Metabolic and Cardiovascular Complications of Highly Active Antiretroviral Therapy for HIV Infection

Abstract

Highly active antiretroviral therapy (HAART) regimens, especially those including protease inhibitors have been shown to cause, in a high proportion of HIV-infected patients, a metabolic syndrome (lipodystrophy/lipoatrophy, dyslipidemia, type 2 diabetes mellitus, insulin resistance) that may be associated with an increased risk of cardiovascular disease. A careful stratification of the cardiovascular risk of HIV-infected patients under HAART is needed according to the most recent clinical guidelines.

Full text

Current HIV Research, 2006, 4, 79-85 79
1570-162X/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd.
Metabolic and Cardiovascular Complications of Highly Active Antiretroviral
Therapy for HIV Infection
Giuseppe Barbaro*
Department of Medical Pathophysiology, University “La Sapienza”, Rome, Italy
Abstract: Highly active antiretroviral therapy (HAART) regimens, especially those including protease
inhibitors have been shown to cause, in a high proportion of HIV-infected patients, a metabolic syndrome
(lipodystrophy/lipoatrophy, dyslipidemia, type 2 diabetes mellitus, insulin resistance) that may be associated
with an increased risk of cardiovascular disease. A careful stratification of the cardiovascular risk of HIV-
infected patients under HAART is needed according to the most recent clinical guidelines.
Keywords: Human immunodeficiency virus, highly active antiretroviral therapy, nucleoside reverse transcriptase inhibitors,
protease inhibitors, metabolic syndome, cardiovascular disease.
INTRODUCTION
The introduction of highly active antiretroviral therapy
(HAART) has significantly modified the course of human
immunodeficiency virus (HIV) disease, with longer survival
and improved quality of life in HIV-infected subjects.
However, HAART regimens, especially those including
protease inhibitors (PIs) have shown to cause in a high
proportion of HIV-infected patients metabolic
(dyslipidemia,insulin-resistance) and somatic (lipodystrophy
/lipoatrophy) changes that in the general population are
associated with an increased risk of cardiovascular disease
(coronary artery disease and stroke), producing an intriguing
clinical scenery.
The purpose of this review is to analyse the metabolic
and cardiovascular complications of drugs used to treat HIV
infections and to define the clinical guidelines for stratifying
the cardiovascular risk and cardiovascular monitoring of
HIV-infected patients receiving HAART.
HAART-ASSOCIATED METABOLIC SYNDROME
Molecular Mechanisms
The development of HAART-associated metabolic
syndrome is complex and a number of factors are involved,
including direct effects of HAART on lipid metabolism,
endothelial and adipocyte cell function, and mitochondria.
PIs-Associated Somatic and Metabolic Alterations
PIs target the catalytic region of HIV-1 protease. This
region is homologous with regions of two human proteins
that regulate lipid metabolism: cytoplasmic retinoic-acid
binding protein-1 (CRABP-1) and low density lipoprotein-
receptor-related protein (LRP) [13,14]. It has been
hypothesized, although without strong experimental support,
that this homology may allow PIs to interfere with these
proteins, which may be the cause of the metabolic and
somatic alterations that develop in PIs-treated patients
*Address correspondence to this author at the Viale Anicio Gallo 63,
00174 Rome, Italy; Tel/Fax: +39-6-7102889; E-mail: g.barbaro@tin.it
[13,14]. The hypothesis is that PIs inhibit CRABP-1-
modified and cytochrome P450-3A-mediated synthesis of
cis-9-retinoic acid and peroxisome proliferator-activated
receptor type-gamma heterodimer. The inhibition increases
the rate of apoptosis of adipocytes and reduces the rate at
which pre-adipocytes differentiate into adipocytes, with the
final effect of reducing triglyceride storage and increasing
lipid release. PIs-binding to LRP would impair hepatic
chylomicron uptake and endothelial triglyceride clearance,
resulting in hyperlipidemia and insulin resistance [13,14].
Ultrastructural analysis of adipocytes in PI-induced
lipodystrophy reveals changes including disruption of cell
membranes, fragmented cytoplasmic rims, irregular cell
outlines, and eventually fat droplets laying free in the
connective tissue, with macrophages around them. Many
adipocytes show variable compartmentalization of fat
droplets with decrease in cell size and abundant,
mitochondria-rich cytoplasm. These findings suggest that
HAART-associated lipodystrophy may be the result of
adipocyte remodeling involving variable combinations of
apoptosis, defective lipogenesis, and increased metabolic
activity in different adipose areas of the body [14].
Vernochet et al. assessed the effect of six different PIs on
the differentiation of cells from four clonal lines. They also
studied the capacity of ritonavir to accumulate both into
drug-sensitive and drug-resistant cultured adipocytes [52]. In
this study adipocyte differentiation of mouse 3T3-F442A,
3T3-L1 and Ob1771 cells as well as embryonic stem cells
were investigated at pharmacological concentrations of
indinavir, saquinavir, ritonavir, amprenavir, nelfinavir and
lopinavir [52]. The authors used a sensitive ELISA to
determine intracellular concentration of ritonavir from 3T3-
L1 and Ob1771 preadipocytes. Nelfinavir and lopinavir
inhibited adipocyte differentiation whereas amprenavir was
ineffective. Indinavir, saquinavir and ritonavir inhibited
differentiation of 3T3-L1 and 3T3-F442A cells but did not
alter differentiation of either Ob1771 or embryonic stem
cells. The authors showed that ritonavir accumulated in
preadipocytes and fully differentiated 3T3-L1 adipocytes as a
function of its extracellular concentration [52]. Although
Ob1771 cells were resistant and 3T3-L1 cells were sensitive
to ritonavir, the drug accumulated to similar levels in both
cases. According to the results of this experimetal study PIs

