Not all clinicians agree that the cholesterol elevations seen in HAART patients are predictive of heart disease.
There is clear evidence that different drugs tend to produce different patterns of cholesterol elevation. For example, in the Atlantic study, after two year on treatment with nevirapine participants experienced a 40% increase in HDL cholesterol levels, but a non-significant change in LDL cholesterol levels. In the indinavir arm of the same study, LDL cholesterol rose significantly (by 14%) but HDL cholesterol levels did not. The total cholesterol levels rose by 22% in both the indinavir and the nevirapine arms in this study, but only one of these changes could be defined as atherogenic.1 Efavirenz treatment has also been shown to elevate HDL cholesterol.
Despite these attempts to downplay the risk of heart disease among people taking protease inhibitors (PIs), other clinicians are more cautious. They point to the fact that heart attacks and other cardiovascular events in people under the age of 45 have been associated with as few as one or two of the risk factors associated with heart disease. A study of HIV-negative individuals from the Framingham database found that very high lipid levels are not necessary for individuals to experience an increased risk of heart disease. Quite marginal increases in the presence of other risk factors such as raised blood pressure and smoking resulted in an elevated risk.2
Although it appears that high triglyceride levels also contribute to cardiac risk in people with HIV, it is not clear how strongly they predict risk, or how much benefit triglyceride-lowering interventions might have. Although some analyses have not shown triglycerides to be an
independent risk factor in the development of heart disease, the
Framingham analysis suggests that the LDL:HDL cholesterol ratio and
triglycerides may be relevant markers of cardiovascular risk in
HIV disease. An analysis from the large D:A:D study also found that higher triglyceride levels were independently associated with a
higher risk of myocardial infarction, or heart attack. The D:A:D researchers suggested, however, that triglycerides had limited prognostic value after taking cholesterol levels into account,
and that triglyceride-lowering therapies would be unlikely to have a substantial impact.3
Studies by FRAM (Fat Redistribution and Metabolic Change in HIV Infection)
and D:A:D investigators have found that intima-media thickness (IMT) was not associated with PI use or HIV status, but rather with 'traditional' risk
factors such as age and body mass index. (An exception found in one
study was an unexpected protective effect
from tenofovir.) 4
5
6 These recent studies are in agreement with older findings that HAART did not impact on the arteries 7
8 or that individuals on PIs had very mild arterial thickening.9
Several recent studies have reached the opposite conclusion – that HIV infection and/or HAART do in fact contribute to hardening of the arteries. The reason for the disparity is not completely explained, but may be due to differences in the techniques used to assess the degree of atherosclerosis. Studies using a common diagnostic measure, carotid IMT, have generally found no difference due to HIV infection or HAART.
One such 'dissenting' study found that outcomes depended on the precise site of the IMT measurement. In the common carotid artery, where IMT is usually measured, differences between HIV-positive patients and matched HIV-negative controls were small and not statistically significant. In contrast, measurements in the carotid bulb showed that HIV increased the extent of atherosclerosis by about the same amount as the strongest traditional
risk factors such as smoking, diabetes and male sex.10
Another study, which found that atherosclerotic risk increased with HIV infection and increased still more with HAART use, used
another different measure (pulse wave velocity) to gauge arterial stiffness.11
Other researchers also suggest that traditional risk factors do not entirely account
for, and therefore underestimate, cardiac risk in people with HIV. One Italian
study used electron-beam tomography (CAT) scanning to identify patients with high-risk levels of calcification and hardening of the arteries. CAT scans identified a need for medical
intervention in roughly 7% of high-risk patients who were not diagnosed as
needing intervention by the Framingham Risk Score or the European
Society for Hypertension guidelines.12
Others have
found that biomarkers not yet in routine use, such as D-dimer, are also independent
predictors of cardiovascular disease and may therefore play an important role
alongside traditional factors in identifying patients at risk.13