 | | Background | | In HIV-infected people treated with antiretroviral therapy (ART), improved life expectancy and the aging process are likely to increase morbidity and mortality from coronary heart disease (CHD). Thus, identification and reduction of modifiable risk factors for CHD are important aspects of primary care for HIV-infected patients. Several risk factors for CHD are common among HIV-infected populations in the United States and Europe. Dyslipidemia is a well-described independent risk factor for CHD that occurs in a high proportion of patients treated with antiretroviral (ARV) medications. Other metabolic abnormalities such as insulin resistance and diabetes may be caused or compounded by ARVs. In addition, some traditional CHD risk factors, including smoking, hypertension, and inactivity, are prevalent in many HIV-infected populations. Before the widespread use of ARV medications, increases in triglyceride (TG) levels and decreases in total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol were reported in individuals with HIV disease. The introduction of combination ART, particularly the use of protease inhibitors (PIs), increased the prevalence of dyslipidemia in HIV-infected patients. In fact, dyslipidemia is associated with certain agents in each of the 3 major classes of ARVs. In the PI class, ritonavir and ritonavir-boosted PIs (with the exception of atazanavir) are particularly likely to cause marked elevations of TG and LDL levels. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) also may contribute to increases in TC, LDL, and TG levels although the effects, particularly with efavirenz, are more variable. Nucleoside analogue reverse transcriptase inhibitors (NRTIs), specifically stavudine, may increase TC and TG levels. The pathogenesis of ARV-induced dyslipidemia is not well understood. Current research suggests that the dyslipidemia observed in patients taking ART is caused by a combination of factors related to HIV disease, ARV regimens, and individual patient characteristics. Lipid abnormalities may appear or worsen within a few weeks to months after starting ART. Not all ARV-treated patients experience lipid abnormalities to the same degree. Patients with a personal or family history of dyslipidemia, glucose intolerance, diabetes, obesity, or a combination of these health problems may be genetically predisposed to lipid abnormalities that become evident once ART is initiated. Published research regarding the relationship between ARVs and the risk of cardiovascular disease has not been conclusive. The largest prospective study of CHD events related to ARVs (the DAD study), showed a small but significant increase in the risk of myocardial infarction among HIV-infected patients treated with ART; moreover, the effect increased with cumulative years of ARV exposure. While awaiting definitive results from this and other studies, it is important to screen and treat patients for lipid abnormalities and for other known CHD risk factors. For patients with CHD or CHD risk equivalents (see below), ARV regimens should, if possible, be selected to minimize the risk of hyperlipidemia. Guidelines for the evaluation and management of dyslipidemia have been developed by the National Cholesterol Education Program (NCEP). These recommendations and follow-up reports are based on studies of HIV-uninfected patients and may not be entirely applicable to HIV-infected patients. Despite this limitation, expert panels generally recommend similar treatment goals when evaluating and managing dyslipidemia in patients with HIV infection. (For recommendations on screening, see chapter Initial and Interim Laboratory and Other Tests.) | |
| SOAP (Subjective, Objective, Assessment, Plan) | | | Subjective | | The history should focus on factors indicating coronary artery disease or cardiovascular risk. CHD risk factors are conditions associated with a greater risk of serious cardiac events. A CHD risk equivalent, such as diabetes, is considered to be equal in risk to known CHD. Both CHD risks and CHD equivalents should be the focus of lifestyle modification strategies and lipid-normalizing treatment.  | Assess for CHD or CHD equivalents.
