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The Journal of Clinical Endocrinology & Metabolism 88(5):1961–1976
Copyright © 2003 by The Endocrine Society
doi: 10.1210/jc.2002-021704
CLINICAL REVIEW 159
Human Immunodeficiency Virus/Highly Active
Antiretroviral Therapy-Associated Metabolic
Syndrome: Clinical Presentation, Pathophysiology,
and Therapeutic Strategies
M. K. S. LEOW, C. L. ADDY,
AND
C. S. MANTZOROS
Division of Endocrinology, Diabetes and Metabolism (M.K.S.L., C.L.A., C.S.M.), Department of Internal Medicine, Beth
Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215; and Division of Endocrinology,
Diabetes, and Hypertension (C.L.A.), Department of Internal Medicine, Brigham and Women’s Hospital, Harvard Medical
School, Boston, Massachusetts 02115
Obesity has been linked to insulin resistance (IR) and type
2 diabetes mellitus (DM) through epidemiological and clinical studies (1, 2). Interestingly, syndromes characterized by
lipoatrophy and lipodystrophy are also associated with profound IR and metabolic abnormalities (3–5). Congenital and
acquired forms of lipoatrophy and lipodystrophy, although
rare, have been well described (6 – 8). Most recently, a lipodystrophic syndrome has been reported with increasing frequency in populations of HIV-infected individuals treated
with highly active antiretroviral therapy (HAART; Ref. 5).
This syndrome, similar to the congenital syndromes discussed briefly below, is also associated with significant metabolic abnormalities, including IR, type 2 DM, and hyperlipidemia. The fact that congenital lipodystrophy/atrophy
syndromes and acquired syndromes such as HIV-associated
lipodystrophy are both characterized by adipose tissue depletion or redistribution emphasizes the importance of the
adipocyte in the pathogenesis of the associated metabolic
disturbances.
In this review, we provide a brief overview of our current
understanding of the pathogenesis of IR and the associated
metabolic abnormalities. Specifically, we provide our current
state of knowledge of the HIV-associated lipodystrophy synAbbreviations: BMI, Body mass index; CAD, coronary artery disease;
CRABP-I, cellular RA binding protein type I; CT, computed tomography; DEXA, dual energy x-ray absorptiometry; DM, diabetes mellitus;
FFA, free fatty acid(s); FKHR, forkhead transcription factor; GLUT4,
glucose transporter 4; HAART, highly active antiretroviral therapy;
HDL, high-density lipoprotein; HMG-CoA, hydroxy-methyl-glutarylcoenzyme A; HOMA, homeostasis model assessment; IGT, impaired
glucose tolerance; IKK, I-␬ B kinase complex; IR, insulin resistance; IRS,
insulin-receptor substrate; LDL, low-density lipoprotein; LPR, LDL receptor; MRI, magnetic resonance imaging; mtDNA, mitochondrial
DNA; NNRTI, non-NRTI; NRTI, nucleoside reverse transcriptase inhibitor; OGTT, oral glucose tolerance test; PAI-1, plasminogen activator
inhibitor-1; PI, protease inhibitor; PPAR, peroxisome proliferator-activated receptor; RA, retinoic acid; rhGH, recombinant human GH; RXR,
retinoic X receptor; Si, insulin sensitivity index; Th, T-helper; TZD,
thiazolidinedione; WHR, waist-to-hip ratio.
drome, including its clinical presentation, pathophysiology,
and current and future therapeutic approaches.
Definition and assessment of IR
IR has been defined as “a state (of a cell, tissue, or organism) in which a greater than normal amount of insulin is
required to elicit a quantitatively normal response” (6), or as
a state in which a subnormal glucose-lowering response is
observed in the setting of a known concentration of insulin
(7, 7a).
Currently, several methods are available to clinically assess IR (7, 8). Perhaps the simplest and most practical method
is to determine fasting insulin and glucose levels (9, 9a). The
homeostasis model assessment (HOMA) of IR (HOMA-IR),
i.e. fasting insulin ⫻ fasting glucose/22.5, has been used by
many to assess IR (10). This method is closely associated (R ⫽
0.88; P ⬍ 0.0001) with what is currently considered to be the
gold standard in the assessment of IR, the euglycemic hyperinsulinemic clamp, discussed below. Fasting and/or peak
insulin and glucose levels after an oral glucose tolerance test
(OGTT) have also been used to calculate the degree of IR
through a variety of methods (9a, 11). Severe IR is typically
characterized by fasting insulin levels greater than 50 –70
␮U/ml or post-OGTT insulin levels above 350 ␮U/ml. In
contrast, fasting insulin levels of 5–20 ␮U/ml and post-OGTT
insulin levels of less than 150 ␮U/ml are seen in normal
individuals (8). Although there are currently no clearly defined normal ranges for fasting insulin, some would argue
that IR should be suspected when fasting insulin levels are
greater than 15–20 ␮U/ml.
Other methods for the in vivo assessment of IR are more
complex and are typically used only in the research setting.
The insulin tolerance test involves obtaining sequential
plasma glucose levels after the iv administration of insulin (9,
9b, 9c). The rate at which plasma glucose declines gives an
indication of insulin sensitivity. Because this test is associated
with the secretion of counterregulatory hormones such as
epinephrine, glucagon, cortisol, and GH, its utility in assess-
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J Clin Endocrinol Metab, May 2003, 88(5):1961–1976
ing insulin sensitivity has been questioned. The frequently
sampled iv glucose tolerance test allows the calculation of the
insulin sensitivity index (Si) by using minimal model kinetic
analysis (8, 9d). In this test, a fixed amount of glucose is
administered iv, followed by frequent blood sampling for
plasma glucose and insulin. Analysis of the data then results
in indices of insulin sensitivity (Si) and glucose effectiveness.
Individuals with severe IR typically have Si values less than
2 ⫻ 104 ␮U/ml䡠min, whereas normal individuals have values
typically greater than 5 ⫻ 104 ␮U/ml䡠min (8). The frequently
sampled iv glucose tolerance test has been shown to correlate
very well with insulin-mediated glucose disposal in the euglycemic hyperinsulinemic clamp technique.
The euglycemic hyperinsulinemic clamp technique is the
gold standard for the assessment of IR. This technique involves the iv infusion of insulin at a fixed rate and the
concurrent iv administration of glucose at a variable rate to
achieve steady state normoglycemia (12, 12a). Glucose disposal rate at steady state is directly proportional to the exogenous glucose infusion rate such that insulin-resistant individuals require the infusion of less glucose, and insulinsensitive individuals require the infusion of more glucose to
maintain normoglycemia. Although currently considered to
be the gold standard in assessing IR, the clamp technique is
typically used only for research purposes.
Congenital lipodystrophies are associated with IR
There are several hypothesized mechanisms for the development of IR. Some of these mechanisms include the role
of lipids, specifically triglycerides, counterregulatory hormone excess (GH and cortisol), and autoantibodies to insulin
or the insulin receptor itself as well as postreceptor defects.
Because IR is associated with both obesity and fat wasting,
the contribution of adipocyte-secreted proteins to its pathogenesis is a current area of active research and is discussed
below.
Although it is adipose tissue excess that is classically associated with IR, this metabolic abnormality is also seen in
diseases of fat wasting and fat redistribution (3, 4). Lipodystrophies are a heterogeneous group of disorders characterized by abnormal body fat distribution, which may be focal,
partial, or generalized. These disorders classically involve
complete or partial lack of adipose tissue. Moreover, they are
typically associated with significant metabolic abnormalities,
which include severe IR, hypertriglyceridemia, and fatty infiltration of the liver (8, 12b).
Generalized lipodystrophies include the congenital SeipBerardinelli syndrome (13, 14) and the acquired Lawrence
syndrome (15). Examples of partial lipodystrophies include
the familial Dunnigan’s (16, 17) and Kobberling’s syndromes
(18), and the acquired Barraquer-Simons’ syndrome (19).
These extremely rare conditions share the common feature of
being associated with severe IR. Interestingly, the severity of
the associated metabolic abnormalities, such as IR, is proportional to adipose tissue depletion.