80 Current HIV Research, 2006, Vol. 4, No. 1 Giuseppe Barbaro
inhibit adipocyte differentiation depending on the cell model
used. Ritonavir seems to accumulate into preadipocytes and
adipocytes, suggesting a direct effect on intracellular targets.
However, intracellular accumulation was clearly not
sufficient as Ob1771 cells remained resistant to the
inhibitory effect of ritonavir [52].
Some data indicate that PIs-associated dyslipidemia may
be caused, at least in part, either by PIs-mediated inhibition
of proteasome activity and accumulation of the active
portion of sterol regulatory element-binding protein
(SREBP)-1c in liver cells and adipocytes [40], or by apo C-
III polymorphisms in HIV-infected patients [19]. Bonnet et
al. have described a two- to three- fold increase in apo-E and
apo C-III, essentially recovered as associated to apo B-
containing lipoparticles [5]. In this study, multivariate
analysis revealed that, among the investigated parameters,
apo C-III was the only parameter strongly associated with
the occurrence of lipodystrophy [5].
Sequence homologies have been described between HIV
protease and human site-1 protease (S1P), which activates
SREBP-1c and SREBP-2 pathways. A polymorphism in the
S1P/SREBP-1c gene confers a difference in risk for
development of an increase in total cholesterol with PIs
therapy. This suggests the presence of a genetic
predisposition to hyperlipoproteinemia in PIs-treated
patients [9]. There is also evidence that PIs directly inhibit
the uptake of glucose in insulin-sensitive tissues, such as fat
and skeletal muscle, by selectively inhibiting the glucose
transporter Glut4 [41].
Tumor Necrosis Factor-Alpha (TNF-alpha) and
Lipodystrophy
The relationship between the degree of insulin resistance
and levels of soluble type-2-TNF-alpha receptor suggests
that an inflammatory stimulus may contribute to the
development of HIV-associated lipodystrophy [42]. TNF-
alpha activates 11-beta-hydroxysteroid dehydrogenase type-1,
which converts inactive cortisone to active cortisol. The
activity of this enzyme is higher in visceral fat compared to
subcutaneous fat. Visceral fat is able to locally produce
cortisol which could act inside adipocytes and increase lipid
accumulation [25].
Mitochondrial Dysfunction and Lipodystrophy
There is evidence for nucleoside-induced mitochondrial
dysfunction in HIV-infected patients treated with nucleoside-
containing HAART because lipodystrophy with peripheral
fat wasting is associated with a decrease in subcutaneous
adipose tissue mitochondrial DNA content [8]. This effect
has been especially described with the use of stavudine and
was correlated with the length of exposure to this drug [47].
HAART regimens with didanosine plus stavudine are more
likely to produce a greater increase in serum lactate and
lipodystrophy than therapies based on zidovudine plus
lamivudine within the first year of therapy [8]. Sobstitution
of stavudine with abacavir or zidovudine improves
mitochondrial indices and fat apoptosis in the setting of
lipoatrophy [38].
Adipocytokines and HAART-Associated Metabolic
Syndrome
Adipocytes secrete a range of adipocytokines which
control insulin sensitivity [53]. There is evidence that an
adipocytokine, adiponectin, a protein product of the apM1
gene, which is expressed exclusively in adipocytes [30],
plays a role in development of HIV-associated
lipodystrophy.
In vitro and animal studies and cross-sectional studies in
humans have shown that adiponectin is inversely correlated
with features of this metabolic syndrome including obesity,
insulin resistance, type 2 diabetes, and coronary heart
disease, as well as congenital and acquired lipodystrophies
in non-HIV infected subjects. This syndrome has recently
been linked to a quantitative trait locus on chromosome
3q27, the location of the apM1 gene [1].
In a study of 112 HIV-infected patients receiving
HAART, adiponectin was significantly correlated with
triglycerides, abdominal visceral fat, extremity fat, insulin
resistance, nucleoside-reverse transcriptase inhibitors
(NRTIs) use, and high density lipoprotein (HDL) cholesterol
levels using bivariate analysis [1]. The association of
adiponectin with insulin resistance became nonsignificant
after adjusting for NRTIs use, suggesting that changes in
adiponectin levels may underlie the worsening effect of
NRTIs use on insulin resistance. This latter effect has been
recently correlated to the length of exposure to NRTIs (odds
ratio: 1.08 for each additional year of exposure to NRTIs)
[7]. The associations of adiponectin with triglycerides and
insulin resistance were also slightly weakened after adjusting
for visceral and extremity fat, indicating that adiponectin
may, in part, mediate the effect of lipodystrophy on
triglycerides and insulin resistance in HIV-infected patients
receiving HAART [1].
In a study of 131 consecutive HIV-infected males under
PIs-based HAART insulin sensitivity correlated positively
with adiponectin and negatively with leptin and interleukin-
6 [53]. Insulin resistance, metabolic defects and
cardiovascular risk markers were strongly correlated with the
adiponectin/leptin ratio, suggesting that adiponectin is
related to lipodystrophy, insulin resistance and metabolic
alterations in HIV-infected patients under PIs-based HAART
and that adiponectin/leptin ratio could predict insulin
sensitivity and potential cardiovascular risk in these patients
[53]. Similar results have been reported also in a cross-
sectional study by Kosmiski et al. [35]. In this study
adiponectin levels were significantly and positively
correlated with insuline sensitivity after adjustment for fat
mass and adiponectin level was also an independent
determinant of insuline sensitivity [35].
HAART and Endothelial Dysfunction
In vitro data suggest that some HAART regimens, such
as those including zidovudine, some non-nucleoside reverse
transcriptase inhibitors (e.g. efavirenz) and PIs disrupt
endothelial cell junctions and cytoskeleton actin of the
endothelial cells leading to endothelial dysfunction [20].
These findings are in agreement with those previously
reported In vivo by Stein et al. [48] and in vitro by Zhong et
al. [56].

