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Metabolic Complications: Lipids and Cardiovascular Risk

Metabolic Complications: Lipids and Cardiovascular Risk. Constance A. Benson, MD. CA Benson, MD. Presented at IAS –USA /RWCA Clinical Conference, June 2005. The International AIDS Society–USA. FRAM Conclusions: Lipid Levels and Insulin Resistance in HIV+ Men vs. Women.

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Metabolic Complications: Lipids and Cardiovascular Risk

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  1. Metabolic Complications: Lipids and Cardiovascular Risk Constance A. Benson, MD CA Benson, MD.Presented at IAS–USA/RWCA Clinical Conference, June 2005. The International AIDS Society–USA

  2. FRAM Conclusions: Lipid Levels and Insulin Resistance in HIV+ Men vs. Women Compared to respective controls: • Both HIV+ men and women have higher triglycerides and insulin levels, but lower direct LDL and HDL • HIV+ men are more prone to hypertriglyceridemia • HIV+ women are more prone to hypercholesterolemia and diabetes • Lipoatrophy is associated with more detrimental metabolic effects (hypertriglyceridemia and insulin resistance) in men than in women

  3. † † † † † † † ACTG 5005s: Median % change in trunk fat from baseline by NNRTI-PI assignment All p>.05 between-groups; † p<.05 within-groups from baseline Dube et al, 4th Lipodystrophy meeting, 2002

  4. ACTG 5005s: Lipid Levels Nelfinavir vs Efavirenz • Lipid levels were increased in all arms at Week 32 • % with TC > 200 mg/dL increased from 13% to 45% • % with HDL-C < 40 decreased from 75% to 48% • 5% on NFV and 6% on EFV had TG > 400 mg/dL • Similar increases in TC, non-HDL-C, and TG levels, although HDL-C and TC:HDL-C trends favored EFV • TC and non-HDL-C increases were greater for d4T/ddI than ZDV/3TC (45 vs 29 mg/dL and 35 vs 26 mg/dL, respectively) Dube M, et al. 11th CROI, 2004; Abstr. 74

  5. BMS 043: Hyperlipidemia with Atazanavir vs Lopinavir/Ritonavir ATVLPV/rP-value ∆RNA wk 48 -1.7 -2.1 0.003 RNA < 400 59% 77% <0.05 RNA < 50 38% 54% <0.05 LDL Chol -6% +5% Total Chol -2% +17% Triglyceride -2% +55% Lipid treatment 5% 19% Cohen: Antiviral Therapy 2003; 8 (Suppl 1):S212 (Abstr. 117)

  6. Hyperlipidemia with Atazanavir/Ritonavir vs Lopinavir/Ritonavir* ATV/rLPV/rP-value ∆RNA wk 48 -1.93 log10 -1.87 log10 NS RNA < 400 56% 58% NS RNA < 50 38% 46% NS Change in lipid levels from Baseline to Week 48: Total Chol -8% +6% < 0.005 HDL-C -7% +2% LDL-C (fasting) -10% +1% Triglyceride -4% +30% < 0.005 *3rd arm with ATV/SQV Johnson M, et al. AIDS 2005; 19:685-94

  7. The 2NN Lipid Substudy ___NVP ___ EFV ___ NVP+EFV ----- baseline Van Leth F, et al. Lancet 2004; 363:1253-63 Van Leth F, et al. PLoS Med 2004; e19

  8. Cardiovascular Disease Risk In HIV Infection • HIV Insight Observational Cohort Study • 10 HIV Outpatient Study (HOPS) sites + 9 additional Cerner sites – medical record abstractions 1991-2002 • 7,542 HIV-1-infected pts in the U.S. • Incidence rate of CVD events was 9.8/1000 pt-yrs of F/U for those exposed to PIs vs 6.5/1000 pt-yrs of F/U for those unexposed (P = 0.0008) • PI use > 60 d was associated with increased risk of CVD events (HR 1.71 [95% CI 1.08-2.74]; P = 0.03) • Smoking, age, HTN, DM, prior CVD were also independent risk factors for CVD events Iloeje UH et al. HIV Medicine 2005; 6:37-44

  9. D:A:D: Relative Risk of MI Associated with Duration of Exposure to PI Therapy Duration of PI exposure D:A:D Study Group, NEJM 2003; 349:1993; El-Sadr W, 12th CROI, 2005; Abstr. 42

