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Daniel A Duprez, MD, PhD On behalf of the SMART/INSIGHT Group University of Minnesota

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, PhD On behalf of the SMART/INSIGHT Group University of Minnesota. Background.

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Daniel A Duprez, MD, PhD On behalf of the SMART/INSIGHT Group University of Minnesota

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  1. 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, PhD On behalf of the SMART/INSIGHT Group University of Minnesota

  2. 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.

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

  4. Lipoprotein Particles VLDL Chylomicron 0.95 Chylomicron VLDL VLDL VLDL Remnants 1.006 IDL Chylomicron Remnants Density,g/mL 1.02 LDL 1.06 HDLl 1.10 Lp(a) HDLs 1.20 5 10 20 40 60 80 1000 Diameter, nm Segrest JP et al. Adv Protein Chem. 1994;45:303–369

  5. 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.

  6. 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

  7. Baseline Characteristics of CVD Cases and Matched Controls

  8. Baseline Lipids of CVD Cases and Matched Controls

  9. Baseline Lipoprotein Particles of CVD Cases and Matched Controls

  10. CVD Event Type and SMART CVD Outcome Type Number • Non-fatal CHD 124 Clinical MI, Silent MI, CABG, PCI, CAD requiring medical therapy • Non-fatal Atherosclerotic non-CHD 62 Stroke, Peripheral Arterial Disease • Non-fatal CHF 26 • Fatal CVD 36 CVD or unwitnessed death

  11. CVD Event Type and Baseline Lipid Particles

  12. HDL Particle Concentrations and Cardiovascular Disease

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

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

  15. Odds Ratios for CVD by Total HDL-p and IL-6 Levels OR=3.36P <0.001 OR=2.58P <0.001 OR=1.49P=0.14 OR for CVD OR=1.00 < 29 Total HDLp(µmol/L) ≥ 29 < 2.4 ≥ 2.4 IL-6pg/mL

  16. 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.

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