Although the etiologies of these disorders include genetic
abnormalities and autoimmune processes, the underlying
pathophysiology of the individual disease phenotypes has
yet to be defined. For example, the phenotypic changes ob-
Leow et al. • Clinical Review
served in the monogenic familial partial lipodystrophy of the
Dunnigan variant may be related to a mutation (R482Q) of
the LMNA gene on chromosome 1q21-q22 that encodes the
nuclear envelope proteins, lamins A and C (20 –22). Such
lamins form a fibrous structural network around the nucleus
and interact with numerous molecules, including transcription factors. However, it remains unknown exactly how this
leads to lipodystrophy and IR.
It has also been hypothesized that IR in these syndromes
may be due to genetic defects in the insulin receptor or
important downstream intracellular signaling proteins such
as insulin-receptor substrate (IRS)-1 and IRS-2. However,
linkage analysis in 10 families with congenital lipodystrophy
failed to show an association with candidate genes (23). Indeed, further elucidation of the pathogenic pathways of lipodystrophic models of IR may be instructive in better defining the pathogenesis of other IR syndromes and may
provide new targets for drug therapies aimed at treating
these conditions.
HIV/HAART-associated lipodystrophy syndrome
It was not until the late 1990s that clinicians began to
observe metabolic and anthropometric changes in HIVinfected patients treated with HAART (5, 24 –28). The development of morphologic changes, including lipoatrophy
and lipohypertrophy, or a combination of the two, were
accompanied by profound metabolic abnormalities such as
hyperglycemia, hyperinsulinemia, hyperlipidemia, and hypertension, which are now commonly referred to as the metabolic syndrome.
Epidemiology. The determination of the prevalence and incidence of HIV/HAART-associated lipodystrophy is somewhat complicated because there are currently no universally
agreed on criteria for its diagnosis. Nevertheless, epidemiological studies have identified several morphologic and
metabolic features, which will undoubtedly provide guidance for the diagnosis of this syndrome in the future. Additionally, these studies have begun to provide important
information that addresses the relative importance of various
risk factors for the development of a syndrome whose pathogenesis will likely prove to be multifactorial.
Several cohort studies have helped to establish prevalence
estimates of HIV-associated lipodystrophy. The prevalence
of this syndrome is estimated to range between 2% and 84%
of patients on protease inhibitor (PI)-containing HAART regimens (5, 29 –31). The large difference in prevalence is undoubtedly due to a lack of consensus for a formal definition
of the syndrome and the subjective nature of patients’ perception of lipodystrophy as opposed to an objective evaluation of fat redistribution. Additionally, prevalence may differ according to the nature of the study (e.g. cohort/
prospective study vs. cross-sectional study) and may vary
due to inherent differences in study populations. One retrospective cohort study showed that 13% of 221 patients
treated with PI therapy for 5 yr developed lipodystrophy,
suggesting that the effect of antiretroviral medication may be
an important contributor to the development of the syndrome (32).
Based on what is currently known about HIV/HAART-
Leow et al. • Clinical Review
associated lipodystrophy from epidemiological studies, the
syndrome typically presents with fat redistribution and anthropometric changes after 10 –18 months of antiretroviral
drug therapy. The median time of onset may vary according
to the specific antiretroviral therapy used, the time being
shorter for those taking the PIs ritonavir and saquinavir,
compared with indinavir or nelfinavir (5).
Observational studies have identified several potential
risk factors for the development of HIV-associated lipodystrophy. These risk factors include: exposure to PIs, the duration of PI and nucleoside reverse transcriptase inhibitor
(NRTI) use, increasing age, gender, duration and severity of
HIV disease, viral load, time since reversal of clinical progression of HIV infection, and extreme changes in body mass
index (BMI; Ref. 33). Multivariate analyses have revealed that
fat accumulation is correlated with female gender, low viral
load, and high BMI, whereas fat depletion is associated with
low BMI and the use of the NRTI stavudine (34). Additionally, these analyses showed that males were at greater risk of
developing metabolic abnormalities, including hypertriglyceridemia, hypercholesterolemia, and hyperglycemia. Another study has suggested that mixed fat redistribution (concurrent fat wasting and fat accumulation) may be related to
effective HIV suppression by HAART (35).
Perhaps the most compelling risk factor identified thus far
has been PI use. Carr et al. (5) showed that 64% (74 of 116)
of patients receiving PI therapy suffered from lipodystrophy,
as opposed to only 3% (1 of 32) of PI-naive patients. That PI
exposure is an important risk factor was reinforced when
Veny et al. (36) showed that the cumulative risk for the
development of lipodystrophy after 6, 12, 18, 24, and 30
months of PI use was 3.2%, 10.7%, 29.1%, 62.5%, and 75%,
respectively. In that study, 47% of the patients receiving PI
therapy developed impaired glucose tolerance (IGT),
whereas 60% of patients receiving PI therapy had dyslipidemia. Although PI use has consistently been associated with
the development of lipodystrophy in many studies, some
studies have not shown such a striking association. For example, Martinez et al. (31) prospectively followed 494 HIVinfected patients for 7 yr after the initiation of antiretroviral
drug therapy, and only 17% of these subjects developed
lipodystrophic changes after a median follow-up of 18
months. Moreover, although subject age and duration of
antiretroviral therapy appeared to confer risk, specific classes
of antiretroviral medications did not appear to be risk factors.
Clinical features and diagnosis. The clinical features of HIV/
HAART-associated lipodystrophy include both lipoatrophy
and lipohypertrophy (36a, 36b). Lipoatrophic changes are
characterized by sc fat depletion in the face, arms, legs, and
gluteal region. Muscles of the extremities may appear more
pronounced, and veins may appear more prominent in fatdepleted regions. The fat wasting observed in this syndrome
should be distinguished from other wasting conditions associated with HIV infection, including the AIDS-wasting
syndrome, malnutrition, cachexia, adrenal insufficiency due
to HIV-related factors, and severe chronic infections. Lipohypertrophy is characterized by truncal obesity, dorsocervical fat accumulation (buffalo hump), and breast enlargement (Ref. 37; Fig. 1). Changes in fat distribution may be
J Clin Endocrinol Metab, May 2003, 88(5):1961–1976 1963
associated with a gradual net weight loss of up to 0.5 kg per
month, and fat may be depleted peripherally while simultaneously accumulating centrally (Fig. 2).
Perhaps the most cost-effective method to assess central fat
accumulation in a clinical setting is to measure the waist
circumference. More accurate assessment of body fat distribution includes the use of skin-fold calipers, bioelectrical
impedance, regional dual energy x-ray absorptiometry
(DEXA), ultrasonography, and whole-body/single-slice
magnetic resonance imaging (MRI), or computed tomography (CT), although these techniques are typically used only
in the setting of research (38 – 41). Single-slice CT or MRI at
the L4 –5 interspace is well correlated with whole-body CT
or MRI measurement of body fat and is a less costly alternative (42).
Metabolic abnormalities are commonly observed in HIV/
HAART-associated lipodystrophy and include hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and hypercholesterolemia. A retrospective cohort evaluation of patients
followed at our medical center reported the cumulative incidence of hyperglycemia, hypercholesterolemia, and hypertriglyceridemia as 5%, 24%, and 19%, respectively, in 221
patients followed for 5 yr after the initiation of PI therapy
(32). Although a diagnosis of IGT and frank type 2 DM is
possible, particularly for those patients with other risk factors, IR most commonly manifests as hyperinsulinemia in the
setting of normoglycemia. Thus, the comparison of a cohort
of patients with HIV-lipodystrophy to age- and BMImatched controls may show no difference in fasting glucose
levels (28), whereas fasting insulin levels and insulin levels
2 h after a glucose challenge can be increased in the lipo-
FIG. 1. HAART-associated fat redistribution syndrome. Buffalo
hump and increased abdominal girth. Courtesy of A. W. Karchmer, C.
Mantzoros, and S. Tsiodras.
