July 10, 2002
There is an increasing concern about the risk of premature cardiovascular disease among HIV-infected persons. Several conflicting reports have addressed this issue, one of these was presented by Holmberg from the U.S. Centers for Disease Control at this meeting (see abstract 4494) -- a report that suggests there is an ever-increasing incidence of myocardial infarctions among a large cohort of persons in the U.S.
A most disturbing and controversial aspect of this study is the strong risk-association with the use of protease inhibitors (PIs) and heart attacks. While this observation could be explained by a number of factors, most compelling are elevations in blood lipid values (cholesterol and triglycerides). The basis for this hypothesis comes from the fact that many HIV medications, including protease inhibitors cause elevations in cholesterol and triglycerides and that elevation in LDL cholesterol (the "bad" cholesterol) and triglycerides are associated with excessive cardiac disease among HIV-negative persons. Treatment of hyperlipidemia can be complex -- additional issues that complicate the medical management of elevated lipids in HIV-infected persons include extra pill burden, side effect profile and drug-drug interactions between many lipid-lowering agents and antiretroviral therapies.
This study was a GlaxoSmithKline-sponsored (the maker of ABC) prospective clinical trial designed to evaluate the effects of switching hyperlipidemic, HIV-infected persons from PI- to ABC-containing HAART on blood lipid levels. In an interview, Dr. Keiser reported that this is the first prospective randomized clinical trial of its kind to evaluate this question.
Subjects were included for the study if they were receiving a virally suppressive HAART regimen of two nukes and a protease inhibitor and had elevated fasting total cholesterol (greater than 200 mg/dl). Patients were then randomized either to continue on their previous regimen or switch their PI to 300 mg twice daily of abacavir (Ziagen).
One hundred four patients enrolled in the study, with 52 randomized to each group. The majority of these patients were either receiving indinavir- or nelfinavir-based treatments. Virologic suppression was maintained for the majority of subjects; there were two (4 percent) patients in the ABC arm who had possible allergic reactions to ABC. Patients in the ABC simplification arm of the study had statistically significant reductions in total cholesterol, LDL cholesterol and triglycerides, compared with patients that continued on PI-based therapy.
These data show that simplification of PI-based therapy with ABC for persons with hyperlipidemia can result in significant reductions in blood lipid values. This study showed that simplification can be done with a minimal risk of significant side effects or virologic failure, though, as pointed out by Dr. Keiser, this should not be entertained in persons with previous mono- or dual-nucleoside therapy. The study organizers should be commended for a well designed randomized study that compares two different treatment approaches -- only through studies of this nature can we really tell which approach is better.
In our clinical practice in Denver, like others around the United States, we have celebrated the ever improving quantity and quality of lives for our patients. With this recognition, comes an increasing burden to assess new health risks, and as best possible mitigate this risk. Risk mitigation must not come at the cost of sacrificing virologic suppression; this study provides an evidenced-based approach for managing PI-induced elevations in blood lipids that is validated by clinical study.
The ready availability of co-formulated ABC in Trizivir (ZDV/3TC/ABC) makes this switch particularly attractive for some patients. So, who gets switched? My approach is to counsel extensively about risk reduction -- getting people to stop smoking, work on diet and exercise. The first patients to be offered this switch approach in my office are likely those with the highest risk of having premature coronary heart disease -- those with strong family histories of cardiac problems or diabetes.
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