Lower levels of beneficial high-density lipoprotein (HDL) cholesterol - but not of harmful low-density lipoprotein (LDL) - were associated with cardiovascular disease in the SMART treatment interruption study, researchers reported on February 11th at the Sixteenth Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal, Canada.
SMART was a large international treatment strategy trial comparing CD4 cell-guided structured treatment interruption versus continuous antiretroviral therapy. More than 5000 participants were randomly assigned either to stop antiretroviral treatment when their CD4 count was above 350 cells/mm3 and resume when it fell below 250 cells/mm3 or to remain on continuous therapy throughout the study.
SMART’s headline finding, first reported three years ago, was that individuals in the treatment interruption arm had a higher rate of opportunistic disease or death, as well as an unexpected increase in serious heart, kidney and liver problems. The following year, SMART investigators reported that individuals who interrupted therapy had a slightly elevated risk of cardiovascular disease, and in 2008 they reported that people who interrupted treatment had higher levels of blood biomarkers of inflammation and coagulation (clotting).
LDL cholesterol plays a role in the build-up of plaque on artery walls, a process that can result in loss of elasticity (atherosclerosis), inflammation, clotting and ultimately blockage of blood flow to the heart or brain. Very low-density lipoprotein (VLDL) particles contain more triglyceride and are also considered harmful. Conversely, HDL carries cholesterol away for disposal and therefore helps prevent atherosclerosis. HDL particles are roughly one-third the size of LDL particles, whilst VLDL particles are many times larger.
Studies in the general population have shown that high LDL (especially small, dense LDL particles) and low HDL levels are predictors of cardiovascular disease. Since HDL was found to decline significantly more in SMART participants who interrupted treatment than in those who remained on continuous therapy, this unfavourable lipid change could offer a possible explanation for the increased risk of cardiovascular events seen in the treatment interruption arm.
In the analysis presented at this year's conference, SMART investigators looked at the relationship between lipoprotein particle size and concentration and the risk of cardiovascular disease, noting that individuals with the same overall HDL level can have different distributions of HDL particle sizes.
Using nuclear magnetic resonance spectroscopy, they measured lipoprotein concentration and size in 248 individuals who experienced cardiovascular events such as heart attacks or strokes by study closure in July 2007, comparing them with 480 age- and sex-matched control patients who did not develop cardiovascular disease.
Most study participants (about 80%) were men and the median age was 49 years. Not surprisingly, those in the cardiovascular disease group were more likely to have cardiovascular risk factors including smoking, diabetes and high blood pressure. Baseline total cholesterol, LDL and triglyceride levels were similar in both groups, but those with cardiovascular disease had a lower median HDL level.
Participants in the treatment interruption arm experienced a greater decrease in HDL levels one month after stopping therapy compared with patients who remained on continuous therapy.
In an unadjusted analysis, the researchers found that lower total HDL and small HDL particle concentrations were associated with a significant 40% to 50% increase in the risk of cardiovascular events (odd ratios of 0.41 and 0.53, respectively).
This association remained after adjusting for demographic characteristics, antiretroviral treatment, HIV viral load, CD4 count, hepatitis B or C co-infection, cardiovascular risk factors, and inflammation and coagulation biomarkers (high-sensitivity C-reactive protein, interleukin 6 and D-dimer).
However, the investigators found that LDL and VLDL particle concentrations and sizes were not significantly associated with cardiovascular disease.
"In the SMART trial, lower total HDL particles and especially small HDL particles are predictive of cardiovascular events in HIV patients," the researchers concluded.
Discussing the findings, presenter Daniel Duprez noted that lipoprotein particle size alone could not explain the detrimental outcomes in the treatment interruption arm, suggesting there are probably multiple interacting factors.
He also said that while lower HDL is associated with higher cardiovascular risk, experts do not know what an optimal HDL level would be for HIV-positive or HIV-negative individuals.
Duprez D et al. High-density lipoprotein particles but not low-density lipoprotein particles predict cardiovascular disease events in HIV patients: strategies for management of ART study. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 149, 2009.