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J Clin Endocrinol Metab, May 2003, 88(5):1961–1976
Leow et al. • Clinical Review
1000 mg/dl and may therefore contribute to the development of acute pancreatitis (50). Hepatomegaly due to fatty
liver may be present due to chronic hypertriglyceridemia
and increased lipid biosynthesis in the liver (Ref. 51; Fig. 3).
Hypercholesterolemia in this syndrome can potentially
predispose individuals to accelerated atherosclerosis and
premature coronary artery disease (CAD; Refs. 52 and 53).
One retrospective study of over 1,300 patients demonstrated
an increased frequency of myocardial infarction in HIVinfected patients receiving PI therapy (54). Many HIVinfected patients may exhibit more than one risk factor for
the development of CAD: hypertriglyceridemia, low highdensity lipoprotein (HDL) cholesterol, increased low-density
lipoprotein (LDL) cholesterol, elevated diastolic blood pressure, decreased tissue plasminogen activator levels, and increased plasminogen activator inhibitor-1 (PAI-1) levels (55,
56). The median time to the development of hypercholesterolemia may precede that of lipodystrophy by 3– 6 months
(57, 58). Thus, it is important that clinicians be quickly alerted
to the potential diagnosis of HIV/HAART-associated metabolic syndrome in HIV-infected patients with any manifestation of IR, particularly if fat redistribution, dyslipidemia,
and/or hyperglycemia are present.
Pathogenesis of HIV/HAART-associated lipodystrophy. The etiology and pathogenic mechanisms of HIV-HAART-associated lipodystrophy remain to be fully elucidated. There is
conflicting evidence as to which class of antiretroviral therapy, if any, may be causative. PIs have emerged as the most
strongly implicated drug class, however NRTI use has been
increasingly targeted as a potential risk factor. Furthermore,
PIs and NRTIs may act synergistically, or it may simply be
that effective treatment of HIV infection may independently
contribute to the development of the syndrome. Moreover,
current evidence points toward a multifactorial etiology,
which includes the interaction of HIV with HAART.
FIG. 2. Fat redistribution syndrome. HIV-infected man with
HAART-associated fat redistribution syndrome characterized by loss
of extremity fat and increased abdominal girth. Courtesy of A. W.
Karchmer, C. Mantzoros, and S. Tsiodras.
dystrophic group, compared with the control group. These
increases are usually correlated with increased waist circumference and loss of peripheral sc fat (28, 43). IR in these
patients may rarely be so severe as to manifest with acanthosis nigricans, hypertrichosis, and hirsutism. Although
overt DM is uncommon in HIV-infected patients, patients
receiving HAART should be closely monitored for the development of IR and/or DM because its diagnosis would
necessitate therapy with lifestyle modifications, antihyperglycemic agents, and/or insulin (44, 45).
Similar to other syndromes of IR, lipid abnormalities are
commonly observed in patients with HIV/HAART-induced
lipodystrophy. Hyperlipidemia is commonly observed in
this population and has been reported in as many as 66% of
HIV-infected patients taking PIs (46 – 48). Hypertriglyceridemia is perhaps the most common lipid abnormality seen
in these patients, and triglycerides have been reported to
increase as much as 6-fold in less than 1 yr of PI therapy (5,
49). Moreover, serum triglyceride levels may exceed 500-
FIG. 3. Abdominal CT scan showing hepatomegaly in a patient with
HAART-associated lipodystrophy. Courtesy of Beth Israel Deaconess
Medical Center (Boston, MA).
Leow et al. • Clinical Review
One of the molecular pathophysiological mechanisms proposed to explain the role of PIs in the development of the
lipodystrophic syndrome is based on the high affinity of PIs
for the catalytic site of HIV-1 aspartyl protease. The catalytic
region of this protease shares about 60% homology with the
sequence of the lipid binding domain of the LDL receptor
(LPR) and the C-terminal region of the cellular retinoic acid
(RA) binding protein type I (CRABP-I; Ref. 59). CRABP-I
facilitates the binding of RA to nuclear RA receptors, and RA
bound to CRABP-I is a better substrate for metabolizing
enzymes than free RA (60, 60a). Thus, CRABP-I binds intracellular RA and facilitates its conversion to 9-cis-RA, a major
ligand of the retinoic X receptor (RXR). RXRs are liganddependent transcription factors of which three isoforms
(RXR␣, RXR␤, and RXR␥) exist (60b). Interestingly, the heterodimerization of RXR␣ with peroxisome proliferator-activated receptor (PPAR)-␥ significantly enhances the binding
affinity of 9-cis-RA to RXR. The complex then serves as a
transcriptional switch by binding to hormone responsive
elements important in coordinating the regulation of target
gene expression, such as adipocyte differentiation (61). The
resultant 9-cis-RA-RXR␣-PPAR␥ molecular complex thus enhances the transcription of genes that rescue adipocytes from
apoptosis and increase adipocyte differentiation (Fig. 4; Ref.
62, 62a). Because PPAR-␥ is preferentially expressed in peripheral adipocyte tissue, it is conceivable that inhibition of
CRABP-I by PIs could result in apoptosis and impaired differentiation of peripheral adipocytes, with relative sparing of
intraabdominal and visceral adipocytes thereby contributing
to the development of the previously described changes in fat
distribution.
PIs may also contribute to IR by inhibiting the LPR, an
important receptor responsible for clearance of triglycerides
in the circulation. The increased levels of free fatty acids
(FFA) in the splanchnic circulation, which are associated
with increased triglyceride synthesis, in turn contribute to IR
via competitive metabolism of substrates (Randle’s cycle).
FIG. 4. The process by which RXR and PPAR interact with 9-cis-RA
to inhibit adipocyte apoptosis and induce adipocyte differentiation.
RXRE, RXR response element; PPRE, PPAR␥ response element.
J Clin Endocrinol Metab, May 2003, 88(5):1961–1976 1965
The exacerbation of hyperlipidemia may cause glucose intolerance and even frank DM in susceptible individuals (63–
65). One study in which HIV-infected patients had a PI replaced with a non-NRTI (NNRTI) demonstrated increased
insulin sensitivity but no improvement in sc adipocyte apoptosis (66). This observation suggests that NNRTIs can influence IR independently of changes in fat mass and supports
the likelihood that the pathogenesis of this syndrome is multifactorial, but it does not negate the potential importance of
PI therapy in the development of IR.
Another potential mechanism whereby PI therapy may
contribute to IR has been suggested by recent in vitro studies
demonstrating that PIs directly inhibit the translocation
and intrinsic activity of glucose transporter 4 (GLUT4), the
insulin-sensitive glucose transporter (67, 68). GLUT4 is predominantly expressed in tissues responsible for whole-body
glucose disposal, such as skeletal muscle and adipose tissue,
and represents the principal glucose transporter isoform mediating insulin-stimulated glucose uptake at these sites. PIs
may therefore directly induce IR through GLUT4 inhibition,
especially given that glucose transport is the rate-limiting
step for whole-body glucose disposal (68a). Further support
of this theory comes from the observation that IR in this
syndrome often precedes the manifestation of lipodystrophy, suggesting that IR due to PI use may be directly mediated by GLUT4 inhibition rather than occurring secondary
to lipodystrophy.
NRTIs, another important class of medications used in
HAART, have also been implicated in the development of
HIV/HAART-lipodystrophy. Use of this medication class
has been associated with mitochondrial toxicity, which may
be accentuated by concurrent PI use. Mitochondrial DNA
(mtDNA) polymerase, an enzyme essential for mtDNA replication, is acutely sensitive to NRTIs (69, 70). mtDNA encodes genes for several integral enzymes of the respiratory
oxidative phosphorylation electron transport chain. Hence, it
is postulated that the crippling of mitochondrial function due
to NRTI use results in the accumulation of pyruvate and the
subsequent development of lactic acidosis, a potent trigger of
adipocyte death (70a). This process may ultimately contribute to the characteristic lipodystrophic changes observed in
this syndrome.
