HDL Cholesterol -- but not LDL -- Predicts Cardiovascular Events in SMART Treatment Interruption Trial

By Liz Highleyman

Evidence continues to accumulate showing that interruption of antiretroviral therapy (ART) is a potentially risky strategy, and that even low-level ongoing HIV replication can cause previously unrecognized detrimental effects throughout the body.

At the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last month in Montreal, Daniel Duprez from the INSIGHT/SMART study team presented findings from an analysis of the relationship between treatment interruption, cholesterol levels, and cardiovascular disease.

As previously reported, SMART included more than 5000 mostly treatment-experienced participants with a baseline CD4 cell count above 350 cells/mm3. They were randomly assigned to either remain on continuous ART ("viral suppression" arm) or to interrupt therapy while their CD4 count was above 350 cells/mm3 and resume when it fell to 250 cells/mm3 ("drug conservation" arm).

The study was discontinued ahead of schedule in January 2006 after it became apparent that participants in the treatment interruption arm not only had a higher rate of AIDS-related opportunistic disease or death due to any cause, but also were more likely to develop serious cardiovascular, liver, and kidney disease. SMART researchers previously reported that high-density lipoprotein (HDL or "good") cholesterol declined more in the treatment interruption arm, and also demonstrated that interrupters had higher levels of blood biomarkers associated with inflammation and coagulation.

Low-density lipoprotein (LDL or "bad") cholesterol contributes to atherosclerosis, or build-up of plaque on artery walls and subsequent inflammation, coagulation, and restriction of blood flow to the heart or brain, potentially resulting in myocardial infarctions (MIs) or strokes. Very low-density lipoprotein (VLDL) is also considered harmful. On the other hand, HDL, which carries cholesterol away from the arteries, is thought to protect against cardiovascular diseases. Studies in the general population have shown that high levels of LDL -- particularly small, low density LDL particles -- and low levels of HDL predict cardiovascular disease.

In the present analysis, the investigators measured lipoprotein particle concentrations and sizes in stored plasma samples from 248 SMART participants who experienced cardiovascular events and 480 matched control patients who did not. About 80% were men and the median age was 48 years. The group that experienced cardiovascular events were more likely to have other relevant risk factors such as smoking, diabetes, and hypertension.

Results

As previously reported, patients in the treatment interruption arm experienced a significantly greater decrease in HDL 1 month after stopping ART than those who stayed on continuous therapy.

By the time the study was halted, participants experienced:

124 instances of non-fatal coronary heart disease (including clinical and "silent" MIs);

62 cases of non-fatal atherosclerotic disease affecting areas other than the heart (e.g., stroke, peripheral artery disease);

26 cases of non-fatal congestive heat failure;

36 fatal cardiovascular disease events.

In unadjusted analyses, lower total HDL was associated with a 41% increase in the risk of cardiovascular events (odds ratio [OR] 0.41; P < 0.0001).

Looking at particle size, a lower concentration of small HDL particles -- but not other sizes -- was significantly associated with cardiovascular disease risk (OR 0.53; P = 0.007).

After adjusting for potential confounding factors (including demographic characteristics, HIV disease status, other cardiovascular risk factors, and inflammation and coagulation biomarkers), there remained a significant independent association between total and small particle HDL concentrations and cardiovascular risk (OR 0.41 and 0.55, respectively).

LDL and VLDL particle sizes and concentrations, however, did not independently predict 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.

Duprez said in his discussion of the findings that lipoprotein particle size and concentration alone could not explain the higher rate of cardiovascular events in the treatment interruption arm, indicating that there may be multiple interacting factors.

The investigators added that the long-term effects of ART on HDL cholesterol and therapy to increase it need to be further studied in randomized trials since, as Duprez noted, it is not currently known what would be an optimal HDL level to prevent cardiovascular disease in people with HIV.

3/06/09

References
D Duprez and 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 (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 149.