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Lipid Abnormalities SUPPLEMENT ARTICLE Lipid Abnormalities Michael Dube1 and Marcy Fenton2 1Indiana University School of Medicine, Wishard Memorial Hospital, Division of Infectious Diseases, Indianapolis, Indiana; and 2AIDS Project Los Angeles HIV Nutrition Program, Los Angeles, California Dyslipidemia is an important clinical problem in individuals infected with human immunodeficiency virus (HIV) who are receiving antiretroviral therapy. Data suggest that increased cardiovascular disease is occurring in this population. HIV-infected individuals should undergo evaluation and treatment regimens based on the current National Cholesterol Education Program guidelines. In most situations, the first interventions should be nonpharmacological and should include diet, exercise, and management of other hygienic risk factors. If pharmacologic therapy becomes necessary, the choices of lipid-lowering agents should be limited to agents with the least likelihood of adverse drug interactions. PREVALENCE with disease progression. During therapy with PIs, in- creases in serum triglycerides may be extreme [6], par- Abnormalities of lipid metabolism are common in HIV- ticularly with ritonavir therapy. In contrast to the pre- infected patients and tend to be accentuated in those PI era, increases in cholesterol have occurred with PIs receiving antiretroviral therapy, particularly with pro- [1, 2, 7–9]. A mean increase in serum cholesterol of 32 tease inhibitors (PIs). Forty-seven percent of PI recip- mg/dL (23%) and a 27% increase in LDL-C occurred ients at one clinic had lipid abnormalities, according 3.4 months after initiation of therapy with a PI [8]. In to the National Cholesterol Education Program HIV-negative volunteers, ritonavir therapy increased (NCEP) guidelines for intervention [1]. Behrens et al. total cholesterol by 24% and triglycerides by 137% [2] reported that 56 (57%) of 98 PI recipients expe- within 2 weeks [10]. In addition, significant elevations rienced hyperlipidemia. Among those, 19% had ele- of both total cholesterol and HDL-C have also occurred vation of low-density lipoprotein cholesterol (LDL-C) during therapy with the nonnucleoside reverse tran- alone, 44% had hypertriglyceridemia alone, and 37% scriptase inhibitors (NNRTI) efavirenz [11] and nevi- had both abnormalities. Thus, dyslipidemia is a com- rapine [12]. Whether these increases in HDL-C are ben- mon problem among HIV-infected individuals receiv- eficial remains speculative. ing treatment. POTENTIAL FOR CARDIOVASCULAR ETIOLOGY MORBIDITY AND MORTALITY Abnormalities of lipid metabolism reported before the Anecdotal reports suggest that serious premature vas- use of HIV-1 PIs include increases in serum triglycer- cular events may be related to PI therapy and abnormal ides [3, 4] and decreases in total and high-density li- lipids [2, 13–15]. The incidence of cardiovascular mor- poprotein cholesterol (HDL-C) [4, 5] that occurred bidity was increased among HIV-infected subjects in general but not among PI recipients, in one abstract [16]. However, duration of PI use was positively as- Reprints or correspondence: Dr. Michael Dube, Indiana University School of Medicine, Wishard Memorial Hospital, Division of Infectious Diseases, 1001 W. sociated with cardiac events in another preliminary re- 10th St., Suite OPW-430, Indianapolis, IN 46202-2879 ([email protected]). port [17]. Although there is currently no definitive ev- Clinical Infectious Diseases 2003;36(Suppl 2):S79–83 ᮊ 2003 by the Infectious Diseases Society of America. All rights reserved. idence that antiviral drug–associated lipid disturbances 1058-4838/2003/3607S2-0005$15.00 will result in increased cardiovascular morbidity and Lipid Abnormalities • CID 2003:36 (Suppl 2) • S79 mortality, many experts speculate that HIV treatment-related factor for cardiovascular disease, even when values are only dyslipidemia will increase the atherogenic tendency, particularly modestly elevated (200–400 mg/dL) [23]. When triglyceride when combined with other HIV-associated metabolic abnor- levels exceed 200 mg/dL, calculation of non–HDL-C (total cho- malities such as insulin resistance [7, 8, 18], visceral adiposity lesterol minus HDL-C) should be performed and considered [19], impaired fibrinolysis [20], and chronic infection and im- a secondary target for intervention [22]. In addition, the high mune activation. Consequently, rationales exist for intervention frequency of low HDL-C in persons with HIV warrants atten- in many individuals. tion [2]. EVALUATION OF CARDIOVASCULAR DISEASE MANAGEMENT: DIET AND NONDRUG RISKS THERAPIES Evaluation of serum lipids should be performed after fasting Nondrug interventions should be the first approach for man- for a minimum of 8 h, and preferably 12 h. The standard agement of abnormal lipid