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Lipid Abnormalities

  1. Michael Dube1 and
  2. Marcy Fenton2
  1. 1Indiana University School of Medicine, Wishard Memorial Hospital, Division of Infectious Diseases, Indianapolis, Indiana
  2. 2AIDS Project Los Angeles HIV Nutrition Program, Los Angeles, California
  1. Reprints or correspondence: Dr. Michael Dube, Indiana University School of Medicine, Wishard Memorial Hospital, Division of Infectious Diseases, 1001 W. 10th St., Suite OPW-430, Indianapolis, IN 46202-2879 (mpdube{at}iupui.edu).
 
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Abstract

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.

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Prevalence

Abnormalities of lipid metabolism are common in HIV-infected patients and tend to be accentuated in those receiving antiretroviral therapy, particularly with protease inhibitors (PIs). Forty-seven percent of PI recipients at one clinic had lipid abnormalities, according to the National Cholesterol Education Program (NCEP) guidelines for intervention [1]. Behrens et al. [2] reported that 56 (57%) of 98 PI recipients experienced hyperlipidemia. Among those, 19% had elevation of low-density lipoprotein cholesterol (LDL-C) alone, 44% had hypertriglyceridemia alone, and 37% had both abnormalities. Thus, dyslipidemia is a common problem among HIV-infected individuals receiving treatment.

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Etiology

Abnormalities of lipid metabolism reported before the use of HIV-1 PIs include increases in serum triglycerides [3, 4] and decreases in total and high-density lipoprotein cholesterol (HDL-C) [4, 5] that occurred with disease progression. During therapy with PIs, increases in serum triglycerides may be extreme [6], particularly with ritonavir therapy. In contrast to the pre-PI era, increases in cholesterol have occurred with PIs [1, 2, 7–9]. A mean increase in serum cholesterol of 32 mg/dL (23%) and a 27% increase in LDL-C occurred 3.4 months after initiation of therapy with a PI [8]. In HIV-negative volunteers, ritonavir therapy increased total cholesterol by 24% and triglycerides by 137% within 2 weeks [10]. In addition, significant elevations of both total cholesterol and HDL-C have also occurred during therapy with the nonnucleoside reverse transcriptase inhibitors (NNRTI) efavirenz [11] and nevirapine [12]. Whether these increases in HDL-C are beneficial remains speculative.

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Potential for Cardiovascular Morbidity and Mortality

Anecdotal reports suggest that serious premature vascular events may be related to PI therapy and abnormal lipids [2, 13–15]. The incidence of cardiovascular morbidity was increased among HIV-infected subjects in general but not among PI recipients, in one abstract [16]. However, duration of PI use was positively associated with cardiac events in another preliminary report [17]. Although there is currently no definitive evidence that antiviral drug—associated lipid disturbances will result in increased cardiovascular morbidity and mortality, many experts speculate that HIV treatment-related dyslipidemia will increase the atherogenic tendency, particularly when combined with other HIV-associated metabolic abnormalities such as insulin resistance [7, 8, 18], visceral adiposity [19], impaired fibrinolysis [20], and chronic infection and immune activation. Consequently, rationales exist for intervention in many individuals.

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Evaluation of Cardiovascular Disease Risks

Evaluation of serum lipids should be performed after fasting for a minimum of 8 h, and preferably 12 h. The standard screening lipid profile should include measurement of total cholesterol, HDL-C, and triglycerides, with calculation of LDL-C, and should be obtained before therapy [21]. This should be repeated 3–6 months after the initiation of HAART, and then yearly. All patients should be screened for other cardiovascular risk factors including family history, smoking, hypertension, menopausal status, physical inactivity, obesity, and diabetes, in addition to potential exacerbating factors such as certain medical illnesses and medications [22].

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Thresholds for Treatment Intervention

Dyslipidemia in patients with well-controlled HIV should have similar, and perhaps greater, long-term consequences for cardiovascular complications compared with the general population. For the purposes of initiating therapy for dyslipidemia, the Panel recommends that the NCEP guidelines [22] should generally be followed for HIV-infected patients. Of note, the new NCEP guidelines now include a category termed coronary heart disease (CHD) “risk equivalents,” which include diabetes mellitus, other atherosclerotic disease, and multiple risk factors that confer a 10-year risk of CHD of >20%. Because of the high risk of CHD in these groups, these individuals should be treated as aggressively as those with established CHD [22]. The NCEP guidelines target primarily LDL-C (table 1). However, elevated triglyceride levels also represent an independent risk factor for cardiovascular disease, even when values are only modestly elevated (200–400 mg/dL) [23]. When triglyceride levels exceed 200 mg/dL, calculation of non—HDL-C (total cholesterol minus HDL-C) should be performed and considered a secondary target for intervention [22]. In addition, the high frequency of low HDL-C in persons with HIV warrants attention [2].