Metabolic and Cardiovascular Complications of HAART Current HIV Research, 2006, Vol. 4, No. 1 81
Fig. (1). Prevalence of the principal clinical and laboratory findings observed in HIV-infected patients after the introduction of
HAART compared to the pre-HAART period.
CLINICAL FINDINGS AND THERAPEUTIC
GUIDELINES
The prevalence of the principal clinical and laboratory
findings observed in HIV-infected patients after the
introduction of HAART compared to the pre-HAART period
is represented in Fig. 1.
Fat redistribution. HIV-associated lipodystrophy or
lipoatrophy, unreported before the introduction of HAART,
was first described in 1998 [13]. It is characterized by the
presence of a dorsocervical fat pad (also known as buffalo
hump), increased abdominal girth and breast size,
lipoatrophy of subcutaneous fat of the face, buttocks and
limbs, and prominence of veins on the limbs. The overall
prevalence of at least one physical abnormality is thought to
be about 50% in otherwise healthy HIV-infected patients
receiving HAART, although reported rates range from 18%
to 83% [26]. Differences in rates might be influenced by age,
sex, the type and duration of antiretroviral therapy, and the
lack of an objective and validated case definition [26]. As in
genetic lipodystrophy syndromes [23], fat redistribution may
precede the development of metabolic complications in HIV-
infected patients receiving HAART. The severity of these
metabolic abnormalities increases with increasing severity of
lipodystrophy, and they are associated with a raised risk of
cardiovascular events: approximately 1.4 cardiac events per
1000 years of therapy according to the Framingham score
[26]. There is no clinically proven therapy for any feature of
lipodystrophy [10]. One approach to treatment of
lipodystrophy in patients treated with PIs is switching to
PIs-free combination regimens. Although large randomized
trials are lacking, some favourable effects have been shown
[11,15,45].
Dyslipidemia. Increased serum total and low density
lipoprotein (LDL) cholesterol and triglyceride levels have
been observed in about 70% of HIV-infected patients with
lipodystrophy [10]. Guidelines for the management of
dyslipidemias in the general population, such as those of the
National Cholesterol Education Program [18,18] also
represent the basis for therapeutic recommendations in HIV-
infected individuals, as reported by the HIV Medicine
Association of the Infectious Disease Society of America and
Adult AIDS Clinical Trial Group [31] and by the Pavia
Consensus Statement [54].
Fibrates and statins can lower HAART-associated
increases in cholesterol and triglyceride levels [31], although
further data on potential interactions between these drugs and
PIs are needed. Most statins are metabolized through the
CYP3A4 pathway and, therefore, inhibition of CYP3A4 by
PIs could lead to notably raised concentrations of statins,
thus increasing the risk of skeletal muscle or hepatic toxic
effects. The statins least influenced by the CYP3A4
metabolic pathway are pravastatin and fluvastatin [31,54].
Fibrates are unlikely to have significant interactions with
PIs, since their principal metabolic pathway is CYP4A.
Omega-3-fatty acids may be helpful, even though not already
tested in this subset of patients.
As for lipodystrophy, an option in the treatment of
dyslipidemia in patients receiving PIs-including HAART is
to switch to a combination regimen without PIs [11,15,45].
Atazanavir, a novel azapeptide PI, seems not to be associated
with significant dyslipidaemia and insulin resistance as seen
with other PIs [44]. The results of a phase 2 randomized trial
that compared lipid changes after 32 weeks of therapy with
atazanavir with those with nelfinavir (each in combination
with stavudine and lamivudine) showed that levels of total
cholesterol and LDL cholesterol increased significantly more
among patients who used nelfinavir (+24% and +28%,
respectively) than among those who used atazanavir (+4%
and +1%, respectively) [27]. However, these data need to be
confirmed by further controlled prospective trials. Of interest
are data indicating that patients never treated with HAART,
who started a PIs-sparing regimen including nevirapine
showed a significant increase of HDL-cholesterol [51].

