Dyslipidemia in the era of HIV protease inhibitors

Dyslipidemia in the Era of HIV Protease Inhibitors James H. Stein

Human immunodeficiency virus protease inhibitors are associated with metabolic abnormalities that may increase risk of atherosclerotic vascular disease, including dyslipidemia, insulin resistance, and central obesity. Dyslipidemia, characterized by hypercholesterolemia and hypertriglyceridemia, small low- and high-density lipoprotein particles, and in some cases lipoprotein(a) excess, can be severe and has been associated with endothelial dysfunction and carotid atherosclerosis. The mechanisms underlying protease inhibitor-associated dyslipidemia have not been elucidated completely, but appear to involve hepatic overproduction of very low-density lipoproteins and to a lesser extent, impaired clearance. Insulin resistance appears to mediate part of the adverse lipoprotein changes observed in patients taking protease inhibitors. Ongoing epidemiological and surrogate endpoint studies are investigating the atherogenicity of these medications. Until the risk associated with use of protease inhibitors is better understood, identifying patients at high risk for adverse vascular events such as heart attacks, cardiac death, and stroke is a high priority. This article reviews the lipid and lipoprotein abnormalities associated with use of protease inhibitors, possible mechanisms for protease inhibitor-associated dyslipidemia, its potential atherogenicity, and use of the National Cholesterol Education Program Adult Treatment Panel III Guidelines for the management of patients with dyslipidemia. Copyright 2003, Elsevier Science (USA). All rights reserved.

H

uman immunodeficiency virus (HIV) protease inhibitors (PIs) confer striking immunologic and clinical benefits that have led to their widespread acceptance as key components of antiretroviral therapy in patients with HIV infection. Unfortunately, up to 60% of patients receiving HIV PIs develop hyperlipidemia, hyperglycemia, and central obesity.1,2 Because these morphologic

and metabolic changes adversely affect several risk factors for atherosclerotic vascular disease, there is great concern that cardiovascular disease may become an important acquired immune deficiency syndrome (AIDS)-related complication.2,3 Indeed, case reports of severe premature coronary artery disease (CAD) in patients receiving HIV PIs already have appeared in the medical literature.4,5 This article focuses on the lipid and lipoprotein abnormalities associated with use of HIV PIs, use of the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III guidelines for the management of patients with this disorder, possible mechanisms for PI-associated dyslipidemia, its potential atherogenicity, and treatment of PI-associated dyslipidemia.

Dyslipidemia Associated With HIV Infection Patients with HIV infection have abnormal lipid metabolism, even in the absence of highly active antiretroviral therapy (HAART) (Table 1).6 It is characterized by hypocholesterolemia with low levels of both low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), a finding that precedes the appearance of hypertriglyceridemia.6,7 Hypertriglyceridemia in patients with AIDS is associated with increases in very low density lipoproteins (VLDL) with nor-

From the Section of Cardiovascular Medicine, University of Wisconsin Medical School, Madison, WI. Address reprint requests to James H. Stein, MD, Section of Cardiovascular Medicine, University of Wisconsin Medical School, H6/315 Clinical Science Center (3248), 600 Highland Ave, Madison, WI 53792. Copyright 2003, Elsevier Science (USA). All rights reserved. 0033-0620/03/4504-0001$30.00 doi:10.1053/pcad.2003.3

Progress in Cardiovascular Diseases, Vol. 45, No. 4, (January/February) 2003: pp 293-304

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Table 1. Hyperlipidemia With HIV Infection Before HAART Hypertriglyceridemia Hypocholesterolemia Low HDL-C and LDL-C Small LDL particles Associated with disease progression Improves with zidovudine, omega-3 fatty acids

mal lipid content and triglyceride-enriched LDL and HDL particles.6 Hypertriglyceridemia appears to be caused by delayed clearance of triglyceriderich lipoproteins, resulting in small, dense LDL particles, however, increased de novo hepatic lipogenesis also has been described and appears to be related to interferon-␣ levels in AIDS patients with weight loss.6-8 Hypertriglyceridemia becomes prominent as asymptomatic HIV infection transitions to AIDS in the presence of an increasing viral load and increased levels of interferon␣.6 The magnitude of the hypertriglyceridemia is related, in part, to the apolipoprotein E (apo E) phenotype and apo E sialylation.9 Both hypocholesterolemia and hypertriglyceridemia are associated with disease progression,10 and zidovudine therapy or omega-3 fatty acid supplementation lower triglyceride levels.6,11,12

