17th annual canadian conference on hiv/aids research (cahr 2008)
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17th Annual Canadian Conference on HIV/AIDS Research (CAHR 2008) Montreal, Quebec / April 24-27, 2008. 17th Annual Canadian Conference on HIV/AIDS Research (CAHR 2008) Montreal, Quebec / April 24-27, 2008. Adapted from the Presentation Nucleoside Analogue Spring 2008 Update on - PowerPoint PPT PresentationTRANSCRIPT
17th Annual Canadian Conference on HIV/AIDS Research(CAHR 2008)
Montreal, Quebec / April 24-27, 200817th Annual Canadian Conference on HIV/AIDS Research
(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?
D.A.D. N Engl J Med 2003.
Exposure to combination antiretroviral therapy (yr)
None <1 1–2 2–3 3–4 >4
Inc
ide
nc
e
(ev
en
ts p
er
1,0
00
pe
rso
n-y
r)
0
1
2
3
4
5
6
7
8
No of events 3 19 14 22 31 47 No of person-yr 5714 4140 4801 5847 7220 8477
Is the Risk of MI Increased With HAART?
D.A.D. N Engl J Med 2003.
0
1
2
3
4
5
6
0
5
10
15
20
25
Re
lati
ve
Ris
k (
%)
Re
lati
ve
Ris
k (
%)
Total cholesterol (per 1-mmol/l
increase)
Exposure to combination ART (per additional yr)
Age (per additional 5 yr)
Triglycerides(per doubling)
Hypertension Current or former smoker
Diabetes Male sex
Total cholesterol (per 1-mmol/l
increase)
Exposure to combination ART (per additional yr)
Age (per additional 5 yr)
Triglycerides(per doubling)
Hypertension Current or former smoker
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
Cum use only
Rel Rate [95% CI]
Cum + recent use
Rel Rate [95% CI]
Cum + recent + past use Rel Rate [95% CI]
ABC Cumulative use (per year) Any recent use Any past use
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]
ddI Cumulative use (per year) Any recent use Any past use
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 monthsPast use = last used more than 6 months prior
D:A:D
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
• 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
2.91.8
1.01.3
Moderate Framingham CV Risk ABC ddI
7.77.7
5.96.0
High Framingham CV Risk ABC ddI
32.523.1
15.919.4
P>0.02 for interaction among groupsP=0.04 for interaction in Mod/High risk and ABC
D:A:D
Sabin C, et al. 15th CROI 2008 Poster 957c and Lancet 2008.
Event Rates in the 1993- 2003 VA Cohort VA
Bozzette S, et al. J Acquir Immune Defic Syndr 2007.
Median Lipid Changes from Baseline to Week 48
mg/dL
JE Hernandez, V Williams, P Wannamaker & K Pappa, GSK R&D, RTP, NC, USA
CAHR Meeting, Montreal, April 2008
Poster # P-171
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)
* P>0.8 among groups (LSMean, ANCOVA)
Median Change in Fasting Glucose (mg/dL) from BL By Regimen Assignment (N=245) ESS40002
Study week
mg/dL
n= 78,86,81 66,72,68 64,71,70 59,73,65 56,62,57 55,59,55 45,49,48 43,44,44
*
Median Change in Insulin (uIU/mL) from BL By Regimen Assignment (N=245) ESS40002
Study week
uIU/mL
n= 78,86,81 61,70,68 50,56,56 42,47,50 41,44,45
*
* P>0.4 among groups (LS Mean, ANCOVA)
Median Change in HOMA-IR from BL By Regimen Assignment (N=237) ESS40002
Study week
*
* P>0.5 among groups (LS Mean, ANCOVA)
n= 76,83,78 58,69,63 50,56,53 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 3.24 ± 3.88 5.54 ± 11.09 .33+
sTNFr2, pg/mL 4.20 ± 1.19 3.21 ± 0.94 .003
*P-value by Wilcoxon rank-sum test BL vs wk 8
+ 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).
All values means ± SE
Young DB, Hernandez JE, et al. Cardiovasc Toxicol 2004;4:179-86 and CAHR Meeting 2008.
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) 37 37 36 36 % Male 76 82 73 87 % Caucasian 50 51 38 63 % AA 32 27 31 23 % Hispanic 14 19 16 15 % Asian 1 2 14 <1 HIV-1 RNA (Log10 C/mL) 4.96 4.84 4.58 4.97 CD4+ cell count (cells/mm3) 192 264 335 343 CDC Class A 62 76 81 50 CDC Class B 23 17 15 7 CDC Class C 15 7 4 3 CDC Class missing <1 <1 <1 40
BL Characteristics in Naïve Subjects(ABC-containing CART, n=5700)
Cutrell A, Hernandez J, Brothers C et al, Submitted and Lancet 2008.