levels. Clinicians should consult with screening lipid profile should include measurement of total dietary specialists as a first step, when initial attempts at dietary cholesterol, HDL-C, and triglycerides, with calculation of LDL- intervention fail to achieve the desired effects, or when intensive C, and should be obtained before therapy [21]. This should be dietary modification becomes necessary. Other nondrug ther- repeated 3–6 months after the initiation of HAART, and then apies are expected to be beneficial, as they are in persons with- yearly. All patients should be screened for other cardiovascular out HIV. For example, structured exercise plus diet resulted in risk factors including family history, smoking, hypertension, a 21% decrease in triglyceride levels in HIV-infected patients menopausal status, physical inactivity, obesity, and diabetes, in [1], and resistance training improved triglyceride levels [24]. addition to potential exacerbating factors such as certain med- Smoking cessation and weight reduction for obesity also im- ical illnesses and medications [22]. prove the overall cardiovascular risk profile. Diet. After assessment of existing dietary habits, the Ther- apeutic Lifestyle Changes (TLC) diet should be prescribed (table THRESHOLDS FOR TREATMENT INTERVENTION 2). For many patients, these changes can be achieved without Dyslipidemia in patients with well-controlled HIV should have radical alterations in dietary habits. These diets also reduce similar, and perhaps greater, long-term consequences for car- serum triglycerides. For patients with low HDL-C, reduction diovascular complications compared with the general popu- of dietary fat will further reduce HDL-C. Monounsaturated fats lation. For the purposes of initiating therapy for dyslipidemia, (e.g., canola and olive oil) should be substituted for saturated the Panel recommends that the NCEP guidelines [22] should fats. Moreover, if carbohydrate intake is increased as ingestion generally be followed for HIV-infected patients. Of note, the of fat is reduced, this may increase triglyceride levels. The man- new NCEP guidelines now include a category termed coronary agement of severe hypertriglyceridemia and hyperchylomicro- heart disease (CHD) “risk equivalents,” which include diabetes nemia requires a very–low-fat diet and avoidance of simple mellitus, other atherosclerotic disease, and multiple risk factors sugars (i.e., use of low–glycemic-index carbohydrates) and al- that confer a 10-year risk of CHD of 120%. Because of the cohol. Fish oils (omega-3 fatty acid supplements) variably de- high risk of CHD in these groups, these individuals should be crease triglyceride synthesis and may be tried in patients with treated as aggressively as those with established CHD [22]. The severe hypertriglyceridemia. NCEP guidelines target primarily LDL-C (table 1). However, Weight reduction. In subjects with central (abdominal) elevated triglyceride levels also represent an independent risk obesity, weight reduction through diet modifications and in- Table 1. Target goals for LDL cholesterol in patients with HIV. LDL-C level, mg/dL Initiate therapeutic Consider Risk Goal lifestyle changes drug therapy 0–1 risk factors for CHD !160 у160 у190 у2 risk factors for CHD !130 у130 у160 (10-y risk р0%) With CHD, or CHD risk equivalent !100 у100 у130 (100–129, (10-y risk 120%) drug optional) NOTE. Adapted from [22]. CHD, coronary heart disease; LDL-C, low-density lipoprotein cho- lesterol. See text for definition of CHD risk equivalent. S80 • CID 2003:36 (Suppl 2) • Dube and Fenton Table 2. National Cholesterol Education Program Therapeutic Lifestyle Changes (TLC) diet. Nutrient Recommendation Total calories Adjust to achieve desired weight Total fat 25%–35% of total calories; keep trans fatty acids low Saturated fat !7% of total calories Polyunsaturated fat Up to 10% of total calories Monounsaturated fat Up to 20% of total calories Cholesterol !200 mg/d Carbohydrates 50%–60% of total calories, predominantly complex carbohydrates Protein ∼15% of total calories NOTE. Adapted from [22]. creased physical activity is an important element of therapy for due to increased levels of lipid-lowering drugs and reduced abnormal lipid levels. Weight reduction enhances the LDL-C efficacy of antiretroviral drugs are a concern. lowering that can be achieved by diet alone. Both weight re- Drug therapy for elevated LDL-C or non–HDL-C. The duction and intensive aerobic exercise also reduce serum tri- hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase in- glycerides, raise HDL-C, lower blood pressure, and decrease hibitors, or statins, reduce the risk of CHD in patients without the risk for diabetes mellitus [25]. However, the effects of weight previous CHD (primary prevention) and risk of recurrent
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