17th Annual Canadian Conference on HIV/AIDS Research (CAHR 2008) Montreal, Quebec / April 24-27,...

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?


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?


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)


Percent

n/N= ABC12/9639

Non-ABC 7/5043

Total19/14682

0.125% 0.139% 0.129%


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


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


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


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

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


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


ATV 400mg 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

17th Annual Canadian Conference on HIV/AIDS Research (CAHR 2008) Montreal, Quebec / April 24-27,...

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Transcript of 17th Annual Canadian Conference on HIV/AIDS Research (CAHR 2008) Montreal, Quebec / April 24-27,...