A Review of the Effects of Antiretroviral Agents on Lipid Panels of HIV-Positive Patients

Special Report

By Jessica C. Song, MA, Pharm D, 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, is Associate Editor for Infectious Disease Alert.

Jessica C. Song and Paul Hsiao report no financial relationships relevant to this field of study.

Introduction

Human Immunodeficiency Virus (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% 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.

Effects of Antiretrovirals / Interaction Risks

The effects of currently marketed antiretroviral agents on lipid profiles of HIV-positive patients and the risk for interactions with lipid-lowering agents are summarized in Table 1.20-49 Current treatment recommendations from the most recently updated DHHS Guidelines20 are highlighted in Tables 2 and 3.

References:

  1. Calza L, Manfredi R, Chiodo F. Dyslipidaemia associated with antiretroviral therapy in HIV-infected patients. J Antimicrob Chemother 2004;53:10-14.
  2. Wohl DA, McComsey G, Tebas P, 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 J2004;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 (suppl): 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 Med2002;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.
  20. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents - A Working Group of the Office of AIDS Advisory Council. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. October 10, 2006. Accessed on July 23, 2007: http://AIDSinfo.nih.gov.
  21. Efavirenz (Sustiva ) prescribing information. Princeton, NJ: Bristol-Myers Squibb; 2007 Jan.
  22. Efavirenz/Emtricitabine/Tenofovir (Atripla ) prescribing information. Foster City, CA: Gilead Sciences and Bristol-Myers Squibb; 2007 March.
  23. Nevirapine (Viramune ) prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2007 June.
  24. Delavirdine mesylate (Rescriptor ) prescribing information. New York, NY: Pfizer Pharmaceuticals/ Pharmacia and Upjohn; 2006 February.
  25. Atazanavir (Reyataz ) prescribing information. Princeton, NJ: Bristol-Myers Squibb; 2007 March.
  26. Tipranavir (Aptivus ) prescribing information. Ridgefield, CT: Boehringer-Ingelheim Pharmaceuticals; 2007 February.
  27. Darunavir (Prezista ) prescribing information. Raritan, NJ: Tibotec Therapeutics; 2006 June.
  28. Ritonavir/Lopinavir (Kaletra ) prescribing information. North Chicago, IL: Abbott Laboratories; 2000 September.
  29. Fosamprenavir (Lexiva ) prescribing information. Research Triangle Park, NC: GlaxoSmithKline Pharmaceuticals; 2007 June.
  30. Ritonavir (Norvir ) prescribing information. North Chicago, IL: Abbott Laboratories; 2006 January.
  31. Saquinavir (Invirase ) prescribing information. Nutley, NJ: Roche Laboratories; 2005 September.
  32. Nelfinavir (Viracept ) prescribing information. New York, NY: Pfizer Pharmaceuticals; 2007 January.
  33. Kumar PN, et al. A prospective 96-week study of the impact of trizivir, combivir/nelfinavir, and lamivudine/stavudine/nelfinavir on lipids, metabolic parameters, and efficacy in antiretroviral naive patients: effect of sex and ethnicity. HIV Med 2006;7:85-98.
  34. Indinavir (Crixivan ) prescribing information. Whitehouse Station, NJ: Merck Pharmaceuticals; 2006 November.
  35. Roberts AD, Muesing RA, Parenti DM, et al. Alterations in serum levels of lipids and lipoproteins with indinavir therapy for HIV-infected patients. Clin Infect Dis 1999;29:441-443.
  36. Enfuvirtide (Fuzeon ) prescribing information. Nutley, NJ: Roche Pharmaceuticals; 2007 January.
  37. Emtricitabine/Tenofovir (Truvada ) prescribing information. Foster City, CA: Gilead Sciences; 2007 May.
  38. Tenofovir (Viread ) prescribing information. Foster City, CA: Gilead Sciences; 2007 May.
  39. Emtricitabine (Emtriva ) prescribing information. Foster City, CA: Gilead Sciences; 2006 December.
  40. Abacavir Sulfate/Lamivudine (Epzicom ) prescribing information. Research Triangle Park, NC: GlaxoSmithKline Pharmaceuticals; 2006 March.
  41. Didanosine (Videx/Videx EC ) prescribing information. Princeton, NJ: Bristol-Myers Squibb Pharmaceuticals; 2000 December.
  42. Abacavir (Ziagen ) prescribing information. Research Triangle Park, NC: GlaxoSmithKline Pharmaceuticals; 2002 August.
  43. Lamivudine (Epivir ) prescribing information. Research Triangle Park, NC: GlaxoSmithKline Pharmaceuticals; 2006 October.
  44. Zidovudine/Lamivudine (Combivir ) prescribing information. Research Triangle Park, NC: GlaxoSmithKline Pharmaceuticals; 2007 March.
  45. Zidovudine (Retrovir ) prescribing information. Research Triangle Park, NC: GlaxoSmithKline Pharmaceuticals; 2006 November.
  46. Abacavir Sulfate/Zidovudine/Lamivudine (Trizivir ) prescribing information. Research Triangle Park, NC: GlaxoSmithKline Pharmaceuticals; 2006 March.
  47. Stavudine (Zerit ) prescribing information. Princeton, NJ: Bristol-Myers Squibb Pharmaceuticals; 2002 January.
  48. Llibre JM, et al. Sustained improvement of dyslipidaemia in HAART-treated patients replacing stavudine with tenofovir. AIDS 2006;20:1407-1414.
  49. Zalcitabine (Hivid ) prescribing information. Nutley, NJ: Roche Pharmaceuticals; 2002 September.