Drug-drug interactions complicate management of HAART-associated dyslipidemia

March 2005

Lipodystrophy and dyslipidemias have been increasingly recognized as a complication of highly active antiretroviral therapy (HAART) in patients with HIV.

Triglyceride levels among patients with HIV have been reported to increase to more than 1,000 mg/dl with antiretroviral agents, and similarly, cholesterol levels may increase to 400 mg/dL. Ongoing antiretroviral therapy, drug-drug interactions, and adverse effects can complicate management of these dyslipidemias. In fact, a study of primary care physicians who regularly treat HIV patients for dyslipidemia found that only 38% of those patients succeeded in achieving National Cholesterol Education Program (NCEP) Adult Treatment Panel II (ATP II) target lipid values.

Lifestyle changes

Therapeutic lifestyle changes are important for patients with HAART-associated dyslipidemia, but rarely will these activities result in correction of dyslipidemia without the addition of lipid-directed drug therapy. Modifications of HAART have also been proposed but these strategies have not been clearly successful. Thus, pharmacological treatment with antihyperlipidemics is commonly employed.

Fibrates and statins

Fibrates such as gemfibrozil, which typically have excellent activity in reducing triglycerides in patients who do not have HIV, appear to be less effective in patients taking antiretrovirals.

Use of bile acid resins in patients with HIV is complicated by absorption interactions, as the bile acid can reduce bio-availability of drugs administered within two hours of the resin. In addition, bile acid resins have predominant effects on total and LDL cholesterol rather than triglycerides, limiting their utility as single agents in the management of HAART-associated hyperlipidemia.

Statins have not been well studied in this setting, because of serious drug-drug interactions mediated by the cytochrome P450 isoenzyme system (CYP 450) that lead to increased statin concentrations and possible rhabdomyolysis, hepatotoxicity and/or myopathy. Such adverse reactions have caused the FDA to issue warnings about the use of these hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors in patients taking an agent that inhibits metabolism. This risk can be greatly reduced by administering a statin not metabolized by CYP450.

Of the available statins, simvastatin (Zocor, Merck) may have the most profound interaction in the setting in protease inhibitor (PI) therapy. In fact, levels of simvastatin are reportedly increased more than 3,000% by concomitant therapy with ritonavir (Norvir, Abbott Laboratories) plus saquinavir soft gel capsule (Invirase, Roche), both given as 400 mg twice daily. Similarly, atorvastatin (Lipitor, Novartis) was increased 80% in the presence of ritonavir/saquinavir. Pravastatin (Pravachol, Bristol-Myers Squibb) may be the HMG CoA reductase inhibitor of choice in this setting, because its levels are not increased as dramatically as other agents. Serum concentrations of pravastatin decreased 50% when coadministered with ritonavir plus saquinavir. This agent also does not appear to alter the pharmacokinetics of nelfinavir (Viracept, Agouron), suggesting that these two agents may be safely coadministered. Fluvastatin (Lescol, Novartis) has recently been approved by the FDA and is another possible option for patients requiring antiretroviral therapy in the setting of HAART. CYP 3A4 is only a minor route of metabolism for fluvastatin, however it is metabolized by CYP 2C9 and is a weak inhibitor of this isozyme. Fluvastatin could theoretically have interactions with the PI nelfinavir. Since only small studies have evaluated this combination, additional data are necessary to demonstrate that fluvastatin and nelfinavir can be safely coadministered. Rosuvastatin (Crestor, AstraZeneca) is also new to the U.S. market and has an attractive drug interaction profile. More experience is necessary before this agent can be recommended.

Combination therapy with statins and fibrates may be an alternative for patients with refractory dyslipidemias, but has not been shown to produce further reductions in triglycerides or total cholesterol compared with gemfibrozil alone in patients with HIV. In addition, risk of rhabdomyolysis may be increased with this combination therapy, so the risk-to-benefit ratio of this management strategy is relatively high.

Other potential pharmacologic therapies for patients with HAART-associated dyslipidemia include niacin, fish oil or ezetimibe (Zetia, MSP Singapore). Niacin can be an effective agent in increasing HDL and modestly lowering total and LDL cholesterol as well as triglycerides and has no appreciable drug-drug interactions with antiretroviral therapy.

However, its effectiveness against the profound dyslipidemias observed with HAART therapy has not been well studied to date. Gastrointestinal and hepatic toxicities can be problematic in this population as well as hyperglycemia, particularly since hyperglycemia has also been reported with PI therapy. Fish oil is attractive because it too lacks appreciable drug interactions with antiretroviral agents, and can have potent triglyceride-lowering effects. Accordingly, several randomized studies have evaluated this treatment approach in patients with HAART-associated dyslipidemia and demonstrated benefit in lowering hypertriglyceridemia but not necessarily more than diet and exercise alone. Finally, ezetimibe is the first in a new class of agents that has been useful in combination with HMG Co-A reductase inhibitors. This is an attractive agent because it is not significantly metabolized by the CYP 450 isoenzyme system. However, one formulation (Vytorin, MSP Singapore) contains both ezetimibe and simvastatin, and simvastatin (as discussed previously) has significant interactions with protease inhibitors. Thus, use of ezetimibe with statins other than simvastatin in the setting of HAART-associated dyslipidemia should be evaluated in controlled clinical trials. Ezetimibe and statin combinations could be considered for cases that are refractory to other treatments.

Assess for cardiac risk factors

Careful assessment for cardiac risk factors is an important part of routine care for people with HIV. Efforts to reduce the risk of cardiovascular morbidity and mortality such as cigarette smoking should be vigorously pursued in at-risk patients. Fasting lipid panels should be considered at baseline for patients initiating antiretroviral therapy.

Lipid panels should be reassessed at four to six weeks and three months after initiating lipid-lowering therapy. If inadequate response to initial pharmacologic therapy occurs after six months of treatment, dosage increase may be considered for statin or niacin therapies. If this is not an option, consider changing to a drug or a combination of drugs with more potent lipid-lowering effects. A change to an antiretroviral regimen with reduced potential to induce hyperlipidemia can also be considered.

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