February 25, 2002
This massive, multi-national, cross-sectional study of 17,852 patients (believe me that's no typo) looked at lipid levels in this cohort depending on the regimen the patient was taking at the time the study was done. It is a cross-sectional study, with all the limitations of this type of study design. The fact that it is massive does not change this basic fact.
The study has yet another problem that took only two questions from the audience to discover: The samples were not done fasting (something extremely important in any metabolic study). In any case, this study does provide a glimpse at the frequency of side effects depending on the regimen the patient is taking.
The study showed that a very significant number of the patients (around 25 percent) receiving any of the potent antiretroviral combinations have problems with their lipids (total cholesterol) that put them at a high cardiovascular risk. A similar proportion, even bigger in patients that are on a protease inhibitor-based regimen, have low levels of HDL cholesterol.
A table summarizing the results, showing the percentage of individuals with elevated values in each combination follows:
|Not Currently On ART
|NRTI + PI
|NRTI + NNRTI
|PI + NRTI + NNRTI
Although total cholesterol levels were similarly elevated in patients whether they were on protease inhibitor or NNRTI-based regimens, the fact that HDL cholesterol levels decreased in patients taking a protease inhibitor put them at a higher cardiovascular risk than patients on NNRTI-based regimens.
For those of you who are not aware, there was an update last year in the National Cholesterol Education Program (NCEP) guidelines, which are now much more aggressive than before. These new guidelines have had a dramatic impact in the way we practice not only HIV care, but internal medicine. You can consult them online at the NIH Web site.
There is also a calculator that assesses one's risk for coronary artery disease that anybody can use. For example a 40-year-old male, smoker, with a total cholesterol of 220 mg/dl, HDL of 35 mg/dl and a normal blood pressure -- a very common scenario -- has a 14 percent risk of having a major cardiovascular event during the subsequent ten years. It is very clear that we need to be much more aggressive than we have been so far in the management of these problems, especially because we are the primary care providers for the great majority of our patients, most of whom do not see other physicians to take care of these "less important" problems.
As a brief summary, the profiles for the major lipids associated with increased cardiovascular risk are:
|LDL Cholesterol -- Primary Target of Therapy|
|100-129||Near Optimal/Above Optimal|
This applies to HIV-positive and to non-HIV-positive patients (the bottom line: it applies to you!). Although we still split hairs about it, there is not a very good biological reason to think that these elevations are not going to be associated with an increased risk of cardiovascular disease. Some cohort studies have started to show an increase in cardiovascular events among HIV-positive patients.
The main question remains, how to treat this problem. Although there have been published guidelines to guide us in the management of this problem, we still have no clue of what to do that works. The current remedies are simply not very effective.
We could switch patients to less toxic NNRTI- or abacavir-based regimens. That strategy seems to work for lowering triglycerides, increasing HDL and not affecting a lot of total cholesterol. The problem is that many of our patients cannot switch. We could use statins, but their utility is limited due to interactions with the protease inhibitor class.
The most popular statins so far have been pravastatin and atorvastatin which are metabolized using a different pathway and can be used safely with protease inhibitors. The rest of the statins are probably not very safe.
Fibrates have been used, but they seem more indicated for the treatment of elevated triglycerides. Gemfibozil and Fenofibrate are the most popular options in this regard. Niacin, an over-the-counter drug, is powerful but its use has been limited because clinicians are worried about the increased risk of insulin resistance, although that "classic" caveat of niacin has not been confirmed in large trials. Bile-sequestering acids are not a very useful option because of interactions with the other drugs that most HIV patients have to take.
Studies like this do not tell us anything that we did not know before, but they show us how widespread the problem of hyperlipidemia is in the developed world, not only in the fast-food paradise of the USA.
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