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) 36 36 37 % Male 77 79 82 % Caucasian 53 51 63 % AA 20 25 23 % Hispanic 17 22 11 % Asian 7 1 1 HIV-1 RNA (Log10 C/mL) 4.65 4.69 4.72 CD4+ cell count (cells/mm3) 337 322 367 CDC Class A 79 79 68 CDC Class B 17 16 26 CDC Class C 4 5 2 CDC Class missing <1 <1 4
BL Characteristics in naïve subjects (non-ABC-containing CART, n=2406)
Cutrell A, Hernandez J, Brothers C et al, Submitted and Lancet 2008.
Percent
n/N= ABC12/9639
Non-ABC 7/5043
Total19/14682
0.125% 0.139% 0.129%
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
ART Regimen
Subjects
0
0.5
1
1.5
2
2.5
3
3.5
Percent
High 95%CI
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
Any ischemic coronary artery disease or disorder:
None 4641.873 27 5.817
ABC CART 7831.88 27 3.447 0.593 (0.348 ,1.010) 0.055
Any Myocardial Infarction or Acute Myocardial Infarction:
None 4652.945 11 2.363
ABC CART 7845.185 13 2.039 0.863 (0.400,1.860) 0.706
Cutrell A, Hernandez J, Brothers C et al, Submitted and Lancet 2008.
Incidence of Serious CV Events D:A:D Study, VA Study & GSK Data Repository
D:A:D1999-2006
VA1993-2003
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%
Incidence 1000/PY 3.3 10 4.39/1.92
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.
Phase IV, randomized (1:1:1:1), double blind, 96-week study conducted at US ACTG sites
Entry criteria:No CD4 cell count restrictionsHIV-1 RNA >1000 c/mLStratified by entry HIV-1 RNA <100,000 c/mL or 100,000 c/mL
ART-naïve subjects, n=1858
Kivexa QD + Truvada placebo +
Efavirenz QD (n=~450) orAtazanavir/r QD (n=~450)
Truvada QD + Kivexa placebo +
Efavirenz QD (n=~450) orAtazanavir/r QD (n=~450)
ACTG5202 Study Design
Clinical Trials with Third Drugs (N>100)
ABC+3TC(BID, QD, or Kivexa)
NNRTI PI NRTI
EFVCNA30021CNA30024
CLASSABCDE
ESS30008ESS30009CAL30001ACTG5202ASSERT
LPV/rKLEANHEAT
ZDVCNA3005CNA3014NZTA4006ACTG5095
etc.
NFVNEATSOLO
ESS30008
ATVARIESSHARE
ACTG5202MERIT
908NEATSOLOCLASS
ESS30008KLEAN
d4TCLASS
Completed trialsTrials in progressTrials with same arms as in ACTG5202
KIVEXA(n=343)
Truvada(n=345)
Total(n=688)
Completion Status
Completed 48 weeks 275 (80%) 262 (76%) 537 (78%)
Prematurely withdrawn 68 (20%) 83 (24%) 151 (22%)
Primary Reason for withdrawal
Adverse event 13 (19%) 20 (24%) 33 (22%)
Protocol violation 2 ( 3%) 0 2 ( 1%)
Protocol defined virologic failure 4 ( 6%) 4 ( 5%) 8 ( 5%)
Lost to follow-up 27 (40%) 30 (36%) 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%)
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.
Subject Disposition by Week 48 HEAT
Smith K, et al. 15th CROI 2008: Poster 774.
HIV-1 RNA <50 c/mL at Week 48 HEAT
12
% P
oin
t d
iffe
ren
ce
-12
Smith K, et al. 15th CROI 2008: Poster 774.
HIV-1 RNA <50 c/mL at Week 48 by Baseline HIV-1 RNA (ITT-E, M=F)
n = 188 205 155 140 343 345
7163
6869 65 67
0
20
40
60
80
100
<100,000 c/mL =>100,000 c/mL Total
Pro
po
rtio
n o
f S
ub
ject
s
ABC/3TC
TDF/FTC
173
201
Median Change from Baseline in CD4 Cell Count (ITT-E, Obs)
Median CD4, 214 429 cells/mm3 193 370
n (obs) KIVEXA = 343 317 310 294 294 285 275 272 Truvada = 345 318 306 297 287 277 270 267
HEAT
Smith K, et al. 15th CROI 2008: Poster 774.