| CHD includes a history of myocardial infarction, unstable angina, stable angina, CHD procedures, or evidence of clinically significant myocardial ischemia. | | | CHD equivalents include diabetes, peripheral vascular disease, carotid artery disease, abdominal aortic aneurysm, transient ischemic attacks, or 2 or more CHD risk factors with a 10-year risk of CHD >20% (see "Calculations to Estimate the 10-Year Risk of Cardiac Events for Men and Women", below, or the online risk calculator at http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof). | |
| | | Assess CHD risks. Major risk factors include hypertension, diabetes, smoking, low HDL, age, and family history of CHD. | | | Assess for causes of secondary dyslipidemias, including diabetes, hypothyroidism, obstructive liver diseases, chronic renal failure, and medications such as corticosteroids or progestins. | | | Screen for other factors that contribute to hyperlipidemia, including obesity, chronic liver diseases, alcohol abuse, high-fat or high-carbohydrate diet, and prothrombotic or proinflammatory states. | | | Screen for health behaviors that increase CHD risk, including smoking, high-fat diet, sedentary lifestyle, and use of recreational drugs such as cocaine or methamphetamine. | | | Review the patient's family history for premature CHD, obesity, diabetes, and lipid abnormalities. | | | Review the patient's medications, with special attention to ARVs known to increase LDL or TG levels (particularly ritonavir and ritonavir-boosted PIs) or decrease HDL. | |
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| Objective | | Check vital signs, weight, and height. Calculate body mass index (BMI). See chapter Initial Physical Examination for information on BMI. Perform a focused physical examination with particular attention to signs of hyperlipidemia, such as xanthelasma, and to the cardiovascular system. |
 | | Table 1. Low-Density Lipoprotein Cholesterol Goals and Thresholds for Treatment* | | *Non-HDL cholesterol target levels are 30 mg/dL higher than corresponding LDL cholesterol levels. | | Adapted from: Adult Treatment Panel III, National Cholesterol Education Program. Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. May 2001; NIH publication 01-3670. http://www.nhlbi.nih.gov/guidelines/cholesterol/ | |
| Lower risk: No CHD or CHD equivalents and <0-1 risk factor | LDL ≥160 mg/dL (≥4.1 mmol/L) | ≥190 mg/dL (≥4.9 mmol/L) (at 160-189 mg/dL, LDL drug therapy is optional) | <160 mg/dL (<4.1 mmol/L) | | Moderate risk: No CHD or CHD equivalents and ≥2 risk factors, with 10-year estimated risk <10% | LDL ≥130 mg/dL (≥3.4 mmol/L) | ≥160 mg/dL (≥4.1 mmol/L) | <130 mg/dL (<3.4 mmol/L) | | Moderately high risk: No CHD or CHD equivalents and ≥2 risk factors and 10-year estimated risk 10-20% | LDL ≥130 mg/dL (≥3.4 mmol/L) | ≥130 mg/dL (≥3.4 mmol/L) | <130 mg/dL (<3.4 mmol/L) (optional goal of <100 mg/dL) | | High risk: CHD or CHD equivalent | LDL ≥100 mg/dL (≥2.6 mmol/L) | ≥100 mg/dL (≥2.6 mmol/L) | <100 mg/dL (<2.6 mmol/L) (optional goal of <70 mg/dL) |
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| | Table 2. Classification of Triglyceride Levels | | Hypertriglyceridemia is an independent risk factor for CHD. In addition, severe hypertriglyceridemia (eg, TG >1,000 mg/dL) increases the risk for pancreatitis. Patients with marked TG elevations should be treated to reduce this risk. | |
| Normal triglycerides | <150 mg/dL | | Borderline-high triglycerides | 150-199 mg/dL | | High triglycerides | 200-499 mg/dL | | Very high triglycerides | ≥500 mg/dL |
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| Plan | | | Diagnostic Evaluation | | Before starting ART, obtain baseline fasting lipid panel, fasting glucose, and comprehensive metabolic panel. | Measure serum lipids after the patient has fasted at least 8 hours (ideally 12 hours). Include TC, HDL, TGs, non-HDL cholesterol with calculated LDL, and TC/HDL cholesterol ratio. | |
Repeat the fasting lipid panel within 3-6 months after starting an ARV regimen, and sooner (1-2 months) for patients who have abnormalities at baseline. Patients with normal lipid values should receive annual screening. Those with abnormal values may need more intensive monitoring (eg, every 4-6 weeks) until the LDL goal is met, after which monitoring every 4-6 months is adequate. If a new ARV regimen is begun, repeat the fasting lipid panel at 3-6 months. Treatment of dyslipidemia usually involves a multimodal approach, including diet and exercise in all cases, and potentially including lipid-modifying medication, changes in ARV medication, or both as indicated. The primary goal of lipid-lowering therapy is to reduce LDL to target levels. Very high TG levels, may have to be reduced before LDL is treated directly (see below). Table 1 shows the LDL levels at which either therapeutic lifestyle change (TLC) or drug therapy should be initiated, as well as the target goals for LDL cholesterol. The response to therapy should be monitored and therapeutic interventions should be intensified or augmented until lipid targets are met. | |