Virally mediated mechanisms pose yet additional hypotheses for the development of HIV/HAART-associated lipodystrophy. The HIV-1 accessory proteins (Tat, Vpr, Vif, Vpu,
Rev, Nef) play important roles in mediating viral replication
and host cell functions. One such protein, Tat, appears to
heighten tissue sensitivity to glucocorticoids by acting as a
coactivator of the positive transcription elongation factor-␤
complex on glucocorticoid-responsive promoters (71). Another accessory protein, Vpr, increases tissue sensitivity to
glucocorticoids by functioning as a coactivator of promoters
of the glucocorticoid receptor together with host cell coactivators p300/CREB-binding proteins (72). In vitro evidence
has also demonstrated that Vpr inhibits PPAR-␥ activity,
which could contribute to IR and adipocyte apoptosis (73).
Furthermore, Vpr antagonizes the insulin-induced translocation of the forkhead transcription factor (FKHR) from the
nucleus to the cytoplasm. Because FKHR binds to the promoter region of insulin-responsive genes, this action of Vpr
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J Clin Endocrinol Metab, May 2003, 88(5):1961–1976
impedes the transcriptional activity of insulin, thereby conferring a state of IR (74).
HIV/HAART-associated lipodystrophy may therefore be
the result of complex interactions of viral factors and antiretroviral agents (Fig. 5). The elaboration of various cytokines due to the combined interaction of HIV viral proteins
and HAART may mediate or in part explain this interaction.
Before the initiation of antiretroviral therapy, CD4 cells are
predominantly of the T-helper (Th)2 profile and primarily
secrete antiinflammatory cytokines such as IL-4 and IL-10.
After the initiation of HAART, the profile of the CD4 cell
changes to the Th1 subtype. Th1-differentiated CD4 cells
secrete primarily inflammatory cytokines such as IL-2, interferon-␥, and TNF-␣ (75). Th1 cells produce significantly
more TNF-␣ than Th2 or Th3 cells, which express cytokines
such as TGF␤. Additionally, HIV proteins such as Tat may
activate nuclear factor-␬B with subsequent induction of
TNF␣. Data from Ledru et al. (76) suggest that the progressive
increase in TNF-␣ during HAART may mediate some of the
metabolic changes observed in the HIV-lipodystrophy syndrome. TNF-␣ inhibits the uptake of FFA by adipocytes
through suppression of lipoprotein lipase activity and leads
to fat wasting. Furthermore, TNF-␣ increases lipogenesis via
the stimulation of hepatic triglyceride synthetase, resulting
in hyperlipidemia (77), which is positively correlated with
FIG. 5. Postulated pathogenesis of the HIV-associated lipodystrophy
syndrome phenotype. PPRE, PPAR␥ response element; RXRE, RXR
response element; TG, triglycerides.
Leow et al. • Clinical Review
the absolute number of TNF-␣-producing CD8 T-cells in
lipodystrophic HIV-1 infected patients. TNF-␣ also causes IR
directly, by inhibition of insulin signaling transduction at the
insulin receptor, by phosphorylating IRS-1 and decreasing
GLUT4 translocation, and indirectly by increasing FFA levels
(78 – 80). Because adipocytes are also known to secrete
TNF-␣, and because of the fat redistribution observed in this
syndrome, the possibility exists that other adipocyte secreted
proteins may also contribute to worsening IR in HIVHAART-associated lipodystrophy.
The role of adipocyte-secreted proteins in HIV-associated lipodystrophy. Adipose tissue is now viewed as a relatively complex
endocrine organ, given its wide array of secreted proteins
and adipocytokines, many of which appear to play a critical
role in metabolism (81). Adipocyte-secreted proteins such as
leptin, adiponectin, adipsin, perilipin, angiotensinogen,
retinol-binding protein, TNF-␣, PAI-1, IL-6, and metallothionein have all been associated with either IR or features of the
metabolic syndrome (78, 82– 88). Additionally, the role of
regulators of adipocyte differentiation such as PPAR-␥ has
been closely examined, given the improvement in insulin
sensitivity after the administration of PPAR-␥-agonists to
insulin-resistant individuals.
Like TNF-␣, other adipocyte-secreted proteins may also
play an important role in the pathogenesis of the metabolic
abnormalities associated with HIV-associated lipodystrophy. Animal models of complete or partial lipodystrophy
have provided insights into the role of adipose tissue in IR.
Transgenic (A-ZIP/F-1) mice with absent white adipose tissue have a phenotype resembling that of syndrome X and are
metabolically similar to humans with generalized lipodystrophy (89). Expression of molecules such as PPAR-␥, insulin
receptors, IRS-1 and IRS-2, and leptin are down-regulated,
whereas TNF-␣ is increased (90 –91). Transplantation of adipose tissue in diabetic, insulin-resistant mice with lipodystrophy and low serum leptin concentrations resulted in
improved glycemia and a decrease in serum insulin concentrations (92). On the basis of these observations, it appears
that adipose-secreted proteins may increase or decrease insulin sensitivity such that an excess or deficiency of adipocytes could determine whether the metabolic state is one of
insulin sensitivity or one of IR.
Leptin is perhaps the best known adipocyte-secreted protein. Although primarily recognized as a central regulator of
neuroendocrine function, energy balance, and reproductive
function (86, 93), leptin deficiency in rodents and humans is
associated with profound IR and hyperlipidemia. This observation lends support to the hypothesis that adipocytesecreted factors are necessary to maintain metabolic normalcy. Indeed, leptin replacement has been observed to
dramatically improve the metabolic profile in both rodents
and humans with leptin deficiency (94 –98). Leptin replacement in congenitally lipodystrophic mice with DM was
shown to dramatically improve, but not fully normalize, the
metabolic abnormalities (97). Oral et al. (98) made similar
observations after humans with congenital lipodystrophy
were treated with leptin. Furthermore, recent studies have
shown that in vivo leptin administration in rodents leads to
activation of signaling molecules and protein expression that
Leow et al. • Clinical Review
overlap, but are distinct from, signaling and protein expression induced by insulin (99), which may in part explain the
mechanism by which leptin improves insulin sensitivity.
These observations in lipodystrophic rodents and congenitally lipodystrophic humans, together with the observation
of decreased leptin levels in patients with HIV/HAARTassociated lipoatrophy (100), further highlight the potential
role of leptin deficiency in the pathogenesis of IR in these
syndromes. It is important to note, however, that leptin administration to lipodystrophic animals and humans has resulted in only partial improvement in the metabolic abnormalities. This observation suggests that leptin, acting in
concert with other adipocyte-secreted proteins, may be necessary to maintain metabolic normalcy.
Adiponectin (adipocyte complement-related protein-30
kDa, Acrp-30, AdipoQ, apM1, GBP28) is a newly discovered
protein that is secreted exclusively by adipocytes (101–104).
Genomewide scans recently mapped a susceptibility locus
for type 2 DM and the metabolic syndrome to chromosome
3q27 (105, 106). The fact that this locus is the location of the
gene encoding adiponectin emphasizes the potential role of
adiponectin deficiency in the development of IR syndromes.
The concentration of adiponectin in plasma is inversely correlated to fasting insulin levels and IR (88). Interestingly,
although secreted exclusively by adipose tissue, levels of
adiponectin are decreased in the setting of obesity, IR, type
2 DM, congenital lipodystrophy, and CAD (87, 88, 107). Similar to other syndromes of IR, HIV/HAART-associated lipodystrophy is also associated with decreased levels of adiponectin (43, 107a). We have shown in a cross-sectional study
of 112 HIV-infected subjects that adiponectin levels were
decreased in those with fat redistribution, characterized by
central fat accumulation and peripheral fat wasting. Adiponectin levels were inversely correlated with fasting insulin
levels, HOMA-IR, and serum triglycerides, and positively
correlated with HDL cholesterol (43).