Dyslipidemia Associated With HIV PIs With the advent of HAART, specifically the use of HIV PIs, hyperlipidemia has become more common and is more severe.1,2,13-16 In the Swiss HIV Cohort, hypercholesterolemia and hypertriglyceridemia were 1.7 to 2.3 times more likely to occur in individuals on PIs containing HAART.17 Hypercholesterolemia (⬎240 mg/dL) and hypertriglyceridemia (⬎500 mg/dL) were identified, respectively, in 60% and 75% of subjects receiving HIV PIs at a tertiary care medical center with incident rate ratios of 2.8 and 6.1 attributable to use of these medications.15 Increased levels of total cholesterol characterize the dyslipidemia associated with use of HIV PIs, with most of the increase in VLDL and intermediate-density lipoproteins (IDL) (Table 2).13,18-20 Increased LDL-C may be detected if measured directly, but this finding is inconsistent.13,18,20 HDL-C tends not to change; however, variable changes in small and large HDL particles have been described.19,20 Hypertriglyceridemia is com-

Table 2. Hyperlipidemia With HIV Infection After HAART Hypercholesterolemia Mostly VLDL-C and IDL-C LDL-C may increase HDL-C tends not to change Hypertriglyceridemia Especially with ritonavir Seen in all lipoprotein subfractions Small LDL and HDL particles Increased apolipoprotein B-100 Increased lipoprotein (a), especially if elevated before

mon and may be especially severe in patients taking ritonavir (Table 2).13,19 Increased triglyceride concentrations have been found in all lipoprotein fractions and are accompanied by increased levels of apolipoprotein B-100, which is associated with increased vascular risk.13,18-22 Similar findings also have been observed in children with HIV-1 infection.23 Lipoprotein (a) excess has been described inconsistently, but may be especially prominent in individuals with high levels before the initiation of HAART.13,19,22

Mechanisms of HIV PI-Associated Dyslipidemia The mechanism(s) by which use of HIV PIs lead to dyslipidemia have not been elucidated, however, several hypotheses have been the subject of intensive investigation (Table 3). Despite superficial similarities between HIV lipodystrophy and other disorders of the hypothalamic-pituitary-adrenal axis, there is no evidence that the metabolic abnormalities observed in people taking PIs is caused by hypercortisolism.18,24

Table 3. Possible Mechanisms for PI-Associated Dyslipidemia Impaired lipoprotein clearance Inhibition of LRP with down-regulation of the LDL receptor Abnormal regulation of apo C-III* Inhibition of LPL Impaired lipoprotein–cell surface interactions Impaired CRABP-1 Increased hepatic cholesterol and triglyceride synthesis Increased hepatocyte accumulation of SREBP-1c* Decreased proteasome activity Improved nutritional status Impaired CRABP-1 Increased hepatic substrate delivery* *May be exacerbated by insulin resistance.

DYSLIPIDEMIA AND HIV PIs

An early hypothesis suggested that PI-associated dyslipidemia was caused by inhibition of the LDL-receptor–related protein (LRP) by HIV PIs.25 LRP is a hepatic receptor that plays a critical role in clearance of apo E– containing particles such as chylomicrons, VLDL, and their remnants. A 12 amino acid sequence (aa 19-30) that spans the catalytic site of HIV-1 protease was found to be 63% homologous with the lipid-binding domain in LRP. LRP is expressed on the capillary endothelium with lipoprotein lipase and this complex cleaves fatty acids from circulating triglycerides, allowing them to be stored in adipocytes. Binding of hepatic and endothelial LRP by HIV PIs could, therefore, lead to hypertriglyceridemia, however, this hypothesis has not been tested. Indirect evidence that HIV PIs inhibit LRP comes from the observation that hemophiliac patients receiving these medications bleed more frequently, possibly because LRP also is the clearance receptor for tissue plasminogen activator and increased levels of tissue plasminogen activator may predispose to bleeding.26,27 PI-mediated inhibition of LRP would be expected to increase lipid concentrations in chylomicrons, VLDL, and their remnants, as have been observed clinically.19,20 In mice, inactivation of the hepatic LRP gene only was associated with hyperlipidemia if the LDL receptor also was disrupted, however, decreased LDL receptor activity has been described in patients receiving HAART.28-30 In a 2-week, double-blind, placebo-controlled study of 21 healthy volunteers, post– heparin lipoprotein lipase activity did not increase in individuals receiving ritonavir, although hepatic lipase activity decreased by 20%.19 In general, decreased levels of hepatic lipase are associated with larger, more buoyant, and less atherogenic LDL particles with more cholesterol in larger HDL2 particles. These findings, however, were not observed in this study and others.19,20 Because weight remained stable in this study, it is unlikely that the observed lipoprotein and enzyme changes could be attributed to changes in body composition, however, the generalizability of these results to individuals with HIV infection undergoing immune reconstitution and on long-term PI therapy is not clear. Because the primary lipoprotein abnormality was an increase in VLDL particles, hepatic overproduction is the most likely cause of the hypertriglyceridemia observed in this study.19 The hepatic overproduction hypothesis is sup-

