawal
Adverse event
Protocol violation
Protocol defined virologic failure
Lost to follow-up
There were 7 deaths during the study, 1 (<1%) in the Kivexa arm and 6 (2%) in the
Truvada arm; none were attributable to study drug.
Smith K, et al. 15th CROI 2008: Poster 774.
HIV-1 RNA <50 c/mL at Week 48
12
-12
Smith K, et al. 15th CROI 2008: Poster 774.
% Point
difference
HEAT
HIV-1 RNA <50 c/mL at Week 48 by
Baseline HIV-1 RNA (ITT-E, M=F)
ABC/3TC
100
Proportion of Subjects
TDF/FTC
80
71
69
63
65
68
67
60
40
20
0
<100,000 c/mL
n=
188
205
=>100,000 c/mL
155
140
Total
343
345
Median Change from Baseline in
CD4 Cell Count (ITT-E, Obs)
HEAT
201
173
Median CD4, 214
cells/mm3
193
n (obs) KIVEXA = 343
Truvada = 345
429
370
317
318
Smith K, et al. 15th CROI 2008: Poster 774.
310
306
294
297
294
287
285
277
275
270
272
267
CNA30024 Study Design
Phase III, randomized, double-blind, multicenter1 study
N = 654
ART naïve
adults2
ABC 300mg BID + ZDV 0mg BID + 3TC BID + EFV QD
ITT-Exposed = 324
ZDV 300mg BID + ABC 0mg BID + 3TC BID + EFV QD
ITT-Exposed = 325
48 wk
• Screening HIV-1 >400 copies/mL, CD4+ >50 cells/mm3
• Enrollment was stratified by screening HIV-1 strata (100K and >100K).
1. 78 sites: 48 in US, 17 in Europe, 13 in Latin America
2. 5 subjects (3-ABC, 2-ZDV) randomized never took drug (ITT-Exposed=649)
Response 50 c/mL through Wk 48
CNA30024
ITT Exposed*
95% CI: (-6.3%, -7.9%)
ABC: 70%
ZDV: 69%
* Using TLOVR Algorithm
CNA30024
Response 50 c/mL at Wk 48
ITT Exposed*
Overall CI
ABC
ZDV
(N=324)
(N=325)
70%
69%
Stratified
(-6.3%, 7.9%)
(-6.3%, 7.9%)
BL RNA  100K
72%
70%
BL RNA > 100K
67%
67%
* Using TLOVR Algorithm
95% CI
CNA30024
CNA30024
Time to vRNA <50 c/mL by
BL vRNA Trizivir + EFV
ESS40013
CNA30024
ARIES Study Design
Phase IIIb, randomized (1:1), open-label,
non-inferiority, international, 84-week study
ATV 400mg QD
ART-naïve
subjects,
N=500
ABC/3TC FDC
(600mg/300mg) QD
ATV 300mg QD
RTV 100mg QD
ABC/3TC FDC
(600mg/300mg) QD
Entry criteria:
Day 1
HIV-1 RNA 1000 c/mL
No CD4 cell count restrictions
Appropriate genotype
HLA-B*5701 negative
Stratified at randomization by baseline
HIV-1 RNA < or  100,000 c/mL
Young B, et al. CAHR 2008, Poster # P-159.
ATV 300mg QD
RTV 100mg QD
ABC/3TC FDC
(600mg/300mg) QD
Week 36
Randomization
Week 84
ARIES Preliminary Data
Enrollment between 28Mar07 and 07Sep07
ATV 400mg QD
ART-naïve
subjects
N=516
ABC/3TC FDC
(600mg/300mg) QD
ATV 300mg QD
RTV 100mg QD
ABC/3TC FDC
(600mg/300mg) QD
ATV 300mg QD
RTV 100mg QD
ABC/3TC FDC
(600mg/300mg) QD
4 cases of suspected
HSR, all SPT neg.
Entry criteria:
Day 1
HIV-1 RNA 1000 c/mL
No CD4 cell count restrictions
Appropriate genotype
HLA-B*5701 negative
Stratified at randomization by baseline
HIV-1 RNA < or  100,000 c/mL
Young B, et al. CAHR 2008, Poster # P-159.
