Antiretroviral Agents and Lipid Profiles of HIV-Positive Patients: Part 2
By Catherine J. Hill, PharmD Candidate; Crystal T. Kimura, PharmD Candidate; Lian Chang, PharmD Candidate; are PharmD Candidates at the University of the Pacific.
Jessica C. Song, MA, PharmD, Pharmacy Residency Coordinator, Santa Clara Valley Medical Center, is Associate Editor for Infectious Disease Alert.
Catherine Hill, Crystal T. Kimura, Lian Chang, and Jessica C. Song all report no financial relationships relevant to this field of study.
Lipid abnormalities can be problematic in HIV-positive patients receiving highly active antiretroviral therapy (HAART) due to the risk of premature coronary artery disease developing in susceptible patients.1,2 As discussed in the previous article, the proportion of patients receiving HAART therapy who develop dyslipidemia depends on the type of anti-retroviral agent included in the treatment regimen. In some cases the dyslipidemic condition may be of sufficient severity to warrant treatment. The preferred agents that can be used for the treatment of dyslipidemia in patients on HAART therapy include hydroxyl-methyl-coenzyme A reductase inhibitors (statins), fibric acid derivatives, niacin, ezetimibe, and fish-oil supplements.2 These agents may be used as monotherapy or in combination. The purpose of this review is to outline treatment guidelines and to discuss the agents used for treatment of dyslipidemia.
Table 1 defines the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) Guidelines' LDL-C goals and cut-points for therapeutic lifestyle changes (TLC), along with drug therapy in different risk categories.
Therapeutic approaches for persons with hyperlipidemia vary depending on the baseline lipid panel. However, unless triglyceride levels exceed 500 mg/dL, LDL-C is the primary focus of lipid-lowering therapy. An LDL-C goal of < 100mg/dL with a baseline value of > 130mg/dL or between 100-129 mg/dL requires TLC and LDL lowering drugs.3 Although a baseline LDL-C value of < 100 only requires TLC and controlling of other associated risk factors, some clinicians may recommend the use of LDL-C lowering drugs for very high-risk patients (refer to footnote c, Table 1).3
Patients with a 10-year Framingham risk of 10-20%, have an LDL-C goal of < 130mg/dL.3 A baseline LDL-C value of < 130mg/dL requires management of associated risk factors and re-evaluation of the patient in one year.3 If a patient's baseline value equals or exceeds 130mg/dL, TLC is required, followed by a three-month follow-up assessment. After three months, if a patient's LDL-C value drops below 130mg/dL, TLC is continued and drug therapy initiation can be considered. Likewise, after three months, if the LDL-C exceeds 130mg/dL, TLC should continue and drug therapy must be initiated.3
Patients with a 10-year Framingham risk of less than 10% have an LDL-C goal of < 130mg/dL.3 Treatment recommendations for this subset of patients are generally the same as above with the exception of the time to consider lipid-lowering therapy. After three months of TLC, if the LDL-C value drops below 160mg/dL, the patient should continue TLC. TLC and drug therapy should be initiated if the LDL-C value persists at a level of 160mg/dL or higher after three months of TLC.3
Patients displaying a < 10% 10-year risk have an LDL-C goal of <160mg/dL.3 The most important treatment element for patients with an LDL-C baseline of < 160 is risk factor control with re-evaluation in one year. Patients with a baseline of > 160mg/dL require TLC for three months, and if they have an LDL-C value > 190mg/dL, continuation of TLC along with drug therapy should be undertaken.3 If LDL-C levels range between < 160mg/dL and 189mg/dL, patients should continue TLC; drug therapy may be an option for patients with severe hypertension and/or continue to smoke cigarettes.3
Since their introduction in the 1980s, there have been at least seven statins approved by the Food and Drug Administration (FDA) for clinical use, with a total of six currently available for use in the United States.4-10 Tables 2-6 highlight key pharmacologic properties of the six statins, and Table 7 highlights the changes in total cholesterol levels.
Dosing varies depending on the statin used for therapy.4-10 Table 2 provides a summary of initial and maximum doses of the six marketed statins. With the exception of atorvastatin4 and fluvastatin,9 the other statins need to be dose adjusted for renal function. Recommendations for initial doses and maximum doses for renally impaired patients are displayed in Table 3.
Of the six currently marketed statins, simvastatin and lovastatin appear to exhibit the highest propensity for interacting with cytochrome p450 (CYP3A4) isoenzymes, whereas pravastatin does not interact with any of the major metabolic CYP450 isoenzymes.4-10
Table 3 highlights major drug interactions observed with simvastatin, lovastatin, and other statins.
