Effects of Antiretroviral Agents on Lipid Panels

Special Report

By Jessica C. Song, MA, Pharm D, Jessica is Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, Pharmacy Clerkship and Coordinator, Pharmacy Residency Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care; she reports no financial relationships relevant to this field of study.

HIV-infected patients have been shown to experience hypertriglyceridemia and/or hypercholesterolemia as a result of their highly active antiretroviral therapy (HAART), along with natural disease progression.1,2 In particular, dyslipidemia associated with HAART therapy has been reported in up to 70-80 percent of HIV-infected individuals. Hypertriglyceridemia appears to be especially problematic in patients receiving protease-inhibitor-based regimens, with the highest frequencies seen in patients treated with ritonavir-based HAART regimens.1 Because of the potential pharmacological interactions with certain antiretroviral agents, many clinicians tend to under-treat HAART-associated dyslipidemias. However, recent literature reports have shown that young HIV-positive individuals receiving protease inhibitors may be at increased risk of experiencing premature coronary artery disease.1 At present, despite the relative lack of treatment recommendations for dyslipidemic HIV-infected patients, most HIV specialists are of the opinion that the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) guidelines could be applicable to their patient population.2

The updated NCEP ATP III guidelines highlighted significant changes in the treatment of high-risk patients, as the panel recommended more intensive LDL-C lowering in very high-risk patients to a goal of less than 70 mg/dL.3 Patients who are classified as very high-risk have established CVD plus one of the following: multiple major risk factors, especially diabetes; severe and poorly controlled risk factors, especially cigarette smoking; multiple risk factors of the metabolic syndrome, especially TG (triglyceride) 200 mg/dL, non-HDL-C 160 mg/dl, and HDL-C (high-density lipoprotein cholesterol) < 40 mg/dL; or acute coronary syndrome (ACS).

Lipid-lowering treatment options for HIV-infected patients include certain hydroxy-methyl-coenzyme A reductase inhibitors (statins), fibric acid derivatives, niacin, ezetimibe, and fish-oil supplements, either provided as monotherapy, or in combination, depending on the specific lipid disorder.2 Bile acid-binding resins (cholestyramine, colestipol, colesevelam) should not be used by HIV-infected patients, as absorption of antiretrovirals may be impaired, and these agents have the potential to increase serum triglyceride levels.2

Statins are commonly used antihyperlipidemic agents that are well tolerated and relatively safe. The most common adverse effects are headache and gastrointestinal-related (i.e., abdominal pain, dyspepsia, nausea), but myopathy and hepatotoxicity have also been of some concern.4 Statin-induced myotoxicities are dose-related and related to the lipophilicity of the drug.5,6 Other drug-related properties that may increase risk of myopathy are high systemic exposure, high bioavailability, limited protein binding, and potential for drug-drug interactions metabolized by cytochrome p450 (CYP) pathways (particularly CYP 3A4).6 While myalgia represents the most common myotoxic event1, myositis and rhabdomyolysis have been reported to cause significant morbidity and mortality worldwide.5,6

Fibric acid derivatives represent the most potent triglyceride-lowering agents, but exert variable effects on LDL-C and modest effects in regards to increasing HDL-C. Unlike statins, fibric acid derivatives do not inhibit CYP3A4, but are more likely to inhibit CYP2C8/2C9.7-10 Niacin derivatives have been shown to be the most potent HDL-raising agents, and also provide moderate reductions in LDL-C and serum triglyceride concentrations.11-13 However, despite the availability of extended-release products that have improved side effect profiles, the initial flushing reaction associated with niacin use has required the use of a gradual dose-titration process and the use of prophylactic aspirin. Furthermore, because of its potential to increase blood glucose concentrations during the initial stages of dose titration, healthcare providers may need to increase the doses of hypoglycemic agents in patients starting niacin therapy.14-15 Ezetimibe has been shown to primarily decrease LDL-C, but to a lesser extent than statins and niacin, thereby limiting its use to providing additional LDL-C reductions in patients receiving other LDL-C-lowering agents.16-17 Fish oil supplements are available as nonprescription products and as a prescription drug. Reductions in serum triglyceride concentrations with fish oil supplements have been shown to be comparable to the reductions associated with fibric acid derivative use, but some patients may experience increases in LDL-C concentrations.18-19

The purpose of this two-part review is to 1) review the drug-interaction potential between antiretroviral agents and lipid-lowering agents, 2) review the propensity of antiretroviral agents to cause hyperlipidemia disorders, 3) review the efficacy and safety profiles of lipid-lowering agents, and 4) develop an algorithm for the treatment of various HAART-associated hyperlipidemia disorders. The review featured in this issue will focus on the first 2 objectives.

References:

1. Calza L, et al. Dyslipidaemia associated with antiretroviral therapy in HIV-infected patients. J Antimicrob Chemother. 2004;53:10-14.

2. Wohl DA, et al. Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy. Clin Infect Dis 2006; 43:645-53.

3. Grundy SM, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.

4. Newman CB, et al. Safety of atorvastatin derived from analysis of 44 completed trials in 9416 patients. Am J Cardiol. 2003;92:670-676.

5. Jamal SM, et al. Rhabdomyolysis associated with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am Heart J. 2004;147:956-965.

6. Thompson PD, et al. Statin-associated myopathy. JAMA. 2003;289:1681-1690.

7. Robins SJ, et al. Relation of gemfibrozil treatment of lipid levels with major coronary events. VA-HIT: A randomized controlled trial. JAMA. 2001;285:1585-1591.

8. Rubins HB, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410-418.

9. Keating GM, Ormrod D. Micronised fenofibrate: an updated review of its clinical efficacy in the management of dyslipidaemia. Drugs. 2002;62:1909-1944.

10. Fenofibrate (Tricor) prescribing information. North Chicago, IL: Abbott Laboratories; 2004 Nov.

11. Knopp RH. Evaluating niacin in its various forms. Am J Cardiol. 2000;86:51L-56L.

12. Niacin extended-release tablets (Niaspan) prescribing information. Miami, FL: Kos Pharmaceuticals, Inc.; 2005.

13. Miller M. Niacin as a component of combination therapy for dyslipidemia. Mayo Clin Proc. 2003;78:735-742.

14. Elam MB, et al. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease. The ADMIT study: a randomized trial. JAMA. 2000;284:1263-1270.

15. Grundy SM, et al. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of Niaspan trial. Arch Intern Med. 2002;162:1568-1576.

16. Ezetimibe (Zetia) prescribing information. North Wales, PA: Merck/Schering-Plough Pharmaceuticals; 2006 May.

17. Caron MF. Ezetimibe: a novel cholesterol absorption inhibitor. Formulary. 2002;37:628-633.

18. Omega-3-acid ethyl esters (Omacor) prescribing information. Liberty Corner, NJ: Reliant Pharmaceuticals; 2007.

19. Caron MF, White CM. Evaluation of the antihyperlipidemic properties of dietary supplements. Pharmacotherapy. 2001;21:481-487.