Mechanisms of Lipid Elevations Associated With the Treatment of Patients With HIV Infection

Peter J. Piliero, MD

In This Article

Clinical Implications and Management of PI-Related Dyslipidemia

While the mechanisms listed above all have experimental evidence that supports their potential role in PI-associated dyslipidemia, determining the exact contribution of each requires additional in vitro as well as in vivo data. Irrespective of the mechanisms of action, PI therapy is clearly associated with both lipodystrophy and dyslipidemia. This has practical implications for the treating clinician.

Dyslipidemia in the general population is associated with an increase in the incidence of CHD. Although a similar association has not definitely been established in HAART recipients, some studies indicate that PI-treated patients may have a higher incidence of CHD compared with HIV-infected patients not receiving PIs.[47,48] In a review of the French HIV Hospital Database, there appeared to be a dose-response relationship between the duration of PI treatment and the incidence of myocardial infarction.[48] Patients who had been treated 18 months or longer had the highest morbidity rates.

The relatively early appearance of CHD events in PI-treated patients may be multifactorial in origin. Potential contributory factors include the degree of dyslipidemia and PI-associated effects on foam cell formation.[39] Foam cells in large numbers may contribute to plaque instability through the release of cytokines. These cytokines then attract additional inflammatory cells into the atheroma. There they activate matrix metalloproteinases, which can degrade the connective-tissue elements that contribute to the fibrous cap.[49]

Although the primary focus of concern with regard to PI-associated dyslipidemia has been its effect on the cardiovascular system, severe PI-induced hypertriglyceridemia has also been associated with the development of acute necrotizing pancreatitis.[24]

The combination of dyslipidemia, insulin resistance, and impaired glucose tolerance seen in PI-treated patients are characteristics of the metabolic syndrome (syndrome X, dysmetabolic syndrome).[50] This syndrome consists of a constellation of concordant metabolic alterations that, in the aggregate, enhance the risk for CHD at any given level of LDL cholesterol. Features of this syndrome include abdominal obesity, elevated TGs, low HDL cholesterol, elevated blood pressure, and impaired glucose tolerance or diabetes-defining fasting glucose levels. The association is strengthened by reported lipodystrophy-associated elevations in blood pressure.[51]

The Adult AIDS Clinical Trial Group has developed preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with HIV and receiving ARV therapy, particularly PIs.[16] These recommendations are based on knowledge concerning the prevalence, treatment, and treatment outcomes of dyslipidemia in non-HIV-infected patients.[50] These recommendations are also based on experience with treatment-related dyslipidemia in other chronically ill populations and the pharmacokinetic profiles of available hypolipidemic agents. In general, it is recommended that plasma lipid profiles be routinely monitored and considered part of the standard management of HAART regimens. Optimal management includes improved exercise and diet strategies, as well as addressing other CHD risk factors such as cigarette smoking and hypertension. If therapeutic lifestyle management fails to normalize the patient's lipid profile, drug therapy should be considered. Pharmacologic agents have been shown to be highly effective in the general population and should be used as necessary in patients infected with HIV. However, while the statins (HMG-CoA reductase inhibitors) are the drugs of choice for hypercholesterolemia, the potential for CYP interactions is cause for concern. Statins metabolized by non-CYP mechanisms, such as pravastatin, are preferred. Simvastatin and lovastatin are contraindicated due to increased drug levels when combined with PIs that may lead to increased toxicity.[52] When hypertriglyceridemia is the predominant feature of the dyslipidemia, a fibric acid derivative should be used.[16,50] The abnormalities in glucose and insulin associated with PI therapy might be managed with one of the thiazolidinediones, agents that activate PPAR-gamma.[53]