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SUPPLEMENT ARTICLE
Lipid Abnormalities
Michael Dube1 and Marcy Fenton2
1
Indiana 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
Abnormalities of lipid metabolism are common in HIVinfected 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.
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
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 ([email protected]).
Clinical Infectious Diseases 2003; 36(Suppl 2):S79–83
2003 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2003/3607S2-0005$15.00
with disease progression. During therapy with PIs, increases in serum triglycerides may be extreme [6], particularly with ritonavir therapy. In contrast to the prePI 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.
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
Lipid Abnormalities • CID 2003:36 (Suppl 2) • S79
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.
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].
EVALUATION OF CARDIOVASCULAR DISEASE
RISKS
MANAGEMENT: DIET AND NONDRUG
THERAPIES
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 LDLC, 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].
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.
Weight reduction. In subjects with central (abdominal)
obesity, weight reduction through diet modifications and in-
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 120%. 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
Table 1.
Target goals for LDL cholesterol in patients with HIV.
LDL-C level, mg/dL
Risk
Goal
Initiate therapeutic
lifestyle changes
Consider
drug therapy
0–1 risk factors for CHD
!160
⭓160
⭓190
⭓2 risk factors for CHD
(10-y risk ⭐0%)
!130
⭓130
⭓160
With CHD, or CHD risk equivalent
(10-y risk 120%)
!100
⭓100
⭓130 (100–129,
drug optional)
NOTE. Adapted from [22]. CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol. See text for definition of CHD risk equivalent.
S80 • CID 2003:36 (Suppl 2) • Dube and Fenton
Table 2.
diet.
National Cholesterol Education Program Therapeutic Lifestyle Changes (TLC)
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
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 1130 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.
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 (1220 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 1500 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 12000 mg/dL), drug therapies may be initiated
concurrently with nondrug interventions.
Fibrates should be prescribed if drug therapy is necessary for
Lipid Abnormalities • CID 2003:36 (Suppl 2) • S81
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.
8.
9.
10.
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 treatmentrelated 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.
11.
12.
13.
14.
15.
16.
17.
18.
19.
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