Week 24
Week 36
Week 84
HIV-1 RNA <400 c/mL at Week 48 According to
BL Viral Load (ITT-E, TLOVR)
Percentage of Patients
<100,000 c/mL
100,000 c/mL
M=F
M/S=F
EPZ+ATV/r
n=
49
62
EPZ+LPV/r
EPZ+FPV/r
ABC+3TC
+EFV
209 235
197 237
123 46
Data on file, GlaxoSmithKline.
ABC+3TC BID ABC+3TC QD ABC+3TC BID
+EFV
+EFV
+EFV
217 167
217 169
198 126
HIV-1 RNA <50 c/mL at Week 48 According to
BL Viral Load (ITT-E, TLOVR)
Percentage of Patients
<100,000 c/mL
100,000 c/mL
M=F
M/S=F
EPZ+ATV/r
n=
49
62
EPZ+LPV/r
EPZ+FPV/r
ABC+3TC
+EFV
209 235
197 237
123 46
Data on file, GlaxoSmithKline.
ABC+3TC BID ABC+3TC QD ABC+3TC BID
+EFV
+EFV
+EFV
217 167
217 169
198 126
Lack of Virologic failure (ACTG Definition) in GSK
Studies by Study Week (% Survival) All Subjects
Study and arms (Ns)
16 weeks
or approx
24 Wks
48 Wks
CNA30024 COM + EFV (325)
98
97
94
CNA30024 ABC+3TC + EFV (324)
97
96
94
CNA30021 ABC BID+3TC +EFV (386)
100
96
93
CNA30021 ABC QD+3TC +EFV (384)
100
97
92
ESS30009 EPZ + EFV (169)
96
96
95
SHARE EPZ + ATV+RTV (111)
100
98
93
KLEAN EPZ+FPV+RTV (434)
98
96
94
KLEAN EPZ+LPV+RTV (444)
98
97
93
HEAT EPZ+LPV+RTV (343)
98
96
89
HEAT TVD+LPV+RTV (345)
97
93
88
Lack of Virologic failure (ACTG Definition) in GSK
Studies by Study Week (% Survival) > 100000 VL
Study and arms (Ns)
16 weeks
or approx
24 Wks
48 Wks
CNA30024 COM + EFV (125)
97
96
95
CNA30024 ABC+3TC + EFV (126)
97
97
93
CNA30021 ABC BID+3TC +EFV (172)
100
97
95
CNA30021 ABC QD+3TC +EFV (166)
100
97
89
ESS30009 EPZ + EFV (46)
95
95
95
SHARE EPZ + ATV+RTV (62)
100
97
93
KLEAN EPZ+FPV+RTV (237)
97
95
92
KLEAN EPZ+LPV+RTV (235)
99
96
92
HEAT EPZ+LPV+RTV (155)
96
94
87
HEAT TVD+LPV+RTV (140)
98
95
90
KIVEXA is Preferred/Recommended on the
DHHS & IAS-USA Guidelines
Preferred - DHHS
NNRTI
EFV
ABC/3TC (for HLA-B*5701 negative patients) or
TDF/FTC
PI
FPV/r BID
LPV/r BID
ATV/r
ABC/3TC (for HLA-B*5701 negative patients) or
TDF/FTC
Recommended – IAS 2006
NRTI
NNRTI
PI
ABC/3TC or ZDV/3TC or TDF/FTC
EFV
FPV/r or LPV/r or
or NVP
ATV/r or SQV/r
Please see guidelines for full information on considerations for choice,
major toxic effects, cautions, and resistance considerations
http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf: Jan 2008.
Hammer S, et al. JAMA 2006;296:827-43.
ABC & KIVEXA, Next Steps…
• Manuscript of GSK MI analysis submitted for
publication
• Groups with large observational cohorts to
repeat DAD analysis (VA, Kaiser)
• Further analysis of markers of inflammation,
impaired thrombolysis and endothelial
dysfunction ongoing (HEAT)
• DSMB review of ACTG 5202 to be repeated in
June
• Additional analysis of ACTG5202 ongoing