Statins induce varying degrees of LDL-C- and triglyceride-lowering in dyslipidemic patients.4-10 As shown in Table 4 and 5, atorvastatin and rosuvastatin appear to possess the most potent LDL-C- and triglyceride-lowering abilities among the six statins.
Adverse effects associated with statin therapy are generally minor and include abdominal pain, flatulence, constipation and headache, but myopathy and hepatotoxicity represent the most serious toxicities associated with this lipid-lowering drug class.11-13 The true incidence of severe myopathy reported in clinical trials was probably underestimated compared with actual rates in nonstudy situations. Patients in clinical trials represent a select group of individuals with no known contraindications to statins and were monitored closely for appearance of adverse effects. Patient factors that increase the risk of statin-induced myopathy include advanced age, female gender, renal insufficiency, hepatic dysfunction, hypothyroidism, diet (grapefruit juice), and polypharmacy.11-33
Treatment of statin-induced myopathy depends on the severity of signs and symptoms. If a patient presents with an elevated CK level (3-10 times upper limit of normal), weekly CK monitoring should be conducted while continuing the same dose. Patients presenting with CK elevations in excess of 10 times the upper limit of normal should have their statin therapy discontinued and then consider rechallenge, dose reduction, or a switch to another more hydrophilic statin, such as pravastatin.11-13
Hepatotoxicity is a rare adverse effect associated with statins that appears to be a dose-related phenomenon.34-36 Clinically significant ALT elevations (> 3 times upper limit of normal) rarely leads to acute hepatic failure, the rate of which is 1 in one million patient-treatment years.36 The majority of transaminase elevations due to statins usually present within 12-16 weeks from the start of treatment.36 The monitoring plan and treatment of statin-induced elevations in ALT depend on the particular agent and the degree of biochemical abnormality observed in the patient. Table 6 summarizes key liver function monitoring recommendations from the manufacturers of the six marketed statins.
Fibric acid derivatives represent the most effective lipid lowering agents for decreasing triglyceride levels.37-40Gemfibrozil and micronized fenofibrates decrease triglyceride levels by 33% and 28.9%, respectively.
Drug interactions implicated with fibric acid derivatives include potentiating warfarin effects and increased nephrotoxicity risk associated with concomitant administration of fenofibrate and cyclosporine.39,40 Rhabdomyolysis associated with co-administration of fibrates (especially gemfibrozil) with statins has been well-documented in the medical literature.14,17,24,27,31
The most common adverse effects associated with fibric acid derivatives include: rash, nausea, vomiting, diarrhea and dyspepsia.37-40 A dose-related hepatotoxicity associated with fenofibrate therapy can occur, causing an increase of transaminases of three times the upper limit of normal in 5.3% of patients.39,40
Other lipid-lowering agents, such as niacin, are not currently indicated for metabolic changes related to antiretroviral therapy because they can potentially induce acute insulin resistance, a risk equivalent for CHD. 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.41-44 Table 8 summarizes the effects of various niacin formulations on LDL-C, HDL-C, and on triglyceride levels.
The most common adverse effects of niacin derivatives include tingling, itching, rash, headache, and flushing that usually begins 10 to 15 minutes within ingestion and can last up to an hour.42 Recently, extended-release products have been formulated to improve the flushing that is associated with immediate-release formulations.43 Initial treatment with aspirin and a gradual dose-titration can be used to minimize the initial flushing effects of niacin.42
As mentioned earlier, niacin derivatives have the potential to increase insulin resistance during the initial stages of dose titration. In the ADMIT trial45, the mean change in glucose concentration was found to be +8.1mg/dl in diabetic patients receiving immediate-release niacin, while the Hemoglobin A1c remained unchanged. The largest increase in glucose levels (~20mg/dL) occurred during weeks 12 to 18, before declining down to baseline levels. Similarly, a different clinical trial with extended-release niacin46 showed a minor increase in Hemoglobin A1c of approximately 0.3% in patients receiving doses of at least 1500 mg/day.
Other adverse effects of niacin products include gastrointestinal upset and increases in uric acid levels. Relative contraindications for use of niacin include gastroesophageal reflux disorder, gout, and diabetes. Absolute contraindications for niacin use include active peptic ulcer disease and hepatic dysfunction.41-44 The manufacturer of extended-release niacin (Niaspan) recommends that liver function tests should be performed prior to and every 6-12 weeks following treatment initiation during the first year of therapy.43 For any elevation in transaminase in excess of 3 times the upper limit of normal, the manufacturer recommends discontinuing the drug.