Table 1
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Table 1

Target goals for LDL cholesterol in patients with HIV.

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Management: Diet and Nondrug Therapies

Nondrug interventions should be the first approach for management of abnormal lipid levels. Clinicians should consult with dietary specialists as a first step, when initial attempts at dietary intervention fail to achieve the desired effects, or when intensive dietary modification becomes necessary. Other nondrug therapies are expected to be beneficial, as they are in persons without HIV. For example, structured exercise plus diet resulted in a 21% decrease in triglyceride levels in HIV-infected patients [1], and resistance training improved triglyceride levels [24]. Smoking cessation and weight reduction for obesity also improve the overall cardiovascular risk profile.

Diet. After assessment of existing dietary habits, the Therapeutic Lifestyle Changes (TLC) diet should be prescribed (table 2). For many patients, these changes can be achieved without radical alterations in dietary habits. These diets also reduce serum triglycerides. For patients with low HDL-C, reduction of dietary fat will further reduce HDL-C. Monounsaturated fats (e.g., canola and olive oil) should be substituted for saturated fats. Moreover, if carbohydrate intake is increased as ingestion of fat is reduced, this may increase triglyceride levels. The management of severe hypertriglyceridemia and hyperchylomicronemia requires a very—low-fat diet and avoidance of simple sugars (i.e., use of low—glycemic-index carbohydrates) and alcohol. Fish oils (omega-3 fatty acid supplements) variably decrease triglyceride synthesis and may be tried in patients with severe hypertriglyceridemia.

Table 2
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Table 2

National Cholesterol Education Program Therapeutic Lifestyle Changes (TLC) diet.

Weight reduction. In subjects with central (abdominal) obesity, weight reduction through diet modifications and increased physical activity is an important element of therapy for abnormal lipid levels. Weight reduction enhances the LDL-C lowering that can be achieved by diet alone. Both weight reduction and intensive aerobic exercise also reduce serum triglycerides, raise HDL-C, lower blood pressure, and decrease the risk for diabetes mellitus [25]. However, the effects of weight reduction on peripheral adipose tissues stores have not been established in patients with HIV but are expected to be minimal in the presence of central obesity because intra-abdominal fat is more sensitive to lipolysis than peripheral fat [26].

Patients with CHD or CHD risk equivalents. The goal for LDL-C is <100 mg/dL in patients with CHD or CHD risk equivalents. In contrast to subjects without CHD, prolonged attempts to lower LDL-C with diet may not be desirable before initiation of drug therapy. If LDL-C is >130 mg/dL, diet and lipid-lowering therapy may be instituted simultaneously in these high-risk individuals.

Monitoring the response to therapy. In patients without CHD, after initiation of the therapeutic diet, lipids should be measured and adherence to the diet assessed after 4 to 6 weeks and again after 3 months.

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Management: Lipid-Lowering Drugs

As for patients without HIV, if lipid levels remain above the target after intensive dietary and lifestyle interventions have been attempted for at least 12 weeks, drug therapy should be considered. In the absence of other CHD risk factors, especially in patients <35 years of age, a longer period of nondrug therapies may be appropriate. Shorter periods of time may be considered in patients with severe elevations of LDL-C (>220 mg/dL) or with multiple risk factors. Drug therapy should only be added to dietary therapy, never substituted for it.

Lipid-lowering therapies for HIV-infected patients with dyslipidemia are conceptually problematic because of the potential for drug interactions (reviewed in [21]). Both increased toxicity due to increased levels of lipid-lowering drugs and reduced efficacy of antiretroviral drugs are a concern.

