HDL Particles but not LDL Particles Predict Cardiovascular Disease Events in HIV Patients:

Results from Strategies for Management of ART Study (SMART)

Daniel A Duprez, MD, PhDOn behalf of the SMART/INSIGHT Group

University of Minnesota

Background

• In the SMART Study, intermittent ART compared to continuous ART was found to cause an excess risk of all-cause mortality and cardiovascular disease.

• ART interruption is associated with a decline in HDL-and LDL-cholesterol.

• Lower levels of HDL-cholesterol are associated with an increased risk of CVD.

Subjects with same HDL-cholesterol can have different HDL-particle concentrations

52-yr man

Total Chol 205 mg/dL

Triglycerides 180 mg/dL

HDL-chol 36 mg/dL

LDL-chol 115 mg/dL

Small LDL-p 1100nmol/L

Large LDL-p 500nmol/L

Large HDL-p 8µmol/L

Small HDL-p 23µmol/L

52-yr man

195 mg/dL

185 mg/dL

36 mg/dL

122 mg/dL

1100nmol/dL

500nmol/dL

3µmol/L

28µmol/L

ChylomicronRemnants

Density,g/mL

Chylomicron

1.20

1.10

1.06

1.02

1.006

0.95

5 10 20 40 60 80 1000

VLDL

IDL

LDL

HDLl

HDLs

Diameter, nm

VLDLRemnants

Lp(a)

VLDL

VLDL

Lipoprotein Particles

Chylomicron

Segrest JP et al. Adv Protein Chem. 1994;45:303–369

Background

• Nuclear magnetic resonance (NMR) enables quantification of concentrations of lipid particles of varying size.

• Data suggest that smaller LDL particle size, specifically a predominance of small dense LDL or a greater number of small LDL particles, is a predictor of coronary artery disease.

• Studies of non-HIV-infected cohorts have also reported that HDL particle sizes are related to ischemic heart disease.

SMART and CVD Outcome:Nested Case-Control Study

• Aim: To describe the relationship of baseline levels of lipoprotein particle size and concentration with CVD

• Baseline and follow-up plasma samples identified for patients who developed CVD (248 patients) prior to study closure on July 11, 2007 and for two matched controls for each CVD case (480 patients). Matching on:

– Country– Age (+/- 5 years)

– Gender; and– Date of randomization (+/- 3 months)

• Conditional logistic used to estimate odds ratios (OR) for CVD with participants in lowest quartile as reference. Adjustment for baseline covariates

– Age, race ART, HIV RNA, CD4+ count, BMI, at smoking, diabetes, hep B/C co-infection, use of lipid BP lowering medication, prior

CVD, and major baseline ECG abnormalities– Also LDL and triglycerides– Also hsCRP, IL-6 and D-dimer

Baseline Characteristics of CVD Cases and Matched Controls

CVD Cases(N=248)

Controls(N=480) P-value*

Demographics

Age (median)Gender (% female)Black (%)

4919.439.1

4919.437.1

NANA

0.50

CD4+ (cells/mm3) (median) 576 620 0.47

HIV RNA ≤ 400 copies/mL 67.6 67.6 0.91

Prior AIDS (%) 37.1 24.8 0.0005

Current smoker (%) 52.4 39.8 0.001

Diabetes (%) 16.9 8.3 0.0007

Blood pressure lowering drugs (%) 45.2 30.6 <0.0001

Lipid lowering drugs (%) 27.8 22.7 0.15

Prior CVD (%) 13.3 5.2 0.0004

* P-value obtained from univariate conditional logistic model.

Baseline Lipids of CVD Cases and Matched Controls

CVD Cases(N=248)

Controls(N=480) P-value*

Total cholesterol (mg/dL) (median) 196 193 0.29

HDL cholesterol (mg/dL) (median) 38 42 0.03

LDL cholesterol (mg/dL) (median) 111 111 0.76

Triglycerides (mg/dL) (median) 193 178 0.39

Total/HDL cholesterol (median) 5.2 4.7 0.05

* P-value obtained from univariate conditional logistic model.

Baseline Lipoprotein Particles of CVD Cases and Matched Controls

Median CVD Cases(N=248)

Controls(N=480) P-value*

Total LDL-p (nmol/L) 1364 1322 0.30

Total VLDL-p (nmol/L) 85.7 81.3 0.38

Total HDL-p (µmol/L) 28.4 30.2 0.0001

* P-value obtained from univariate conditional logistic model.

CVD Event Type and SMART CVD Outcome

Type Number

- Non-fatal CHD 124Clinical MI, Silent MI, CABG, PCI, CAD requiring medical therapy

- Non-fatal Atherosclerotic non-CHD 62Stroke, Peripheral Arterial Disease

- Non-fatal CHF 26

- Fatal CVD 36CVD or unwitnessed death

CVD Event Type and Baseline Lipid ParticlesCVD Event Type N Cases Unadj. OR (4th/1st Q) P-value

Non-Fatal CHD 124

Total VLDL-p 2.8 (1.3 – 6.0) 0.007

Total LDL-p 2.0 (1.0 – 3.9) 0.05

Small LDL-p 2.2 (1.1 – 4.2) 0.02

Total HDL-p 0.4 (0.2 – 0.8) 0.006

Non-Fatal Atherosclerotic CHD 62

Total HDL-p 0.2 (0.1 – 0.6) 0.005

Non-Fatal CHF 26

Total HDL-p 1.1 (0.3 – 4.1) 0.90

Fatal CVD 36

Total HDL-p 0.3 (0.1 – 1.1) 0.08

HDL Particle Concentrations and Cardiovascular Disease

Un-adjusted Adjusted

HDL Particle (μmol/L) OR (4th/1st) P-value OR (4th/1st) P-value

Total 0.41 <0.0001 0.41 0.001

Large 0.69 0.09 0.68 0.16

Medium 0.91 0.67 1.07 0.80

Small 0.53 0.007 0.55 0.03

Difference in HDL Particle Concentration (µmol/L) One Month After Randomization

Baseline Average

DC-VS Difference at 1 Month P-value

Total HDL p 29.2 -2.2 <0.0001

Large HDL p 5.8 -0.3 0.10

Medium HDL p 4.9 -1.1 0.002

Small HDL p 18.5 -0.9 0.03

DC = Treatment InterruptionVS = Continuous ART

Impact of Covariate Adjustment on the Odds Ratio for 4th vs. 1st Quartile of Total HDL-p

Total HDLp OR (4th/1st) P-value

Unadjusted 0.41<0.0001

Adjusted for major risk factors, excluding lipids

0.41 0.01

Also adjusted for LDL, TG 0.41 0.001

Also adjusted for IL-6hsCRPD-dimer

0.500.500.49

0.020.020.02

Odds Ratios for CVD by Total HDL-p and IL-6 Levels

0

1

2

3

4

≥ 2.4 < 2.4≥ 29

< 29

Total HDLp(µmol/L)

OR

fo

r C

VD OR=2.58

P <0.001

OR=3.36P <0.001

OR=1.49P=0.14

OR=1.00

IL-6pg/mL

0

1

2

3

4

Conclusions

• In the SMART Trial lower total HDL-p and especially small HDL-p are predictive for cardiovascular events in HIV patients.

• Intermittent ART therapy (DC) is associated with a decrease in HDL-p concentration in comparison with continuous therapy (VS) after one month.

• The long-term effects of ART on HDL-chol and particles and therapy to increase it need to be further studied in randomized trials in HIV patients.