295 ported by the demonstration that in HepG2 cells, several protease inhibitors (ABT-372, saquinavir, nelfinavir, and ritonavir) increased triglyceride synthesis, and that ritonavir also increased cholesterol synthesis.31 In fasting mice treated with a nonionic detergent that inhibits triglyceride clearance, nelfinavir and ritonavir more than doubled triglyceride levels.31 Impaired remnant clearance cannot be excluded, however, because animal models and single-cell models do not adequately reflect the complexity of human lipoprotein metabolism, especially in the presence of chronic infection and multidrug therapy. Indeed, recent studies suggest that insulin resistance and variable expression of apolipoprotein C-III gene polymorphisms in the presence of PIs may mediate dyslipidemia.32 Apo C-III is a plasma inhibitor of VLDL lipolysis that interferes with clearance of remnant lipoproteins, directly inhibits LPL, and interferes with binding of lipoproteins to the glycosaminoglycan cell-surface matrix where lipolytic enzymes and lipoprotein receptors are located.33 Apo C-III also inhibits HL.34 Several polymorphisms in and around the apo C-III gene have been identified, some of which have been associated with hypertriglyceridemia and elevated levels of remnant lipoproteins (SstI).32,33 Variants in 2 polymorphic sites in the promoter region of apo C-III (⫺455 and ⫺482) have been found in a putative insulin-response element and at least 2 nucleotide substitutions have been identified at these sites that impair insulin-mediated suppression of apo C-III promoter activity.32,35 During HIV treatment there is a very strong association between PI therapy, apo C-III variants, and dyslipidemia characterized by hypertriglyceridemia and low HDL-C.32 Although there was no association between apo E genotype and lipid levels, apo E4 carriers had higher levels of remnant lipoproteins, in agreement with a previous report that this allele is associated with HIV PI-associated dyslipidemia.32,36,37 Based on these findings, another hypothesis has been advanced suggesting that HIV PIs may interfere with normal regulation of the apo C-III that, in conjunction with a variant allele, would lead to overexpression of apo C-III.32 Also, the promoter region of apo C-III contains a peroxisome-proliferator-activated receptor–retinoic acid receptor recognition element.38 Based on homology between HIV-1 protease and cytoplasmic retinoic acid binding protein (CRABP-1), it has been hy-

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Although none of these mechanisms adequately explain all of the metabolic abnormalities seen in patients with PI-associated dylipidemia or lipodystrophy, they provide promising avenues for research and are very active areas of investigation. It is likely that PI-associated dyslipidemia is a very complex and multifactorial process with multiple abnormalities affecting hepatocytes, adipocytes, and endothelial enzymes.

Fig. 1. One model for PI-associated dyslipidemia. Adapted from Mooser et al.29

Are the Metabolic Changes Associated With HIV PIs Atherogenic?

pothesized that PIs may impair activation of the peroxisome-proliferator-activated receptor ␣– retinoic acid receptor heterodimer, thus affecting the transcription of several genes involved in lipid metabolism.25,32 Substitutions in insulin-response elements, in conjunction with drug-induced impairment of peroxisome-proliferator-activated receptor ␣–retinoic acid receptor function, could lead to defective down-regulation of apo C–III synthesis, increased apo C–III activity, and hypertriglyceridemia with remnant lipoprotein excess.32 This hypothesis does not fully explain why HIV PIs and genetic apo C–III variations do not significantly affect apo C–III levels, yet have greater effects on apo E and triglyceride levels.32 It does, however, provide a plausible link between HIV PI-associated hyperlipidemia and insulin resistance, which is associated with PI therapy.39 This topic is discussed in the symposium by Dr. Kotler elsewhere in this issue. In mice, administration of ritonavir leads to activation of genes under the control of sterol-regulatory element-binging protein (SREBP)-1c.40 SREBP-1c transcription does not appear to increase, suggesting that inhibition of proteasome activity may lead to increased levels of SREBP-1c and apo B-100 in hepatocytes.29,41 Other mechanisms that may increase hepatic SREBP-1c in patients on HIV PIs include improved nutritional status, hyperinsulinemia, and impaired function of CRABP-1 (as earlier, Fig 1).29 Furthermore, increased levels of SREBP-1c have been described in 3T3 preadipocytes after exposure to ritonavir and in a mouse model of congenital lipodystophy.29,42,43 If the resulting hypoleptinemia worsens insulin resistance, hepatic overexpression of SREBP-1c also may increase, further contributing to dyslipidemia.29