| Treatment for Hypercholesterolemia | | All patients with elevated lipid levels should initiate TLC. If pharmacologic intervention is indicated, hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the first-line treatment for most patients. These agents can be effective in reducing TC, LDL, and non-HDL cholesterol levels in HIV-infected patients (Table 3). In patients with serum TGs >400 mg/dL, the LDL cholesterol calculation is unreliable. In this situation, non-HDL cholesterol (TC minus HDL) can be used as a surrogate target of therapy; the non-HDL goal is 30 mg/dL higher than the LDL goal. For these individuals, dietary intervention is warranted, and drug therapy to decrease LDL (or non-HDL) can be considered if TC is >240 mg/dL or HDL cholesterol is <35 mg/dL. For those with TG levels of 200-500 mg/dL, achieving the LDL cholesterol target is the primary goal and lowering non-HDL cholesterol levels is a secondary goal (see Table 1 for LDL intervention levels). (For treatment of high TGs, see "Treatment of Hypertriglyceridemia" below.) Clinicians should note that PIs interact with most statins and can significantly increase serum statin levels, thus increasing the risk of rhabdomyolysis. Of the statin drugs, pravastatin is the least affected by PIs and is the recommended statin for patients with hypercholesterolemia without hypertriglyceridemia. Atorvastatin, if used, must be initiated cautiously and at a low dosage (note that atorvastatin may lower TGs as well as TC and LDL levels). Lovastatin and simvastatin should not be used in patients taking PIs (Table 4). Cerivastatin has been removed from the market in the United States because of reports of fatal rhabdomyolysis. Other available HMG-CoA reductase inhibitors include rosuvastatin and fluvastatin. These agents have not been as well studied as the others, but given their metabolic pathway, no significant interactions with PIs would be expected. Be aware that various formulations and combination products contain
these statins. Check the generic name of components in new or unfamiliar cardiac prescriptions to determine whether they contain lipid-lowering agents. Recommended starting dosages of statins in patients taking PIs are as follows: | Pravastatin: 20 mg orally daily | | | Atorvastatin: 10 mg orally daily | |
Niacin may be effective as adjunctive therapy, but may worsen insulin resistance. Ezetimibe (Zetia) has not been studied thoroughly in HIV-infected individuals, but in HIV-uninfected patients, it has been effective in combination with statins for patients whose cholesterol is not controlled adequately with a statin alone. Bile acid sequestrants generally should be avoided because they may interfere with the absorption of other drugs, and may increase TG levels. When given concomitantly, statins and fibrates increase the risk of rhabdomyolysis; these must be used cautiously and with careful monitoring. |
| | Table 3. Drug Treatments for Lipid Abnormalities | |
| Isolated high LDL, non-HDL cholesterol | Statin | Fibrate | Start with pravastatin or atorvastatin. Use low statin dosages and titrate upward; patients taking PIs may have increased risk of myopathy. | | Isolated high triglycerides | Fibrate | Statin, N-3 (omega-3) fatty acids | Start with gemfibrozil or fenofibrate. Combined statin and fibrate may increase myopathy risk. | | High cholesterol and triglycerides (TG level 200-500 mg/dL) | Statin | Fibrate | Start with pravastatin or atorvastatin. Use fluvastatin, rosuvastatin, gemfibrozil, or fenofibrate as alternative. Combined statin and fibrate may increase myopathy risk. | | High cholesterol and triglycerides (TG level >500 mg/dL) | Fibrate | N-3 (omega-3) fatty acids, niacin, statin | Start with gemfibrozil or fenofibrate. Niacin is associated with insulin resistance. May need to add statin if cholesterol is not controlled adequately. |
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| | Table 4. Interactions between Statin Agents and Antiretroviral Medications* | | * Note that various formulations and combination products contain statins and other lipid-lowering agents. Check the generic name of components in new or unfamiliar cardiac prescriptions to determine whether they contain lipid-lowering agents. | |
| Atorvastatin | | Some CYP3A4 metabolism. | | | Large increase in atorvastatin levels when given with protease inhibitors (PIs). Use lowest possible dosage. Monitor antilipid activity and titrate the statin dosage cautiously. | | | Monitor closely. | |
| | Fluvastatin | | Metabolized by CYP2C9, so no significant interactions with PIs or nonnucleoside reverse transcriptase inhibitors (NNRTIs) are expected. Decreased levels of nelfinavir are likely. | |
| | Lovastatin; Simvastatin | | Extensively metabolized by CYP3A4. Statin levels are increased substantially if coadministered with PIs. These should not be used in patients taking PIs. | |
| | Pravastatin | | Renal excretion and some hepatic metabolism. Levels of pravastatin are increased 30% when it is given with lopinavir/ritonavir. Levels of pravastatin are decreased 35% when it is given with ritonavir/saquinavir and decreased 40% when it is given with efavirenz. The clinical significance of these changes in pravastatin levels is unknown. | | | PI and NNRTI concentrations are not affected. Titrate pravastatin dosage based on antilipid activity. | |
| | Rosuvastatin | | Metabolized by CYP2CP and CYP2C19. Mostly excreted in bile. No significant interactions with PIs or NNRTIs expected. Studies are ongoing. | |