Mechanistically, adiponectin increases insulin sensitivity
by inhibiting target hepatic gluconeogenic enzymes such as
phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (108). Adiponectin also reduces IR by up-regulating
the expression of molecules involved in fatty acid combustion and muscle energy expenditure with overall reduction
of triglycerides in muscle and liver as demonstrated in obese
mice (109). Interestingly, one in vitro study demonstrated that
TNF-␣ decreased the expression of the apM1 gene and its
gene product, adiponectin, from 3T3-L1 adipocytes (110).
That HAART has been associated with increased TNF-␣ levels in some studies may explain the decreased adiponectin
levels in this patient population. Additionally, PPAR-␥ agonists, a class of medications associated with improved insulin
sensitivity and increased adipocyte differentiation, have
been shown in in vitro, animal, and human models to increase
adiponectin secretion (111–113). The inhibition of the RXRPPAR-␥ heterodimer by PIs may therefore further implicate
the importance of adiponectin deficiency in the pathogenesis
of HIV/HAART-associated lipodystrophy. Bastard et al.
(114) recently showed that sterol-regulatory-element-binding-protein-1c was decreased in a cohort of patients with
HAART-induced lipoatrophy and that this was associated
with decreased expression of PPAR-␥ and leptin, decreased
J Clin Endocrinol Metab, May 2003, 88(5):1961–1976 1967
adipocyte differentiation, and increased levels of TNF-␣.
Most recently, Yamauchi et al. (111) reported decreased serum adiponectin and leptin levels in a murine model of
lipoatrophy. Partial restoration of insulin sensitivity and
lipid abnormalities was observed after either adiponectin or
leptin was administered. However, the coadministration of
adiponectin and leptin was able to fully correct the metabolic
abnormalities. These observations all suggest that the combined effects of adipocyte-secreted proteins are necessary to
maintain a normal metabolic state and that it is the relative
proportions of adipocyte-secreted proteins that determine
insulin sensitivity or resistance.
The fact that lipodystrophic syndromes are associated
with fat wasting and/or fat redistribution leads to the hypothesis that an excess or deficiency of important adipocytesecreted proteins may explain the IR seen in these patients.
Hypoadiponectinemia and hypoleptinemia have been noted
in patients with congenital and acquired lipodystrophies (43,
100, 107), and leptin replacement in a similar cohort of patients resulted in significant improvement in insulin sensitivity and serum triglycerides (98).
Other adipocytokines such as IL-6 may also be mediators
of IR (85). These cytokines, including TNF-␣, may activate the
I-␬ B kinase complex (IKK), resulting in serine phosphorylation of IRS-1 and inhibition of insulin signaling. Blocking
the effects of the IKK cascade is predicted to increase insulin
sensitivity, thereby implying that IKK may be an excellent
new target for the development of novel drugs to treat IR in
obesity (115). Resistin, yet another newly discovered adipocyte-secreted protein, also appears to be positively correlated
with IR in rodent models. However, its pathogenic role in
humans is currently debated (116). Lastly, PAI-1, although
not related specifically to IR, is closely linked to the metabolic
syndrome, given its association with defective fibrinolysis
and cardiovascular morbidity and mortality (82, 83), as are
other defects in the hemostatic system including hyperuricemia, microalbuminuria, increased factor VIII, and fibrinogen (117, 118).
Adrenal and gonadal hormones may also play a role in the
IR observed in HIV/HAART lipodystrophy. Excess of counterregulatory hormones such as cortisol is one proposed
mechanism of IR (119), especially given that the phenotype
of this syndrome is reminiscent of Cushing’s syndrome. The
association of Cushing’s syndrome with IR is well known.
Although the plasma level of cortisol is typically normal
in the setting of most cases of HIV/HAART-associated
lipodystrophy and these individuals have normal overnight
suppression of cortisol secretion after an evening dose of
dexamethasone, subtle abnormalities on the hypothalamicpituitary-adrenal axis have been detected (120). In a crosssectional study of HIV-infected subjects using HAART,
Christeff et al. (121) showed that subjects with and without
lipodystrophy had higher cortisol levels than non-HIVinfected controls. Moreover, subjects with lipodystrophy had
significantly lower dehydroepiandrosterone levels and an
increased cortisol/dehydroepiandrosterone ratio compared
with nonlipodystrophic HIV-infected controls. Christeff et al.
(121) suggest that these findings may be explained by alterations in steroid metabolism due to changes in P450 enzymes
secondary to HAART and that the fat redistribution, which
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J Clin Endocrinol Metab, May 2003, 88(5):1961–1976
is associated with IR, may be due to a subsequent imbalance
between lipogenesis and lipolysis. Consideration has also
been given to the possibility that local glucocorticoid excess
may lead to IR (121a, 121b). The overexpression of 11-␤
hydroxysteroid dehydrogenase type 1, an oxidoreductase
that catalyzes the conversion of inactive keto-precursors of
steroids to active glucocorticoids in the adipose tissue of
transgenic mice, resulted in the development of visceral obesity, insulin-resistant DM, and hyperlipidemia (122). Thus, it
is possible that fat redistribution and the metabolic syndrome
could involve amplification of glucocorticoid effects selectively confined to adipose tissue via the local action of 11-␤
hydroxysteroid dehydrogenase type 1 without plasma hypercortisolemia. This proposed mechanism lends credence to
the IR and hyperlipidemia, which are commonly associated
with visceral fat accumulation (123–125).
Gonadal androgens have also been associated with IR in
HIV/HAART lipodystrophy. Hadigan et al. (126) observed
that insulin concentrations and IR, as measured by HOMAIR, were inversely associated with serum free testosterone
levels (P ⬍ 0.05) in 50 HIV-infected men with AIDS-wasting
syndrome. Hypogonadal men were randomized to either
testosterone replacement (300 mg im every 3 wk) or placebo
for 6 months. Subjects that received testosterone showed a
reduction in HOMA-IR (⫺0.6 ⫾ 0.7 vs. ⫹1.41 ⫾ 0.8; P ⫽ 0.05,
compared with placebo), which may be due to a significant
increase in lean body mass compared with placebo-treated
men (P ⬍ 0.02). Interestingly, Hadigan et al. (127) also
showed that women with HIV-lipodystrophy characterized
by central fat accumulation had increased insulin and androgen levels as well as an increased LH/FSH ratio compared with nonlipodystrophic HIV-infected women and
non-HIV infected women, similar to what has been observed
in women with polycystic ovarian syndrome. The fact that
insulin levels and androgen levels were positively correlated
with truncal adiposity, but not with each other, emphasizes
the importance of truncal adiposity in both IR and hyperandrogenemia. Nishizawa et al. (128) recently demonstrated
that androgens decrease adiponectin secretion in 3T3-L1 adipocytes, which may in part explain these associations.
Current management strategies and the future
Given the increasing prevalence of HIV/HAART-associated lipodystrophy coupled with the decline in mortality in
this patient population, it has become increasingly important
to diagnose and treat the metabolic and anthropometric abnormalities associated with this syndrome.
Fat redistribution. Currently, there is no single effective Food
and Drug Administration (FDA)-approved measure for the
treatment of fat redistribution in HIV/HAART-associated
lipodystrophy. Although few studies have investigated the
impact of formal exercise programs on anthropometric
changes and metabolic abnormalities, some have suggested
potential benefits as has been shown in non-HIV-infected
populations. One study of 18 HIV-infected men showed that
16 wk of resistance training resulted in no change in total
body fat mass as measured by DEXA (129); however resistance training in this cohort did result in a significant reduction in serum triglycerides. In addition, 12 wk of aerobic
Leow et al. • Clinical Review
exercise did result in decreased BMI, sc fat, and abdominal
girth in a small cohort of patients (130). Sixteen weeks of
combined resistance training and aerobic training in 10 HIVinfected subjects resulted in an overall decrease in total body
fat by 2.1% (P ⬍ 0.01). Most of this change occurred due to
loss of truncal fat, which was decreased by 1.1 kg (P ⬍ 0.03;
Ref. 131). Lastly, one recent case report has suggested that an
exercise program combined with a moderate fat, low glycemic index, and high-fiber diet can reverse many of the lipodystrophic changes observed in HIV-infected patients (132).