Drug therapy for elevated LDL-C or non—HDL-C. The hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, reduce the risk of CHD in patients without previous CHD (primary prevention) and risk of recurrent CHD events (secondary prevention) [27] in patients without HIV. On the basis of limited pharmacokinetic data [28] and the likelihood of significant interactions, the Panel recommends that when statin therapy is necessary, low initial dosages of either pravastatin (20 mg daily) or atorvastatin (10 mg daily) be used, along with careful clinical monitoring. Fluvastatin is an alternative statin, but there are no data on fluvastatin interactions with PIs. Therapy with lovastatin and simvastatin should be avoided.

The fibrates (gemfibrozil and fenofibrate) are well-tolerated alternative agents when hypercholesterolemia is accompanied by elevated triglycerides, but fibrates are less effective than statins for reducing LDL-C. Niacin lowers LDL-C and triglyceride levels but produces frequent cutaneous flushing and pruritus. Because niacin causes insulin resistance [29, 30], niacin should be avoided as first-line therapy in patients receiving PIs or in patients with fat redistribution, because both conditions are associated with reduced insulin sensitivity. Bile-sequestering resins are not recommended because their effects on antiviral drug absorption are not known.

Drug therapy for elevated triglycerides. The absolute value at which drug therapy should be given for isolated hypertriglyceridemia has not been defined, but in the absence of CHD risk factors or hypercholesterolemia, elevations >500 mg/dL (unresponsive to nondrug therapies) carry an increased risk of pancreatitis. Drug therapy should therefore be considered for these individuals. For patients with extreme elevations (i.e., triglycerides >2000 mg/dL), drug therapies may be initiated concurrently with nondrug interventions.

Fibrates should be prescribed if drug therapy is necessary for hypertriglyceridemia. Treatment is with gemfibrozil [1] (600 mg bid) or fenofibrate (54–160 mg once daily). If treatment with a fibrate results in inadequate lowering of serum triglycerides, or if LDL-C levels remain elevated, a cautious trial of niacin or a statin (see above) may be considered, with careful monitoring for symptoms of skeletal muscle toxicity.

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Consideration for Switching Antiretroviral Therapies

Where virologically appropriate, substitution of a new antiviral agent with a lesser tendency to induce dyslipidemia for an existing agent with a greater tendency may be considered. In NNRTI-naive patients, substitution of nevirapine for a PI improves serum lipids in some studies [31] but not in others [32, 33]. The substitution of efavirenz for a PI has not consistently had a beneficial effect [34]. Improvement in lipid levels have also been reported with the substitution of abacavir for PIs [35, 36]. Rates of virologic relapse when an NNRTI or abacavir is substituted for PIs have been acceptable. When triglyceride levels remain markedly elevated despite aggressive interventions, it may be reasonable to change ritonavir to another PI or non—PI-based regimen or to select the lowest effective dose of ritonavir when it is used to increase the levels of other PIs.

To our knowledge, there are no studies that compare the effects of switching antiretroviral treatment with the effects of adding lipid-lowering agents to ongoing successful therapy. Clinicians will need to weigh the potential risks of new treatment-related toxicities and the possibility of virologic relapse when switching antiviral drugs against the potential risks of drug interactions and toxicities from lipid-lowering agents added to antiretroviral drug regimens.

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Footnotes

  • Note added in proof. Since submission of this paper, the following articles have been published with regard to cardiovascular disease outcomes and HIV: (1) Bozzette SA, Ake CF, Tam HK, Chang SW, Louis TA. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection. N Engl J Med 2003; 702–10; (2) Holmberg SSD, Moorman AC, Williamson JM, et al. Protease inhibitors and cardiovascular outcomes in patients with HIV-1. Lancet 2002; 360:1747–8; and (3) Klein D, Hurley LB, Quesenberry CP Jr, Sidney S. Do protease inhibitors increase the risk for coronary heart disease in patients with HIV-1 infection? JAIDS J Acquired Immune Defic Syndr 2002; 30: 471–7. The following reports of controlled clinical trials of lipid-lowering drugs in HIV-infected subjects have also been recently published: (1) Doser N, Kubli S, Telentic A, et al. Efficacy and safety of fluvastatin in hyperlipidemic protease inhibitor-treated HIV-infected patients. AIDS 2002; 16:1982–3; and (2) Miller J, Brown D, Amin J, et al. A randomized, double-blind study of gemfibrozil for the treatment of protease inhibitor-associated hypertriglyceridaemia. AIDS 2002; 16:2195–200.

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