Although the morphologic and metabolic changes associated with use of HIV PIs superficially resemble an atherogenic lipoprotein profile, type II diabetes mellitus, and a body fat distribution associated with CAD, it is not clear if they truly represent increased risk for atherosclerotic vascular disease. Many of the individuals described in the case reports had hyperlipidemia before using these medications or had other risk factors for atherosclerotic vascular disease such as cigarette use, cocaine use, and/or being middle-aged men. Registry data ascertained from discharge diagnoses of members of the Kaiser Permanente Northern California health maintenance organization allowed the identification of 4,541 HIV-positive individuals who had 53 myocardial infarctions, encompassing 14,703 patient-years.44 The CAD event rate for individuals with HIV infection was higher than in HIV-negative controls, but use of PIs did not increase risk.44 In an update presented at the 9th Conference on Retroviruses and Opportunistic Infections, these investigators45 reported after 5.5 years of follow-up that the rate of CAD events remained higher among HIV-infected cases (P ⫽ .003) and there was a trend toward more myocardial infarctions, but there still was no association between treatment and risk for CAD. Furthermore, an analysis of 8.5 years of data from the Immunology Case Registry of the Veterans Administration AIDS Service did not reveal increased rates of CAD events.46 In this abstract, the 36,766 HIV-infected patients seen for an average of 40 months had 121,936 patient-years of follow-up. All-cause mortality declined and cardiovascular deaths did not change. A small decline was seen in hospitalizations for cardiovascular events. In contrast, the data from the French Hospital Database on HIV, which was started in 1989, identified 54 myocardial infarctions among 19,795 individuals exposed to HIV PIs, encompassing

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36,907 patient-years of treatment.47 The standardized mortality rate relative to the general population was 1.7 for individuals who had been taking HIV PIs for at least 18 months and 3.7 for individuals who had been taking PIs for greater than 30 months. Both of these increases were statistically significant and similar values were obtained as compared with HIV-positive individuals.47 Likewise, in a cross-sectional assessment of 5,676 ambulatory HIV-infected patients from 9 clinics participating in the HIV Outpatient Study, the incidence of myocardial infarction increased after the introduction of HIV PIs (P ⫽ .0124).48 Data were collected from patients seen between 1993 and 2001. The unadjusted odds ratio, based on the incidence of myocardial infarction in 13 of 3,013 individuals taking HIV PIs, was 5.77 (P ⫽ .009), and this remained statistically significant after adjustment for standard risk factors. In summary, observational data from various cohorts have yielded conflicting results. All of these studies are limited by a low incidence of adverse coronary heart disease events, use of discharge or other diagnostic codes to ascertain events, lack of data regarding medication compliance, and nonsystematic assessment of CAD risk factors. Long-term follow-up and more systematic data analysis, preferably in the context of prospectively designed cohort trials, is needed before reliable estimates of the CAD risks associated with HIV infection and its treatment are understood. While we await such data, surrogate end-point data also suggests that the metabolic changes in patients taking HIV PIs are atherogenic. In 2 crosssectional studies, use of PIs was associated with an increased incidence of carotid atherosclerotic plaque as compared with HIV-positive individuals not taking HIV PIs and HIV-negative controls49,50; however, one study did not find this association.51 Furthermore, HIV-infected women with lipodystrophy also have been reported to have increased carotid intima-media thickness, compared with age-, sex-, and race-matched population controls.50 The presence of carotid atherosclerosis and increased carotid intima-media thickness has been associated strongly with future CAD events, as discussed elsewhere in this issue.52,53 Use of PIs has been associated with endothelial dysfunction, an early and initiating step in atherosclerosis that predicts future adverse cardiovascular events.20,54-56 In a cross-sectional study of 37 HIV-infected individuals, subjects receiving PIs

had significantly impaired endothelial function, the main predictor of which was the use of a PI.20 In subjects receiving HIV PIs, triglyceride-rich lipoproteins and cholesterol-rich remnants predicted endothelial dysfunction, suggesting that the metabolic changes associated with PIs, especially dyslipidemia, might increase cardiovascular risk. The association between use of HIV PIs and endothelial dysfunction has been verified independently by 2 other investigators.57,58 Finally, a recent report suggests that saquinavir and amprenavir interfere with HDL activity by up-regulating macrophage scavenger receptor class B-type I, leading to increased cholesterol uptake and foam cell formation.59 Thus, the weight of evidence from laboratory and atherosclerosis imaging studies suggests that PI-associated metabolic changes are atherogenic.