It remains to be determined whether dietary factors contribute to changes in body composition or whether dietary
manipulation alone can help to reverse fat redistribution.
Two cross-sectional studies of HIV-infected patients showed
no association between total fat or saturated fat intake and
fat redistribution. However, total energy intake was increased in the fat redistribution compared with the nonfat
redistribution group (133, 133a). Although interventional
studies examining the potential benefits of exercise and dietary interventions in improving changes in body composition and fat distribution have not yet been performed, it is
recommended that diet and exercise plans be included in the
treatment regimens for patients with HIV-lipodystrophy.
Ongoing studies are under way to determine whether
changes in various antiretroviral regimens might improve
lipodystrophy while maintaining HIV infection treatment
goals. There is some suggestion that substituting a NNRTI
for a PI may lead to some improvement in lipodystrophic
changes (134 –135a). Because there are no definitive therapies
for fat redistribution to date, it is important to recognize that
the central fat accumulation seen in many of these patients
has been long associated with an increased risk for cardiovascular disease (136). This point further emphasizes the
need for future interventional studies that target fat redistribution and the associated metabolic changes. Lastly, one
needs to consider that lipodystrophic changes may be perceived as disfiguring by some patients and may ultimately
affect their compliance with antiretroviral therapy.
IR and glucose homeostasis abnormalities. HIV-infected patients
on HAART require regular surveillance to monitor for the
development of IGT or DM. This can be accomplished by
performing an OGTT or by obtaining a measurement of
fasting blood glucose. As in non-HIV-infected patients, diet
and exercise are the initial step in the management of IGT and
DM. One cross-sectional study of HIV-infected subjects suggested that diets with a high polyunsaturated-to-saturated
fat ratio and diets low in fiber are associated with increased
IR, as measured by an OGTT (137), but other studies did not
confirm these associations (133a). Thus, although specific
diet interventional studies are not available, nutritional
counseling is important in these patients. Roubenoff et al.
(132) studied the combined effects of a low-fat, high-fiber diet
and an intense exercise regimen (aerobic plus resistance
training) in one HIV-infected subject with fat redistribution.
IR, as measured by HOMA-IR, was noted to decrease by 52%
(from 29.23 to 14.05). However, Yarasheski et al. (129) found
no significant change in fasting insulin levels in 18 HIVinfected subjects treated with a 16-wk program of resistance
exercise training. As in treating non-HIV-infected patients
Leow et al. • Clinical Review
with DM, pharmacological therapy should be initiated if
treatment goals are not achieved with diet and exercise alone.
Because IGT and DM are diagnoses characterized by IR, use
of insulin-sensitizing therapies such as metformin and thiazolidinediones (TZDs) may specifically target the underlying
mechanism of disease.
Metformin acts as an insulin-sensitizing agent primarily
by inhibiting hepatic gluconeogenesis and, to a much lesser
extent, by promoting peripheral glucose uptake. It has been
commonly used in the treatment of obese patients with type
2 DM and dyslipidemia. Metformin used in patients with IR
results in modest weight reduction, and it has been shown
to decrease plasma insulin, triglycerides, LDL cholesterol,
and FFA (138). Thus, metformin has been studied in a cohort
of HIV-infected subjects with fat redistribution. In one study,
27 subjects received placebo or metformin, 850 mg three
times daily for 8 wk (139). Metformin-treated subjects were
observed to have significant improvements in fasting insulin
(18.4 ⫾ 4.1 vs. 41.7 ⫾ 14.6 mIU/ml; P ⬍ 0.01) and visceral
adipose tissue as measured by DEXA scan (121.8 ⫾ 49 vs.
231.4 ⫾ 52 cm2; P ⬍ 0.01) compared with subjects treated with
placebo. More recently, Hadigan et al. (140) made similar
observations after 26 HIV-infected subjects were randomized
to receive metformin, 500 mg two times daily, or placebo for
12 wk. Compared with placebo-treated subjects, metformintreated subjects had a 20% decrease in insulin levels 120 min
after a 75-g OGTT and were also noted to have significant
decreases in body weight and diastolic blood pressure. Additionally, metformin was well tolerated, with few side effects. Although these initial studies support the use of metformin in HIV-lipodystrophy, longer term interventional
studies are necessary to further evaluate its efficacy and
safety.
TZDs are PPAR-␥ agonists that improve insulin sensitivity
by increasing glucose transport and peripheral glucose disposal as well as by promoting adipocyte differentiation (141,
142). Interestingly, recent studies have shown that TZDs
increase the expression and plasma concentrations of adiponectin, which may explain the associated improvement in
insulin sensitivity with their use (112, 113). Rosiglitazone and
pioglitazone have been approved and are currently used for
the treatment of type 2 DM (143, 144). However troglitazone,
also a TZD, was taken off the market by the FDA because of
rare, but life-threatening, hepatic toxicity, which has not been
reported with use of other TZDs (145). Before its removal
from the market, troglitazone was administered for 3 months
to six HIV-infected patients with DM (146). Four of the six
subjects were observed to have significant improvement in
insulin sensitivity, and two of these four subjects had normalization of insulin sensitivity after 3 months of therapy.
Overall, there was a decrease in total body fat, visceral adipose tissue, serum triglycerides, and serum very LDL,
whereas increases in lean body mass, sc adipose tissue, and
serum HDL were noted. The results of this study may have
been confounded, in part, because troglitazone up-regulates
CYP3A, leading to decreased levels of PIs that are also metabolized by CYP3A. Currently available TZDs do not appear
to have this effect. Troglitazone was also studied in a cohort
of subjects with congenital lipodystrophy with similar improvements (147). Although TZD therapy typically results in
J Clin Endocrinol Metab, May 2003, 88(5):1961–1976 1969
modest weight gain in non-HIV infected patients, the noted
improvements in body fat distribution, insulin sensitivity,
and serum lipids warrant further investigation. Two recent
pilot studies looking at the effect of rosiglitazone in the
treatment of HIV-infected patients have demonstrated conflicting results. In the first study, eight subjects were treated
with 8 mg of rosiglitazone for 6 –12 wk (148). After treatment,
the glucose disposal rate during a hyperinsulinemic-euglycemic clamp improved from 3.8 ⫾ 0.4 to 5.99 ⫾ 0.9 mg
glucose/kg lean body mass/min (P ⫽ 0.02), an improvement
of 59 ⫾ 22%. The authors found that sc adipose tissue increased by 23 ⫾ 10% (P ⫽ 0.05) and that visceral adipose
tissue decreased by 21 ⫾ 8% (P ⫽ 0.04). Another group
performed a similar study, randomizing 30 patients with
HAART-associated lipodystrophy to 8 mg of rosiglitazone or
placebo for 24 wk (149). Compared with placebo, the rosiglitazone group had a significant decrease in fasting insulin
(13 ⫾ 2 to 9 ⫾ 1 mU/liter vs. 10 ⫾ 2 to 16 ⫾ 6 mU/liter; P ⬍
0.05). However, this improvement in insulin sensitivity was
accompanied by significant increases in triglycerides compared with the placebo group (P ⬍ 0.05), and there were no
significant changes in sc fat, visceral fat, or waist-to-hip ratio
(WHR) compared with the placebo group. Ongoing studies
are currently being performed to determine the long-term
safety and efficacy of the use of this class of medications in
the treatment of HIV/HAART-associated lipodystrophy and
the metabolic syndrome.
Dyslipidemia in HIV-associated lipodystrophy syndrome. Although the National Cholesterol Education Program (NCEP)
guidelines are not specifically targeted to the HIV-infected
patient population, it is not unreasonable to follow the NCEP
guidelines, taking into consideration each patient’s risk factors for the development of CAD or other hyperlipidemic
disorders such as pancreatitis.
