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Suspending Antiretrovirals Has Fast Negative Impact on HDL Particle Concentrations: interruptions reduce HDL and this predicts risk for cardiovascular disease in SMART
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16th Conference on Retroviruses and Opportunistic Infections,
February 8-11, 2009, Montreal
Mark Mascolini
Analysis of SMART trial participants found that interrupting antiretroviral therapy rapidly lowered high-density lipoprotein (HDL) particle concentration when compared with continuing treatment [1]. In contrast with SMART enrollees who did not get diagnosed with cardiovascular disease during the study, those who did had significantly higher concentrations of total HDL particle and small HDL particle concentrations when the study began. Low-density lipoprotein (LDL) particle concentration did not predict heart disease in the SMART group. The findings offer more insight into why people in the SMART treatment interruption arm ran a higher risk of serious cardiovascular disease than people in the steady-therapy group [2].
Earlier SMART analyses showed that interrupting antiretrovirals lowered both HDL and LDL cholesterol [2]. Lower "good" HDL cholesterol levels boost the risk of cardiovascular disease. However, HDL and LDL particle concentrations can differ in two people with the same age and the same HDL or LDL levels. Earlier research found that HDL particle concentrations correlate with risk of ischemic heart disease and suggest that smaller LDL particle size predicts coronary artery disease.
To investigate these variables in SMART study participants, Daniel Duprez and colleagues analyzed baseline and follow-up plasma samples in 248 people diagnosed with cardiovascular disease during the study and, for each of them, two SMART participants without heart disease matched for country, age within 5 years, gender, and date of randomization in SMART. Logistic regression to estimate odds ratios (OR) of cardiovascular disease factored in age, race, antiretroviral therapy, viral load, CD4 count, body mass index, smoking, diabetes, hepatitis B and C coinfection, use of lipid and blood pressure medication, prior heart disease, and major electrocardiographic abnormalities at study entry.
Median age stood at 49 years in the 248 cases with cardiovascular disease and in the 480 controls, 19% in each group were women, and about 38% in each group were black. CD4 count and viral load were also similar in the two groups, as was use of lipid-lowering drugs. But the heart disease patients had higher rates of prior AIDS (37% versus 25%, P = 0.0005), diabetes (17% versus 8%, P = 0.0007), and prior cardiovascular disease (15% versus 5%, P = 0.0004). Also, people who got diagnosed with heart disease during SMART were more likely to be taking drugs for hypertension (45% vs 31%, P < 0.0001).
Baseline lipids were similar in cases and controls, except for HDL cholesterol (median 38 versus 42 mg/dL in cases vs controls, P = 0.03) and total-to-HDL cholesterol ratio (5.2 vs 4.7, P = 0.05). Baseline total LDL particle concentration and very low-density lipoprotein concentration were similar in the two groups, but the cases with cardiovascular disease had a significantly lower total HDL particle concentration than controls without heart disease (28.4 vs 30.2 micromol/L, P = 0.0001).
Multivariate analysis comparing highest versus lowest quartile concentrations determined that lower levels of two variables independently predicted cardiovascular disease: total HDL particle concentration (OR 0.41, P = 0.001) and small HDL particle concentration (OR 0.55, P = 0.03).
One month after randomization in SMART, total HDL particle concentration fell significantly in the treatment interruption group versus the steady-therapy group (-2.2 micromol/L, P < 0.0001), as did medium HDL particle concentration (-1.1 micromol/L, P = 0.002) and small HDL particle concentration (-0.9 micromol/L, P = 0.03), but not large HDL particle concentration (-0.3 micromol/L, P = 0.10).
Duprez concluded that total HDL particle concentration, and particularly small HDL particle concentration, predicted risk of cardiovascular disease in SMART. The study linked intermittent antiretroviral therapy to falling HDL particle quotients when compared with continuous therapy. Duprez called for further study of how long-term antiretroviral therapy affects HDL cholesterol and HDL particles.
References
1. Duprez D, INSIGHT/SMART Group. High-density lipoprotein particles but not low-density lipoprotein particles predict cardiovascular disease events in HIV patients: Strategies for Management of ART study. 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2009. Montreal. Abstract 149.
(Slide presentation available online at http://www.retroconference.org/2009/data/files/webcast.htm. Click on Wednesday, then on Play Audio and Slides at Pathogenesis of HIV Complications, then on Index, then on Daniel Duprez.)
2. Phillips AN, Carr A, Neuhaus J, et al. Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial. Antivir Ther. 2008;13:177-187.
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