Application of NCEP ATP III Guidelines The most important focus of the NCEP ATP III guidelines is adjusting the intensity of risk reduction therapy to the patient’s risk for having a CAD event.60 In the new guidelines, the highest-risk patients, those with established CAD, are treated most aggressively with an LDL-C target of less than 100 mg/dL. In addition, patients without established CAD, but with a similar 10-year risk for having a myocardial infarction or dying of CAD (⬎20%), are considered to have a coronary risk equivalent and are treated as aggressively. Patients with coronary risk equivalents include those with type II diabetes mellitus, cerebrovascular disease, peripheral vascular disease, an abdominal aortic aneurysm, or multiple risk factors that lead to a 10-year risk estimate of greater than 20%.60 In NCEP ATP III, the first step in risk assessment is counting the number of categoric risk factors that modify LDL-C goals. These include cigarette smoking, hypertension (blood pressure ⱖ140 mm Hg or on antihypertensive medication), low HDL-C (⬍40 mg/dL), family history of premature coronary heart disease (male first-degree relative ⬍55 years old, female first-degree relative ⬍65 years old), and advanced age (men ⱖ45 years old, women ⬎55 years old). For patients who have 2 or more risk factors for CAD, a risk assessment tool based on the Framingham Heart Study is used to estimate the 10-year risk for myocardial infarction or sudden cardiac death. The advan-

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Table 4. Lipid Goals and Cutpoints for Therapy in NCEP ATP III

Risk Category

LDL-C Goal

LDL-C to Initiate Therapeutic Lifestyle Change

Coronary heart disease or risk equivalent ⱖ 2 risk factors and 10-year risk ⱕ 20% 0-1 risk factors

⬍100

ⱖ100

ⱖ130*

⬍130

⬍130

ⱖ130

⬍160

⬍160

ⱖ160

10-year risk 10% to 20%: ⱖ130 10-year risk ⬍10%: ⱖ160 ⱖ190†

LDL-C to Consider Drug Therapy

Non–HDL-C Goal

⬍190

*LDL-C 100-129 mg/dL, drug therapy optional, consider treating HDL-C and triglyceride disorders. †LDL-C 160-189 mg/dL, drug therapy optional.

tages of risk assessment based on Framingham data are that it is easy to use, accurately relates independent CAD risk factors to an individual’s CAD risk, and it identifies a low-risk state that can serve as the denominator to assess the impact of risk factors in individuals. It also is accurate in white and black American populations and reasonably accurate with recalibration in Hispanic, Japanese, Native American, and European populations.61-63 Unfortunately, it does not account for predisposing risk factors such as obesity, physical inactivity, and socioeconomic status, or conditional risk factors such as triglycerides, lipoprotein(a), lipoprotein particle size, homocysteine, and high-sensitivity C-reactive protein levels. It also does not account for genetic susceptibility (eg, family history).61,62 Several (but not all) of these parameters have been evaluated by the Framingham investigators and they did not provide independent, incremental predictive value to the parameters included in assessment, however, their affect on individual coronary heart disease risk should not be ignored. It is especially relevant to patients with HIV infection that published risk-prediction algorithms address short-term (10-year) risk, which may not be the appropriate time frame for young patients. Furthermore, Framingham algorithms do not account for duration of exposure to risk factors. Someone who smoked heavily but quit more than a year before evaluation is assessed the same as a lifelong nonsmoker. On the other hand, a lipid abnormality may not have been present before HIV infection or use of some HIV PIs. The Framingham algorithm underestimates severe abnormalities of individual risk factors, such as heavy tobacco use, severe dyslipidemia, or severe hypertension. Finally, age is the primary factor in risk assessment by this technique. On a population basis, younger individuals are at very low risk

of a short-term (10-year) coronary heart disease event, however, those with extreme risk factor abnormalities may represent a large burden of young individuals with coronary heart disease events.61,62 With these caveats, use of categoric risk factors and Framingham risk assessment is a good starting point and considering conditional and predisposing risk factors (as outlined previously) may help refine risk estimates in individuals. After determining the appropriate risk category, LDL-C goals are identified next, as in Table 4.60 A new feature of the NCEP ATP III guidelines is that an HDL-C less than 40 mg/dL is considered low. Furthermore, a triglyceride level less than 150 mg/dL is defined as normal and greater than 200 mg/dL is defined as high. Although LDL-C remains a primary target for most patients, if severe hypertriglyceridemia (ⱖ500 mg/dL) is present, triglyceride reduction becomes a primary target. If moderate triglyceride elevations are present (200500 mg/dL), non-HDL cholesterol (non–HDL-C) becomes a secondary target for therapy after LDL-C levels have reached the goal level (Table 4).60 Non-HDL cholesterol is obtained by subtracting HDL-C from total cholesterol. Non-HDL cholesterol correlates well with apolipoprotein B-100 levels and represents all cholesterol carried by all lipoproteins currently considered to be atherogenic, including LDL, VLDL, IDL, and lipoprotein(a).60,64 It is useful in individuals with high triglyceride levels because it makes no assumptions about the relationship between triglycerides and VLDL cholesterol (VLDL-C) levels, such as are inherent in the Friedewald formula for estimating LDL-C. Its use also makes treatment of triglyceride disorders less confusing. Non-HDL cholesterol is an independent predictor of cardiovascular events.64,65 The non-HDL cholesterol target for each risk category is simply 30 points