Nonpharmacological therapies such as dietary intervention are the initial step in treating the lipid abnormalities
associated with HIV-lipodystrophy. Diets high in omega-3
essential fatty acids, as found in fish oil, and mono- and
polyunsaturated fatty acids, as found in walnuts and olive
oil, have been shown to benefit some non-HIV-infected patients with hypertriglyceridemia (150 –153), although no specific interventional studies of diet have been conducted in
HIV-infected subjects. Two cross-sectional studies of HIVinfected subjects showed no significant difference in the total
or saturated dietary fat intake between subjects with and
without fat redistribution and lipid abnormalities (133, 133a).
However, another observational study of 85 consecutively
enrolled HIV-infected patients with fat redistribution demonstrated a strong association of polyunsaturated fats with
hyperlipidemia in this patient population (137). Because
some patients with hyperlipidemia may have concomitant
fat wasting, the advice of a dietician is recommended to
avoid unnecessary weight loss that might result from a lowfat diet. Exercise, weight loss, if appropriate, and reduced
alcohol consumption may additionally contribute to decreased serum triglyceride levels (154, 155). Although dietary
interventions and lifestyle changes may offer some improvement in serum lipid elevations, pharmacological therapy is
usually necessary to achieve treatment goals.
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J Clin Endocrinol Metab, May 2003, 88(5):1961–1976
The hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA)
reductase inhibitors (statins), although efficacious in lowering total and LDL cholesterol in non-HIV-infected patients,
have not been studied in HIV-infected patients whose primary lipid abnormality is hypertriglyceridemia. Atorvastatin and higher doses of simvastatin (40 mg and 80 mg) have
both been shown to exhibit some effect in lowering serum
triglycerides compared with the other HMG-CoA reductase
inhibitors (156 –158). It is important to remember that the
pharmacokinetics of these medications are variably altered
when coadministered with some antiretroviral therapies.
The HMG-CoA reductase inhibitors and many antiretroviral
medications, specifically PIs, are metabolized by the cytochrome-P450 enzyme system in the liver. Competition for the
same enzyme system may therefore contribute to significant
drug interactions between medication classes such that the
half-life of a given statin may be increased or decreased. The
ACTG 5047 trial investigating the interaction of PIs and
HMG-CoA-reductase inhibitors found that levels of atorvastatin and simvastatin, two commonly used HMG-CoAreductase inhibitors, are increased by 343% and 2676%, respectively, in the presence of the PIs ritonavir and saquinavir
(159). Conversely, the level of pravastatin was reduced by
nearly 50%. However, none of the statins altered the level of
ritonavir or saquinavir to any significant degree. One should
therefore be cautious in prescribing a statin concurrently
with a PI, and serious consideration should be given to use
of pravastatin if a statin is deemed necessary. Concomitant
statin and PI therapy obligates strict adherence to regular
monitoring of liver chemistries. One should also bear in mind
that most HIV-infected patients are taking other medications
that may alter the pharmacokinetics of statin metabolism.
Caution is therefore warranted with the use of this class of
lipid-lowering agents.
Fibric acid derivatives, including clofibrate, fenofibrate,
and gemfibrozil, do not appear to interact with antiretroviral
agents. Although studies to directly compare the available
agents in this class have not been performed, this is perhaps
the best class of lipid-lowering agents to treat hypertriglyceridemia and low HDL cholesterol, which are the primary
lipid abnormalities associated with HIV-lipodystrophy
(159a). Although use of these agents can lower serum triglycerides by as much as 55% (160), these medications have
not been extensively evaluated in HIV-infected patients. One
retrospective study of eight HIV-infected patients taking
both a PI and a minimum of 4 wk of gemfibrozil showed a
decrease in median triglyceride levels from 1803 mg/dl to
300 mg/dl, but safety data were not provided (49). Another
study examined 24 HIV-infected patients treated with diet
and exercise, gemfibrozil, atorvastatin, or gemfibrozil plus
atorvastatin (161). Although use of a fibric acid derivative in
combination with a statin may potentially result in rhabdomyolysis, this was not reported in the study, and there were
no reported increases in creatinine phosphokinase or liver
transaminases. A reduction in serum cholesterol compared
with baseline was noted in all three pharmacologically
treated groups: gemfibrozil (⫺32%; P ⫽ 0.002), atorvastatin
(⫺19%; P ⫽ 0.004), and combination therapy (⫺30%; P ⫽
0.004). Triglyceride reduction was similar between the gemfibrozil-treated (57%; P ⫽ 0.01) and combination therapy
Leow et al. • Clinical Review
groups (60%; P ⫽ 0.01) but was not significantly lowered in
the atorvastatin-only group. Although use of fibric acid derivatives may be the safest means of lowering serum triglycerides, use of these agents needs to be balanced with
potential gastrointestinal side effects, which may limit their
use. The use of any particular statin or fibrate in HIV-infected
patients on PI-containing HAART should be guided by established drug interaction data and dictated by individual circumstances after appropriate risk vs. benefit considerations.
Other lipid-lowering therapies used in non-HIV-infected
patients may not be suitable for HIV-infected patients. Resins, such as cholestyramine and colestipol, are commonly
associated with gastrointestinal side effects, which may limit
their use. Additionally, these agents may result in increased
triglyceride levels (160) and impairment of the absorption of
other medications. Niacin is another lipid-lowering agent
that is effective in lowering LDL and total cholesterol in
non-HIV-infected patients. However, niacin may not be suitable for use in HIV-infected patients with hyperlipidemia
because it may cause significant side effects, including flushing, liver toxicity, hyperglycemia, and worsening of IR. For
these reasons, use of resins and niacin is not currently recommended for the treatment of hyperlipidemia in HIVinfected patients.
The effect of changing antiretroviral regimens on the metabolic
syndrome. Because specific antiretroviral therapies have been
associated with the development of lipodystrophy in HIVinfected patients, some studies have evaluated the role of
changing antiretroviral treatment regimens with the therapeutic goal of reversing the metabolic changes observed in
this syndrome, while at the same time maintaining adequate
HIV suppression. Some studies have assessed the effect of
substituting one PI for another in a given antiretroviral regimen. Because ritonavir is reportedly the PI most commonly
associated with lipodystrophy, one study retrospectively examined the effect of substituting this PI with another PI, such
as nelfinavir or indinavir, on hyperlipidemia (48). Both
plasma cholesterol and triglycerides were significantly reduced 29 – 63 d after the substitution, however these data
represent observations from only seven subjects.
Other studies have examined the effect of substituting a
NNRTI for a PI. In one prospective open-label pilot trial, 40
patients with an undetectable viral load on a PI-containing
regimen were switched to the NNRTI, nevirapine (163). Fasting triglyceride levels were significantly decreased (31%; P ⫽
0.005) a mean of 24 wk after the change; however, cholesterol
levels were not significantly different. The virologic status
worsened after the change in antiretroviral therapies in one
subject, but this change improved after resumption of the PI.
In a similar uncontrolled study, 20 subjects with an undetectable viral load were switched from a PI to the NNRTI,
efavirenz (164). Six months after the change, triglycerides
had decreased by 31% (P ⫽ 0.03), total and HDL cholesterol
levels were not significantly different, and the viral load
became detectable in one subject. Although these studies
demonstrate an encouraging improvement in serum triglycerides after changing from a PI to a NNRTI, other studies
have not shown significant changes in lipid profiles (165,
166). However, one study, although not showing any im-
Leow et al. • Clinical Review
provement in the lipid parameters of 138 subjects followed
for 6 months after changing from PI-based therapy to nevirapine, did show modest improvements in lipodystrophic
changes (167). Body fat redistribution was present in 70% of
subjects at the time of randomization and was partially improved in 50% of these subjects 6 months after the PI was
replaced by nevirapine.
Although these studies have demonstrated no significant
reduction in antiretroviral efficacy, the change in medication
classes did not significantly reverse all lipodystrophic
changes, and only modest improvement in morphologic
changes was observed. However, one study did show favorable improvements in dyslipidemia and IR. Martinez et al.