  10. Carotid Intima-Media Thickness in HIV Infection • 148 HIV-1-infected adults vs 63 age- and sex-matched controls • Older age, LDL, smoking, Latino ethnicity, and HTN and nadir CD4+ cell count < 200/L were independent predictors of abnormal IMT • Mean BL IMT 0.91 in HIV-1-infected vs 0.74 mm (p<0.0001) in controls • Progression at 1 year FU 0.074 mm in HIV+ vs 0.006 mm in controls • Age, Latino ethnicity, and nadir CD4+ < 200 were predictors of greater IMT progression • Carotid IMT was higher and progressed more rapidly among HIV-1-infected pts than in controls Hsue PY, et al., Circulation 2004; 109: 1603-8

  11. Metabolic Syndrome and CVD Risk • 327 Nutrition for Healthy Living Study participants • 23% had metabolic syndrome (> 3 of the following: abdominal obesity, ↑’d TG, low HDL-C, HTN, ↑’d FBS) • Those with metabolic syndrome were: • More likely to have carotid IMT > 0.8 mm (17% vs 7%) • More likely to have coronary calcium (80.3% vs 46.7%) • than those without metabolic syndrome • HIV-1-infected persons with metabolic syndrome may be at higher risk for CVD events Mangili A, et al., 12th CROI 2005; Abstr. 861

  12. Clinical Implications • Mounting evidence that HIV-1 disease-associated metabolic syndrome and longer term use of PIs is associated with increased risk of CHD • Particularly in those with other underlying risk factors • Insufficient data to weigh individual PIs compared with other risk factors • Conclusion: More aggressive intervention to reduce risk factors in those who require PI use is warranted.

  13. Guidelines: IDSA/ACTG and IAS-USA • Fasting lipid profile(total cholesterol, HDL-C, LDL-C, triglycerides)prior to starting ART • Repeat yearly and within 3-6 months of starting new ART • Assess number of CHD risk factors and determine level of risk • If > 2 risk factors, perform 10-year risk calculation (http://hin.nhlbi.nih.gov/atpiii/calculator.asp) • Modify lifestyle factors (diet, smoking, HTN) Dube MP, et al., CID 2003; 37:613 Schambelan M et al., J Acquir Immune Def Syndr 2002; 31:252

  14. Antiretroviral Therapy and Approaches to Treatment for HIV-1-Infected Patients with Hyperlipidemias • Use a PI that is less likely to cause hyperlipidemia • Switch to a non-PI containing regimen • Treat with lipid lowering agents

  15. A Randomized Study of Switching from a PI to NVP, EFV, or ABC (LIPNEFA) • Substudy of 90 patients; (NVP n=29; EFV n=32; ABC n=29) • 10 endpoint = change in lipid levels from BL to 24 months • Overall, 27% had trunk fat accumulation + dyslipidemia • Overall improvement in TC, LDLc, HDLc, TC:HDLc, insulin resistance; TG levels remained the same NVP EFV ABC TC +2% -6% -13%* LDLc -17%* -10%* -15%* HDLc +21%* +15%* +5% TC:HDLc -19%* -14%* -12% Fisac C, et al. 11th CROI 2004; Abstr. 78 and AIDS 2005; 19:917-25 *P<0.05

  16. IDSA-AACTG Guidelines • If non-lipid interventions unsuccessful based on risk group, consider altering ART regimen or adding lipid-lowering drugs • Serum LDL-C above threshold or TG 200-500 mg/dl with elevated non-HDL-C • Add a statin (pravastatin 20-40 mg QD or atorvastatin 10 mg QD) • Serum TGs > 500 mg/dL • Add a fibrate (gemfibrozil 500 mg BID or fenofibrate 54-160 mg QD) Dube MP, et al., CID 2003; 37:613

  17. IDSA-AACTG Guidelines • LDL-C or non-HDL-C levels that fail to respond to full dose statin therapy • Add a fibrate or niacin • Pravastatin or fluvastatin preferred when combined with a fibrate • TG levels that fail to respond to fibrate therapy • Add a fish oil supplement or niacin • Addition of a statin is not generally recommended when elevated TG is the predominant abnormality Dube MP, et al., CID 2003; 37:613

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