DYSLIPIDEMIA AND HIV PIs

higher than the corresponding LDL-C target, representing the normal VLDL-C concentration. Finally, the NCEP ATP III has identified metabolic syndrome as a secondary target for intervention. Metabolic syndrome is characterized by central (abdominal) obesity accompanied by hyperinsulinemia with or without glucose intolerance. It is associated with an increased future risk of developing type II diabetes mellitus; hypertension, hyperuricemia, a prothrombotic state, and a proinflammatory state frequently are present, as is an atherogenic lipoprotein phenotype (low HDL-C, hypertriglyceridemia, and small dense LDL particles).60 Although metabolic syndrome superficially resembles HIV PI-associated lipodystrophy in that high insulin levels, an atherogenic lipoprotein profile, and central obesity are present, they differ in that lipoatrophy and the development of a dorsocervical fat pad are not present with metabolic syndrome. It is not known if the prognostic implications of PI-associated lipodystrophy are the same as in metabolic syndrome. Guidelines for the diagnosis of metabolic syndrome are presented in Table 5. Patients with metabolic syndrome are encouraged to lose weight, predominantly by balancing caloric intake and expenditure to obtain and maintain a desirable body weight.60 This involves dietary modification and increased physical activity. It also involves treatment of CAD risk factors associated with metabolic syndrome including hypertension, prothrombotic state, and atherogenic dyslipidemia.

Treatment of PI-Associated Dyslipidemia (Table 6) Intuitively, the most straightforward approach to treating PI-associated dyslipidemias is to switch to a PI that is less likely to cause dyslipidemia or to a non–PI-containing regimen, a strategy that may be particularly effective if the patient is taking

Table 5. NCEP ATP III Guidelines for Diagnosis of Metabolic Syndrome Waist circumference ⬎40 in in a man, ⬎35 in in a woman Triglyceride level ⱖ150 mg/dL HDL-C ⬍40 mg/dL in a man, ⬍50 mg/dL in a woman Blood pressure ⱖ130/85 mm Hg Fasting plasma glucose ⱖ110 mg/dL NOTE. Requires 3 or more of the factors listed.

299 Table 6. Treatment of HIV PI-Associated Dyslipidemia Switch antiviral therapy, if possible PI-sparing regimen PI with less adverse lipid effects Diet Calorie restrict to ideal body weight Modest carbohydrate restriction, more protein as tolerated Substitute mono- and omega-3 polyunsaturated fats for other dietary fats Medications Statins for increased LDL-C, increased triglyceride level (if ⬍500 mg/dL) Fibrates for increased triglyceride level if ⱖ500 mg/dL Fish oils: second-line treatment for increased triglyceride levels Niacin: second-line treatment for all dyslipidemias

ritonavir (Table 6). In some studies, substituting nonnucleoside reverse-transcriptase inhibitors for the PI had a beneficial effect.14,66,67 This is discussed in the recommendations of the Adult AIDS Clinical Trial Group (ACTG) Cardiovascular Disease Focus Group for the evaluation and management of dyslipidemia in adults with HIV and receiving antiretroviral therapy.14 Switching therapy to a non–PI-containing regimen currently is being investigated in a randomized study sponsored by the ACTG 5103. Use of nevirapine may be especially useful for increasing HDL-C levels.68 Atazanavir, a new PI, appears to have neutral lipid effects and similar antiviral efficacy as other PIs, making it an attractive agent from a lipid standpoint for treatment of HIV infection.69 Currently, however, immunologic and virologic considerations—such as antiviral efficacy, induction of resistance, or viral relapse—should take priority over dyslipidemia in managing HIV infection. Dietary modification involves institution of therapeutic lifestyle changes (TLCs) as defined by the NCEP ATP III.60 TLCs involve increased physical activity, weight reduction, dietary modification, and increased physical activity. The TLC diet involves reduced intake of cholesterol-increasing nutrients similar to the previous Step II diet, such that saturated and trans-fatty acids account for less than 7% of daily caloric intake and dietary cholesterol is reduced to less than 200 mg/d. A similar diet was associated with a small reduction in LDL-C in a trial of dietary intervention.70 In TLC, dietary fat at can make up 25% to 35% of daily caloric intake, provided that intake of saturated and trans-fat is restricted. This allows for an