Phase III, randomized, double-blind, multicenter1 study
N = 654ART naïve
adults2
ABC 300mg BID + ZDV 0mg BID + 3TC BID + EFV QDITT-Exposed = 324
ZDV 300mg BID + ABC 0mg BID + 3TC BID + EFV QDITT-Exposed = 325
48 wk
1. 78 sites: 48 in US, 17 in Europe, 13 in Latin America2. 5 subjects (3-ABC, 2-ZDV) randomized never took drug (ITT-Exposed=649)
• Screening HIV-1 >400 copies/mL, CD4+ >50 cells/mm3
• Enrollment was stratified by screening HIV-1 strata (100K and >100K).
CNA30024 Study Design
Response 50 c/mL through Wk 48 ITT Exposed*
* Using TLOVR Algorithm
ABC: 70%ZDV: 69%
95% CI: (-6.3%, -7.9%)
CNA30024
Response 50 c/mL at Wk 48ITT Exposed*
ABC (N=324)
ZDV (N=325)
95% CI
Overall CI 70% 69% (-6.3%, 7.9%)
Stratified (-6.3%, 7.9%)
BL RNA 100K 72% 70%
BL RNA > 100K 67% 67%
* Using TLOVR Algorithm
CNA30024
CNA30024
CNA30024
Time to vRNA <50 c/mL by BL vRNA Trizivir + EFV ESS40013
CNA30024
Entry criteria: HIV-1 RNA 1000 c/mL No CD4 cell count restrictions
Appropriate genotypeHLA-B*5701 negative
Stratified at randomization by baseline HIV-1 RNA < or 100,000 c/mL
Phase IIIb, randomized (1:1), open-label, non-inferiority, international, 84-week study
ART-naïve subjects,
N=500
Day 1 Week 36
Randomization
Week 84
ATV 300mg QDRTV 100mg QD
ABC/3TC FDC(600mg/300mg) QD ATV 300mg QD
RTV 100mg QD
ABC/3TC FDC(600mg/300mg) QD
ATV 400mg QD
ABC/3TC FDC(600mg/300mg) QD
ARIES Study Design
Young B, et al. CAHR 2008, Poster # P-159.
Entry criteria: HIV-1 RNA 1000 c/mL No CD4 cell count restrictions
Appropriate genotypeHLA-B*5701 negative
Stratified at randomization by baseline HIV-1 RNA < or 100,000 c/mL
Enrollment between 28Mar07 and 07Sep07
ART-naïve subjects
N=516
Day 1 Week 36 Week 84
ATV 300mg QDRTV 100mg QD
ABC/3TC FDC(600mg/300mg) QD ATV 300mg QD
RTV 100mg QD
ABC/3TC FDC(600mg/300mg) QD
ATV 400mg QD
ABC/3TC FDC(600mg/300mg) QD
ARIES Preliminary Data
Week 24
Young B, et al. CAHR 2008, Poster # P-159.
4 cases of suspectedHSR, all SPT neg.
HIV-1 RNA <400 c/mL at Week 48 According to BL Viral Load (ITT-E, TLOVR)
Per
cen
tag
e o
f P
atie
nts
n = 49 209 235 197 237 123 46 217
Data on file, GlaxoSmithKline.
62 167 198 126
M=F
M/S=F
<100,000 c/mL100,000 c/mL
EPZ+ATV/r EPZ+LPV/r EPZ+FPV/r ABC+3TC ABC+3TC BID ABC+3TC QD ABC+3TC BID +EFV +EFV +EFV +EFV
217 169
HIV-1 RNA <50 c/mL at Week 48 According toBL Viral Load (ITT-E, TLOVR)
Per
cen
tag
e o
f P
atie
nts
n = 49 209 235 197 237 123 46 217
Data on file, GlaxoSmithKline.
62 167 198 126
M=F
M/S=F
<100,000 c/mL100,000 c/mL
EPZ+ATV/r EPZ+LPV/r EPZ+FPV/r ABC+3TC ABC+3TC BID ABC+3TC QD ABC+3TC BID +EFV +EFV +EFV +EFV
217 169
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
http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf: Jan 2008.
Please see guidelines for full information on considerations for choice, major toxic effects, cautions, and resistance considerations
Preferred - DHHS
NNRTI EFV ABC/3TC (for HLA-B*5701 negative patients) or
TDF/FTC
PI FPV/r BIDLPV/r BIDATV/r
ABC/3TC (for HLA-B*5701 negative patients) or
TDF/FTC
KIVEXA is Preferred/Recommended on the DHHS & IAS-USA Guidelines
Recommended – IAS 2006
NRTI NNRTI PI
ABC/3TC or ZDV/3TC or TDF/FTC EFV
or NVP
FPV/r or LPV/r or
ATV/r or SQV/r
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