February 7, 2001
Concerns about the toxicity of antivirals have focused on multiple areas. The concept of lipodystrophy is made up of alterations in lipids, fat deposition, fat loss, changes in insulin and glucose levels, and bone metabolism. The changes in glucose, insulin, and lipids may have the most far-reaching effects, as they will create potentially additional risk factors that could result in cardiovascular disease. This may be the only complication that is potentially lethal and at best troublesome, so it is of obvious concern to quantify the risk so that patients and providers can analyze the risk benefit of HIV medicine with the risk of vascular disease and choose what is best. Previous work by Grunfeld has suggested that the risk would be low on a hypothetical basis, using the guidelines of the Framingham study and presumed lipid levels and risk factors based on age.
This study by Henry et al. followed a cohort of individuals who had been on a protease inhibitor and two-NRTI regimen (indinavir, AZT, and 3TC) with a median time of enrollment of 24 months. They were then randomized to receive either abacavir or placebo with the median time on meds equal to 41.7 months. The group was analyzed using fasting studies for a variety of cardiovascular risk factors including glucose, insulin, homocysteine, total cholesterol with fractionation to HDL and LDL, triglycerides, and three other lipid subtypes. These values were then compared to the ages of the cohort, their smoking history, diabetes, blood pressure. The combination of their demographics and blood data allow for the generation of a cardiovascular disease score which was between average and moderately above average level of risk for a coronary event in the next ten years. Additional calculations were done on glucose and insulin levels to create a marker for insulin resistance. This cohort exceeded the index and 56% were characterized as having insulin resistance, as well as elevations in triglycerides, total cholesterol, and low HDL.
Grinspoon spoke of additional risk factors for vascular disease elevated in patients on protease inhibitors beyond the ones above. It is clear that there is some increased risk for coronary disease. The reason is not clear -- since the risk may be a result of the medicines or the disease itself. Chronic inflammation can predispose to coronary disease and Henry plans a further evaluation of additional risk factors in future work. Klein showed that over a four-year period proteases did not increase coronary events in a hospital-based setting, but did have an unexplained increase in coronary heart disease events but not true heart attacks (see abstract 655). Krause found some increased rates of heart attacks in France during an 18-month follow-up associated with protease inhibitors (see abstract 657).
I think that the lipid and inflammatory changes do represent increased risk for coronary disease. We should help our patients do everything they can to modify these risk factors, with the first imperative to stop patients from smoking. This is the largest additive risk factor and will improve things greatly.
The choices after that are complex and include diet, exercise, medicines, and careful evaluations of changes in medicines. One must be deliberate in changing meds to trade a risk in the future of coronary disease destabilizing HIV disease. We should tell our patients: Live as healthy a lifestyle as possible, consider antioxidant vitamins, and plan your HIV medical choices wisely.
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