Ezetimibe, currently the only drug in its class, acts to decrease cholesterol absorption by acting on the brush border enzymes along the enterocyte lining the intestinal lumen. This results in less LDL-C particles formed due to a decrease in VLDL particles secreted into the blood stream. The decrease in LDL-C particles triggers an increased uptake of LDL-C particles from the systemic circulation.47-48
The potential for drug interactions appears to be minimal, as ezetimibe does not undergo biotransformation by CYP450. Unfortunately, when used as monotherapy, this agent induces modest reductions in LDL-C (18%) and triglycerides (8%). However, when used in combination with a statin, reductions of an additional 11-15% in LDL-C and 7-13% in triglycerides have been reported.47-48
Ezetimibe is available as a 10 mg tablet, taken once daily. It is generally well tolerated with the most common side effects being headache, upper respiratory tract infections, abdominal pain, and diarrhea.47,48
Fish oil supplements (Docosahexaenoic Acid (DHA)/Eicosapentaenoic Acid (EHA)) like Lovaza® induce reductions in triglyceride levels to a degree comparable to the changes observed with fibric acid derivatives.49,50 Although the mechanism of action has not been fully elucidated, some investigators have proposed that DHA/EHA are poor substrates for the enzymes responsible for triglyceride synthesis. In patients with triglycerides > 500mg/dL, triglyceride and non-HDL-C levels have been shown to decrease 44.2% and 13.2% from baseline respectively.49 HDL-C and LDL-C levels increased 9.1% and 44.5% from baseline respectively. Recommended dosing of DHA/EHA (Lovaza) is four grams (4 capsules) daily or split dosing of two grams twice daily.49
The most common adverse effects associated with DHA/EHA include dyspepsia and eructation. Patients concomitantly taking warfarin should exercise caution as the patient has an increased risk of bleeding.49,50
Patients should be encouraged to adhere to TLC along with their lipid-lowering regimens, but if they fail to achieve LDL-C goals or are at risk of myopathy with maximal doses of statins, combination therapy should be considered. Table 9 summarizes the effects of numerous combination lipid-lowering regimens on LDL-C, HDL-C, and on triglyceride levels.
- Calza L, et al. Dyslipidemia associated with antiretroviral therapy in HIV-infected patients. J Antimicrob Chemother. 2004;53:10-14.
- Wohl DA, et al. Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy. Clin Infect Dis. 2006;43:645-653.
- 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.
- Atorvastatin (Lipitor) prescribing information. New York, NY: Pfizer Pharmaceuticals;2005 November.
- Simvastatin (Zocor) prescribing information. Whitehouse Station, NJ: Merck Pharmaceuticals; 2005 August.
- Pravastatin (Pravachol) prescribing information. Princeton, NJ: Bristol-Myers Squibb Company; 2003 March.
- Lovastatin (Mevacor) prescribing information. White House Station, NJ: Merck & Co.; 2005 November.
- Lovastatin (Altocor) prescribing information. Weston, Fl: Andrx Laboratories, Inc.; 2002 July.
- Fluvastatin (Lescol XL) prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2006 April.
- Product information. Crestor. Wilmington, DE. AstraZeneca Pharmaceuticals LP, 2003.
- Newman CB, et al. Safety of atorvastatin derived from analysis of 44 completed trials in 9,416 patients. Am J Cardiol. 2003;92:670-676.
- Jamal SM, et al. Rhabdomyolysis associated with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am Heart J. 2004;147:956-965.
- Thompson PD, et al. Statin-associated myopathy. JAMA. 2003;289:1681-1690.
- Pierce RL, et al. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA. 1990;264:71-75.
- Grunden JW, Fisher KA. Lovastatin-induced rhabdomyolysis possibly associated with clarithromycin and azithromycin. Ann Pharmacother. 1997;31:859-863.
- Gruer PJ, et al. Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol. 1999;84:811-815.
- Shek A, Ferrill MJ. Statin-fibrate combination therapy. Ann Pharmacother. 2001;35:908-917.
- Ballantyne CM, et al. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med. 2003;163:553-564.
- Castro JG, Gutierrez L. Rhabdomyolysis with acute renal failure probably related to the interaction of atorvastatin and delavirdine. Am J Med. 2002;112:505.
- Bottorff M. Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol. 2000;85:1042-1043.
- Hsyu PH, et al. Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother. 2001;45:3445-3450.
- Piliero PJ. Interaction between ritonavir and statins. Am J Med. 2002;112:510-511.