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| Treatment of Hypertriglyceridemia | | Patients with TG levels between 200 and 500 mg/dL should begin non-drug interventions such as diet modification, reduction in alcohol consumption, aerobic exercise, and smoking cessation. When TG level is >500 mg/dL, a low-fat diet (<15% of caloric intake) is recommended to help prevent pancreatitis, and pharmacologic therapy will probably be required. Patients with CHD or CHD equivalents, those at high risk of CHD, and those with TG levels >200 mg/dL may need pharmacologic therapy. Fibrates are the first-line drug option for isolated hypertriglyceridemia and are an alternative treatment for combined hypertriglyceridemia and hypercholesterolemia. Fenofibrate or gemfibrozil reduce TG levels effectively in patients on ARVs. Because they are not metabolized by the cytochrome P450 hepatic enzyme system, they do not have significant drug interactions with ARVs. Fibrates are contraindicated in patients with renal failure. Recommended dosages of these agents are as follows: | Fenofibrate: 50-200 mg orally daily | | | Gemfibrozil: 600 mg orally twice daily, 30 minutes before meals | |
If a fibrate alone is inadequate in reducing TGs, several options are possible. A statin (notably atorvastatin, which acts on TGs as well as cholesterol) could be added cautiously, although there is an increased risk of skeletal muscle toxicity with concomitant use of a fibrate and a statin. N-3 (omega-3) fatty acid supplements, administered at 2 g 3 times a day, have decreased TG levels in patients taking ART. Niacin also decreases both TG and TC levels, although its clinical utility is restricted because of associated insulin resistance and flushing. | |
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| Patient Education | | |
| Review the importance of reducing cardiovascular risk factors. | | | Educate patients about the benefits of diet and exercise in improving lipid levels and reducing cardiovascular risk. | | | If lipid-lowering medications are prescribed, advise patients on possible adverse effects, and advise them to call the clinic if these develop. | |
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| References | | | The appearance of external hyperlinks does not constitute endorsement by the Department of Veterans Affairs of the linked Web sites, or the information, products or services contained therein. | | |
| Adult AIDS Clinical Trials Metabolic Guides: Lipid Disturbances. August 2002. Accessed February 7, 2006. Available online at aactg.s-3.com/metabolic/default.htm. | | | Calza L, Roberto M, Chiodo F. Comparison between switching therapy from protease inhibitors to a NNRTI and lipid-lowering therapy with pravastatin or bezafibrate for the management of HAART-related dyslipidemia. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston. Abstract 859. | | | De Truchis P, Kirstetter M, Perier A, et al. Maxepa-VIH Study Group. Treatment of hypertriglyceridemia in HIV-infected patients under HAART by (n-3) polyunsaturated fatty acids: A double-blind randomized prospective trial in 122 patients. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston. Abstract 39. | | | Dube MP, Stein JH, Aberg JA, et al. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis. 2003 Sep 1;37(5):613-27. | | | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001 May 16;285(19):2486-97. | | | Friis-Møller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003 Nov 20;349(21):1993-2003. | | | Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004 Jul 14;292(2):191-201. | | | Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004 Jul 13;110(2):227-39. | | | Martinez E, Arnaiz JA, Podzamczer D, et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. N Engl J Med. 2003 Sep 11;349(11):1036-46. | | | Milinkovic A, Lopez S, Vidal S. A randomized open study comparing the effect of reducing stavudine dose vs switching to tenofovir on mitochondrial function, metabolic parameters, and subcutaneous fat in HIV-infected patients receiving antiretroviral therapy containing stavudine. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston. Abstract 857. | | | Moyle G, Sabin C, Cartledge J, et al. A 48-week, randomized, open-label comparative study of tenofovir DF vs abacavir as substitutes for a thymidine analog in persons with lipoatrophy and sustained virological suppression on HAART. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston. Abstract 44LB. | | | National Cholesterol Education Program (NCEP), National Heart, Lung, and Blood Institute, National Institutes of Health. Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). NIH Publication No. 02-5215. September 2002. Available online at www.nhlbi.nih.gov/guidelines/cholesterol/index.htm. | | | Schambelan M, Benson CA, Carr A, et al. Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel. J Acquir Immune Defic Syndr. 2002 Nov 1;31(3):257-75. | | | Shor-Posner G, Basit A, Lu Y. Hypocholesterolemia is associated with immune dysfunction in early human immunodeficiency virus-1 infection. Am J Med. 1993 May;94(5):515-9. | | | Sension M, Grinsztejn B, Molina J. A1424067: Improvement in lipid profiles alter 12 weeks of switching to atazanavir from boosted or unboosted protease inhibitors in patients with no previous PI virologic failure and hyperlipidemia at baseline. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston. Abstract 858. | | | Stein JH. Managing cardiovascular risk in patients with HIV infection. J Acquir Immune Defic Syndr. 2005 Feb 1;38(2):115-23. | |
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