300 increased use of omega-3 polyunsaturated fats, which have triglyceride-lowering effects in addition to preventing sudden cardiac death. Good sources of omega-3 polyunsaturated fats include fatty fish (eg, salmon, mackerel, sardines, and tuna) and foods rich in ␣-linolenic acid (eg, scallops, flax, and certain nuts). It also allows for the increased intake of monounsaturated fats (up to 20% of total calories) that are found in olive oil, canola oil, certain nut oils, and avocadoes. The use of monounsaturated fats instead of other fats can lead to improvements in HDL-C levels. Increased fiber intake also is an important part of the diet (20-30 g/d) with an emphasis on soluble fiber (10-25 g/d). This modification can lower cholesterol levels by 5% to 8% if used along with dietary cholesterol restriction (⬍200 mg/d). Indeed, low intake of fiber and high intake of polyunsaturated fats (all, not omega-3) has been associated with insulin resistance and hyperlipidemia, making them attractive but as yet unstudied targets for dietary modification.71 Finally, increased use of plant stanol/sterol margarines (2 g/d) can lead to additional LDL-C reductions of 10% to 14%.60 For many patients, TLC is not enough to normalize lipids and pharmacologic therapy is required; however, patients receiving HIV PIs may be at higher risk for side effects, such as myopathy and elevated hepatic transaminase levels.70,72 For patients above their LDL-C targets in whom triglyceride levels are less than 500 mg/dL, statins are the preferred agents because they are proven to reduce coronary events and effectively reduce LDL cholesterol by 18% to 55% and triglyceride levels by 7% to 30%.4,14,60,70,73,74 Principal side effects include reversible elevations in hepatic transaminase levels, myalgia, and, rarely, myopathy with rhabdomyolysis. In a retrospective study of 115 patients on PIs and statins (mostly atorvastatin), the rate of myopathy or hepatitis was 7.5% compared with 0.3% in HIV-negative historic controls, so caution is necessary when prescribing these medications.72 The use of statins metabolized by cytochrome P-450 3A4 is discouraged because serum levels can increase dramatically in the presence of HIV PIs. The most significant pharmacokinetic effect has been noted with simvastatin, for which nelfinavir increased the area under the curve (AUC) by 505% and the maximum concentration by 517%.75 Even more dramatic increases in simvastatin concentrations were observed in combination with ritonavir and

JAMES H. STEIN

saquinavir, however, simvastatin also was associated with a reduction in saquinavir levels.68 Accordingly, simvastatin and the structurally similar lovastatin should be avoided in patients taking PIs. Lesser effects have been observed with atorvastatin for which nelfinavir increased its AUC by 74% and the maximum concentration by 122% and both ritonavir and saquinavir increased its AUC by 79%.68,76 More significant increases were seen when atorvastatin was used in HIV-negative individuals in combination with ABT-378/ritonavir.77 Although fluvastatin is not metabolized by cytochrome P-450 3A4, its antilipidemic effects are quite weak and this medication may not be very effective. Pravastatin also is not metabolized by this mechanism, however, its serum concentrations may be decreased by ritonavir and saquinavir and increased slightly (1.3-fold) by ABT-378/ ritonavir.68,77 Although it appears to be safe to use in patients taking PIs, and relatively safe in combination with fibrates, its effects on total cholesterol, LDL-C, and triglyceride levels are modest.70 Because of safety considerations, pravastatin may be considered as a first-line agent for treatment of PI-associated dyslipidemia. Atorvastatin may be used with caution, starting with low doses and titrating appropriately when additional lipid lowering is needed.4,78,79 Bile acid sequestrants can be used as second-line agents in patients with elevated LDL-C levels, however, they should be avoided in individuals with triglyceride levels greater than 200 mg/dL because of their tendency to worsen hypertriglyceridemia. Colesevalam, a new bile acid sequestrant, is better tolerated than older resins such as cholestyramine. It is available as a pill and causes less constipation and flatulence. It also does not significantly bind other medications, which is of special importance to patients with HIV on complex medical regimens. Fibric acid derivatives are the first choice of therapy for patients with severe hypertriglyceridemia (⬎500 mg/dL).14,60 They are proven to reduce coronary events in patients with lesser degrees of hypertriglyceridemia in the presence of hypercholesterolemia or low levels of HDL-C.80,81 Their principal side effects are abdominal discomfort, hepatotoxicity, and myopathy with rhabdomyolysis. In a retrospective study of 81 patients on PIs and fibrates (mostly gemfibrozil), the rate of myopathy or hepatitis was 1.5%, so caution also is necessary when prescribing these medications.72 Fibrates reduce triglyceride levels by 20% to 50%

