February 26, 2002
Metabolic changes, including increased blood sugar and cholesterol, are a significant concern in some patients on protease inhibitors. Body shape changes, including fat loss and fat redistribution are a problem for a significant number of patients. These are not simply an effect of protease inhibitors, rather they appear to result from a complex interaction of disease effects, genetic factors and drug effects. A large number of case reports and several studies have looked at the effect of switching from a protease inhibitor-containing regimen to a protease inhibitor-sparing regimen on cholesterol, triglycerides and body shape changes. In this study, patients were randomized to switch to abacavir, efavirenz or nevirapine. This head-to-head comparison of switching strategies is a unique feature of this study.
In this study, patients on a protease inhibitor-containing regimen with a viral load below 200 copies for a mean of 20 months were randomized to switch to abacavir, efavirenz or nevirapine while staying on the same two nucleosides. For this paper, a subset of 92 patients underwent intensive study of metabolic changes. At baseline, about 50 percent had clinical lipodystrophy. Sixty-six percent had at least one abnormal lipid value. Baseline characteristics were relatively similar between those with and without lipodystrophy, although insulin levels were higher and insulin resistance was higher among those with abnormal body shape.
After six months of treatment with the switch regimen, there was a substantial improvement in lipids in all three groups. Total cholesterol decreased significantly in all three groups, with changes ranging from 4 to 13 percent. LDL cholesterol ("bad cholesterol") decreased by 15 percent in the abacavir group, 8.6 percent in the efavirenz group and 7 percent in the nevirapine group. HDL cholesterol ("good cholesterol") increased by 18 percent in the nevirapine group, 7.7 percent in the efavirenz group, and decreased by 8 percent in the abacavir group. Triglycerides decreased by 29.5 percent in the nevirapine group, 4 percent in the efavirenz group and increased by 9.9 percent in the abacavir group.
The ratio of total cholesterol to HDL cholesterol is one of the best indicators of cardiovascular risk (at least in non-HIV infected persons). This indicator improved mostly in the nevirapine group, with a 20 percent change compared to 17 percent in the efavirenz group and 8.3 percent in the abacavir group. When patients with clinical lipodystrophy were compared to those without, the switch resulted in greater improvement in those without lipodystrophy.
Insulin levels did not change in those switched to efavirenz or abacavir. In the nevirapine group, insulin dropped by 20 percent but this change was not statistically significant.
This study is consistent with most other switch studies that have shown improvement in lipids when patients switched to protease inhibitor-sparing regimens. It appears that the improvements may be more impressive when nevirapine is the new agent.
It is reasonable to assume that improved lipid profiles will translate into decreased risk of heart disease and other vascular complications, because this has been clearly shown in non-HIV-infected people who are able to change their cholesterol and HDL-to-total cholesterol ratio. A word of caution however. Although it seems very reasonable to assume that these changes will have a benefit when they reverse PI-related changes in cholesterol, this remains to be proven. It is important to put this into context of other cardiovascular risks. Cholesterol increases have the greatest impact in persons with other risk factors, including family history of early heart disease, hypertension, sedentary life style, and most importantly, smoking and diabetes. Thus, we need to look at the total number of risk factors. Changing regimens to decrease cholesterol will be most important in people with pre-existing heart disease, or other risk factors. For those with no other risk factors and modest elevations of cholesterol (200-240) it is not clear that changing antiviral regimens is necessary.
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