- Cheng CH, et al. Rhabdomyolysis due to probable interaction between simvastatin and ritonavir. Am J Health Syst Pharm. 2002;59:728-730.
- van Puijenbroek EP, et al. Possible increased risk of rhabdomyolysis during concomitant use of simvastatin and gemfibrozil. J Intern Med. 1996;240:403-404.
- Federman DG, et al. Fatal rhabdomyolysis caused by lipid-lowering therapy. South Med J. 2001;94:1023-1026.
- Hare CB, et al. Simvastatin-nelfinavir interaction implicated in rhabdomyolysis and death. Clin Infect Dis. 2002;35:e111-e112.
- Pierce LR, et al. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA. 1990;264:71-75.
- Spach DH, et al. Rhabdomyolysis associated with lovastatin and erythromycin use. West J Med. 1991;154:213-215.
- Lewin JJ 3rd, et al. Rhabdomyolysis with concurrent atorvastatin and diltiazem. Ann Pharmacother. 2002;36:1546-1549.
- Lee AJ, Maddix DS. Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin. Ann Pharmacother. 2001;35:26-31.
- Duell PB, et al. Rhabdomyolysis after taking atorvastatin with gemfibrozil. Am J Cardiol. 1998;81:368-369.
- Modi JR, Cratty MS. Fluvastatin-induced rhabdomyolysis. Ann Pharmacother. 2002;36:1870-1874.
- Evans M, Rees A. Effects of HMG-CoA reductase inhibitors on skeletal muscle: Are all statins the same? Drug Saf. 2002;25:649-663.
- de Denus S, et al. Statins and liver toxicity: A meta-analysis. Pharmacotherapy. 2004;24:584-591.
- Davidson MH, et al. Lipid-altering efficacy and safety of simvastatin 80 mg/day: Worldwide long-term experience in patients with hypercholesterolemia. Nutr Metab Cardiovasc Dis. 2000;10:253-263.
- Gershovich DE, Lyman AE Jr. Liver function test abnormalities and pruritis in a patient treated with atorvastatin: Case report and review of the literature. Pharmacotherapy. 2004;24:150-154.
- Robins SJ, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: A randomized controlled trial. JAMA. 2001;285:1585-1591.
- Rubins HB, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410-418.
- Keating GM, Ormrod D. Micronised fenofibrate: An updated review of its clinical efficacy in the management of dyslipidaemia. Drugs. 2002;62:1909-1944.
- Fenofibrate (Tricor ) prescribing information. North Chicago, IL: Abbott Laboratories; 2004 Nov.
- Knopp RH. Evaluating niacin in its various forms. Am J Cardiol. 2000;86:51L-56L.
- Meyers CD, et al. Varying cost and free nicotinic acid content in over-the-counter niacin preparations for dyslipidemia. Ann Intern Med. 2003;139:996-1002.
- Niacin extended-release tablets (Niaspan) prescribing information. Miami, FL: Kos Pharmaceuticals, Inc; 2005.
- Miller M. Niacin as a component of combination therapy for dyslipidemia. Mayo Clin Proc. 2003;78:735-742.
- 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. Arterial Disease Multiple Intervention Trial. JAMA. 2000;284:1263-1270.
- 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.
- Ezetimibe (Zetia) prescribing information. North Wales, PA: Merck/Schering-Plough Pharmaceuticals; 2006 May.
- Caron MF. Ezetimibe: a novel cholesterol absorption inhibitor. Formulary. 2002;37:628-633.
- Omega-3-acid ethyl esters (Lovaza) prescribing information. Liberty Corner, NJ: Reliant Pharmaceuticals; 2007 June.
- Caron MF, White CM. Evaluation of the antihyperlipidemic properties of dietary supplements. Pharmacotherapy. 2001;21:481-487.
- Rosenson RS. The rationale for combination therapy. Am J Cardiol. 2002;90:2K-7K.
- McKenney J. Combination therapy for elevated low-density lipoprotein cholesterol: The key to coronary artery disease risk reduction. Am J Cardiol. 2002;90:8K-20K.
- Xydakis AM, Ballantyne CM. Combination therapy for combined dyslipidemia. Am J Cardiol. 2002;90:21K-29K.
- Bays H. Existing and investigational combination drug therapy for high-density lipoprotein cholesterol. Am J Cardiol. 2002;90:30K-43K.
- Brown AS. Use of combination therapy for dyslipidemia: A lipid clinic approach. Am J Cardiol. 2002;90:44K-49K