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and increase HDL-C levels by 10% to 20%. Only one small uncontrolled study has been published showing the effect of gemfibrozil in patients taking HIV PIs; however, a 16-week placebo-controlled trial of 36 patients only showed modest efficacy (24% reduction in serum triglyceride levels) with gemfibrozil treatment.79,82 More significant reductions have been seen in individuals with profound hypertriglyceridemia (⬎1,000 mg/dL) with fenofibrate and bezafibrate.83,84 Adverse effects on immune parameters were not observed. As triglyceride-lowering agents, fibrates have less effect on cholesterol-rich lipoproteins and in many patients are unlikely to normalize the lipid profile. The effects of pravastatin, fenofibrate, and their combinations currently are being investigated in an ACTG 5087. The combination of a statin and a fibrate should be used only with caution because of an increased risk for myopathy and rhabdomyolysis. Niacin, which lowers LDL-C, triglyceride, and Lp(a) levels, and increases HDL-C levels, is an attractive therapy, however, it can cause insulin resistance and at higher doses can be hepatotoxic. Other side effects include flushing, hyperuricemia, and dry skin. Combination therapy with statins also increases the risk for myopathy, but generally is well tolerated and is a useful approach for treating patients with combined dyslipidemias who are not on antiretroviral medications. The safety and tolerability of a longer-acting preparation (Niaspan; Kos Pharmaceuticals, Miami, FL) currently is being tested in ACTG 5148. Fish oil capsules (5-9 g of docosohexanoic acid and eicosopentanoic acid daily) are effective at reducing VLDL production and lowering triglyceride levels in patients with hypertriglyceridemia, however, weight gain and gastrointestinal side effects are common. Drug interactions, hepatotoxicity, and myopathy have not been described with fish oil supplements, making them especially attractive in patients with HIV who already are taking statins. Low-dose (1 g/d) fish oil supplementation has been proven to reduce recurrent cardiac events in survivors of myocardial infarction.85 Finally, use of insulin-sensitizers such as metformin and thiazolidenediones also may improve PI-associated dyslipidemia, especially if impaired glucose tolerance or diabetes mellitus are present. Because these medications may affect the pathogenesis of PI-associated lipodystrophy, their use is being investigated intensively.

Conclusions HIV PIs are associated with metabolic abnormalities that may increase the risk for atherosclerotic vascular disease, including dyslipidemia, insulin resistance, and central obesity. Dylipidemia, characterized by hypercholesterolemia with increases in VLDL and IDL cholesterol and triglyceride levels, small LDL and HDL particles, and in some patients Lp(a) excess, can be severe and has been associated with endothelial dysfunction and carotid atherosclerosis. The mechanisms underlying PI-associated dyslipidemia have not been elucidated completely, but appear to involve hepatic overproduction of VLDL and to a lesser extent, impaired clearance. Insulin resistance almost certainly plays a role in mediating adverse lipoprotein changes. Ongoing epidemiologic and surrogate end-point studies are investigating the atherogenicity of these medications. Until the risk associated with these medications is better understood, identifying patients at high risk for adverse vascular events such as heart attacks, cardiac death, and stroke is a high priority. The NCEP ATP III guidelines emphasize adjusting the intensity of risk reduction therapy to the patient’s level of CAD risk, as estimated by risk factor summing and quantitated by use of the Framingham risk assessment tool. Unfortunately, these tools may be less helpful in patients with HIV infection taking PIs. High-risk individuals with CAD or a coronary risk equivalent need to be identified and treated to their LDL-C and non–HDL-C targets. Therapeutic lifestyle changes should be initiated for all individuals above their targets. Pharmacologic therapy should be initiated simultaneously with TLC in patients with CAD or a coronary risk equivalent, or who have more than 2 risk factors and a 10-year risk greater than 10%. Choice of lipid-altering therapy is complex and not well studied. Switching to a different PI or using a non–PI-based therapy are options, as are intensive dietary changes such as a low-fat, low-cholesterol diet with increased intake of omega-3 polyunsaturated and monounsaturated fatty acids, stanol/ sterol margarines, and soluble fiber. Statins and fibrates are the preferred lipid-lowering agents, but they are not always effective. Ongoing trials are needed to improve identification of patients at increased CAD risk and optimal prevention therapies.

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