(168) followed 23 subjects whose PI was replaced by nevirapine. Six months after PI withdrawal, total cholesterol decreased by 22% (P ⫽ 0.0005), triglycerides decreased by 57%
(P ⫽ 0.0001), glucose decreased by 15% (P ⫽ 0.008), fasting
IR index decreased by 45% (P ⫽ 0.0001), and WHR decreased
from 0.91 to 0.85 (P ⫽ 0.048). A total of 91% of the subjects
self-reported improvement in body fat redistribution, particularly peripheral fat wasting, and only one patient had
significant worsening in the viral load. Although changing
PI-based therapy to NNRTI-based therapy may present a
viable option for the treatment of HAART-associated lipodystrophy, long-term follow-up data are not currently available. Although there are seemingly few adverse outcomes
associated with changes in HAART, it is not known whether
these changes may induce the development of drug resistance in HIV infection. This further highlights the need for
larger, controlled trials with long-term follow-up. Changes in
HAART should therefore be made only under the guidance
of HIV-infection specialists.
Novel approaches. The challenge of understanding medical disorders such as HIV/HAART-associated lipodystrophy at the
molecular level has become increasingly important for the development of new and efficacious therapies. The development
of novel therapeutic approaches for the treatment of this syndrome will undoubtedly rely on the use of genetics and molecular biology to better define therapeutic targets for the treatment of IR and fat redistribution, as perhaps evidenced by the
use of recombinant therapies such as human GH.
Recombinant human GH (rhGH) was approved for the
treatment of HIV-associated wasting in 1996 (169). Although
GH deficiency has not been observed in patients with HIV/
HAART-associated lipodystrophy, the reduction in total
body and visceral fat mass after the administration of rhGH
(9.5 ␮g/kg䡠d) to non-HIV-infected men with abdominal obesity (170) has prompted the investigation of rhGH therapy in
HIV-infected patients with lipodystrophy. Early studies using pharmacological doses of rhGH (4 – 6 mg/d) demonstrated improvement in body fat redistribution as evidenced
by decreased mean change in trunk fat mass or decrease in
WHR, however worsening glucose tolerance was also noted
in rhGH-treated subjects (171–173). In follow-up to these
initial studies, an open-label study was conducted to evaluate the effects of a lower pharmacological dose of rhGH (3
mg/d) in eight HIV-infected men with fat redistribution
(174). Significant decreases in total body fat (17.9 ⫾ 10.9 vs.
13.5 ⫾ 8.4 kg; P ⫽ 0.05), primarily in the trunk region, and
J Clin Endocrinol Metab, May 2003, 88(5):1961–1976 1971
increases in lean body mass (62.9 ⫾ 6.4 vs. 68.3 ⫾ 9.1 kg; P ⫽
0.03) were observed after 6 months of therapy. However,
insulin-mediated glucose disposal, as measured by the hyperinsulinemic-euglycemic clamp, decreased significantly
after 1 month of therapy before returning to baseline after 6
months of therapy. Importantly, rhGH therapy in this study
resulted in IGF-I levels that were up to three times the upper
limit of normal range. A companion study of five HIVinfected subjects showed that the same dose of GH (3 mg/d)
resulted in significant improvement in serum lipids after 6
months of therapy (175). Total cholesterol deceased by 25%
(P ⬍ 0.01), LDL cholesterol decreased by 30% (P ⬍ 0.01), HDL
increased by 15% (P ⬍ 0.01), and triglycerides decreased
(data not given; P ⬍ 0.01). These improvements in serum
lipids were accompanied by significant increases in fasting
endogenous glucose production (12.0 ⫾ 0.7 vs. 14.9 ⫾ 0.9
␮mol/kg䡠min; P ⬍ 0.03) after 1 month of therapy, however
this was not significantly different from baseline after 6
months of therapy. Most recently, 30 HIV-infected subjects
were studied in a 24-wk prospective open-label trial of GH
6 mg/d vs. rhGH 4 mg on alternate days (176). Visceral fat,
as measured by MRI, decreased by an average of 42% (P ⬍
0.001) in the 6 mg/d group (n ⫽ 24) and by an average of 15%
(P ⬍ 0.01) in the alternate day therapy group (n ⫽ 10). Of
note, four subjects in the study developed DM, and side
effects included myalgias and joint pain. Because of the variable improvement in features of the metabolic syndrome and
because of the significant increases in IGF-I, which may potentially lead to long-term adverse effects in these immunocompromised patients (177), rhGH cannot currently be recommended for treatment of HIV/HAART-associated
lipodystrophy. Use of this therapy clearly warrants close
monitoring for the development of glucose intolerance
and/or DM. Future studies are necessary to investigate the
metabolic effects of lower rhGH doses in an attempt to keep
IGF-I in the normal range.
One promising therapy for the treatment of HIV/HAARTassociated lipodystrophy is leptin, the product of the Ob
gene. The levels of this adipocyte-secreted protein are markedly decreased in both lipodystrophic humans and animal
models of lipodystrophy (92, 100, 107). Leptin deficiency in
mice causes increased hepatic lipogenesis through the action
of the sterol regulatory element binding protein-1c and accentuates hepatic gluconeogenesis through down-regulation
of IRS-2 (178). The hyperglycemia, in turn, stimulates insulin
secretion and initiates a vicious cycle of IR. Predictably, leptin has been shown to dramatically improve IR and diabetes
in mice with lipodystrophy (97). Recently, nine patients with
congenital and acquired (non-HIV) lipodystrophy received
twice daily recombinant leptin via sc injection for 4 months
to achieve physiological leptin concentrations (98). Subjects
were observed to have significant improvements in hyperglycemia, hyperinsulinemia, hypertriglyceridemia, as well
as a significant decrease in fatty infiltration of the liver. In
light of a recent study demonstrating leptin deficiency in
patients with HIV/HAART-associated lipodystrophy (100),
leptin replacement in this patient population theoretically
could reverse many of the metabolic abnormalities observed
in this syndrome. Although recombinant leptin is not yet
commercially available, trials of leptin administration to
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J Clin Endocrinol Metab, May 2003, 88(5):1961–1976
HIV-infected patients with the lipodystrophy syndrome are
currently under way.
Given that recent data have shown complete normalization of IR after the coadministration of leptin and adiponectin
in a murine model of lipoatrophic diabetes (111) and that
patients with HIV/HAART lipodystrophy have both leptin
and adiponectin deficiencies (43, 100), attention is now additionally focused on future trials of adiponectin, either alone
or with leptin, as another treatment option for this syndrome.
Undoubtedly, other newly discovered adipocyte-secreted
proteins, such as resistin, will also be investigated to explore
the potential pathogenic role they may play in the development of IR. As our knowledge of the complex endocrine
functions of the fat cell expands in tandem with our ability
to manipulate gene expression, we may ultimately have viable options for the treatment of HIV/HAART-associated
lipodystrophy and other IR syndromes.
Conclusions
In summary, HIV/HAART-associated lipodystrophy is
most likely a multifactorial disorder due to the interplay of
viral, host, and drug-related factors. Among the many drugs
used to treat HIV infection, PIs and NRTIs have emerged as
two classes of medications that may play a pathogenic role.
The synergy between medication classes such as these and
viral factors results in a characteristic phenotype typified by
lipodystrophic changes, lipid abnormalities, and IR. It is
hoped that ongoing research into the molecular mechanisms
of IR in the context of HIV infection and antiretroviral therapy will ultimately provide viable treatment options for patients with this syndrome. Given the heightened risk for the
development of cardiovascular disease and DM in this growing patient population and the decreased mortality now associated with HIV infection, these therapies will prove to be
crucial.
Acknowledgments
Received October 31, 2002. Accepted February 19, 2003.
Address all correspondence and requests for reprints to: Christos S.
Mantzoros, M.D., D.Sc., Division of Endocrinology, Diabetes and
Metabolism, Department of Internal Medicine, 99 Brookline Avenue,
Research North 325, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, Massachusetts 02215. E-mail: cmantzor@
caregroup.harvard.edu.
This work was supported by an American Diabetes Association Clinical Research Grant and National Institutes of Health (NIH) Grant DK58785-R01 (to C.S.M.), and by NIH Grant K30-HL04095 (to Harvard
Medical School).
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