82 Current HIV Research, 2006, Vol. 4, No. 1 Giuseppe Barbaro
Table 1. Cardiovascular Risk Stratification of HIV-Infected Patients Receiving Haart [54]
1. All HIV-infected patients should have cardiovascular risk factors evaluated according to the Framingham score before receiving HAART. The use
of Framingham score and other non-invasive investigations of cardiovascular risk may help in the decision regarding the use of antiretrovirals and
other treatment. Blood tests for preventive cardiology (eg, complete blood count to determine anemia and/or other hematologic abnormalities,
determination of serum electrolytes, assessment of renal and hepatic function, assessment of thyroid function) should be routine before and during
HAART (every 3-6 months).
2. Routine assessment (at least twice a week) of blood pressure in HIV-infected patients is important because these patients seem to be at higher risk of
developing hypertension and of developing it at a younger age than the general population. Predisposing conditions including vasculitis, acquired
glucocorticoid resistance, acute and chronic renal failure, and drug interactions should be carefully assessed.
3. Before HAART is started, lipid profiles should be measured after an 8-12 hour fast to establish a baseline, and the measurements should be repeated
routinely during the HAART therapy. Serum glucose and hemoglobin A1C measurements are especially indicated for patients on HAART.
4. Fasting lipids and glucose should be measured before the initiation of HAART and at regular 3-6 month intervals thereafter. For patients with
elevated triglyceride levels at baseline, lipid measurements should be repeated within 1-2 months of starting HAART.
5. The routine evaluation of coagulation parameters is probably not advisable until the benefit of widespread screening is assessed in prospective
studies. However, clinicians should be aware of the increased risk of coagulative disorders in patients on HAART, especially in those with HAART-
associated metabolic syndrome, and should check coagulative parameters (D-dimer, plasminogen activator inhibitor-1, tissue-type plasminogen
activator antigen, protein S, protein C and antithrombin III) at least once a year in patients on HAART.
6. Elevated plasma homocysteine level is recognized as independent factor for atherosclerosis and cardiovascular disease. It is caused by genetic
variants [homozygous mutations (C677T and A1298C) of the MTHFR gene], malnutrition, drugs or renal failure. Especially when above 10
micromol/l, it can be treated with dietary supplementation of folic acid, vitamin B6, and vitamin B12. Plasma homocysteine level should be checked
at least once a year in HIV-infected patients with at least two major cardiovascolar risk factors and in those who receive PIs.
According to a recent study, lipid profile improves by
replacing PIs with efavirenz, nevirapine or abacavir with
more marked results in non-lipodystrophic patients. In
contrast, this strategy does not seem to be effective for
reversing body fat abnormalities [21]. According to another
study the efavirenz-induced increase in HDL-cholesterol is
influenced by the multidrug resistance gene 1 C3435T
polymorphism [2].
Dysglycemia
Insulin resistance (elevated C-peptide and insulin) and
type 2 diabetes mellitus have been observed in 8% to 10%
of the patients with lipodystrophy [10].In managing glucose
abnormalities in HIV-infected patients receiving HAART, it
is important to remember that some glitazones are
metabolized by the CY3A4 pathway, which could increase
the risk of developing myositis and hepatitis if used
simultaneously with PIs [54]. Although some studies have
shown that the use of glitazones for the treatment of HIV-
associated lipodistrophy or lipoatrophy leads to an
improvement in insulin resistance, contrasting findings
suggest that further work is needed [12].
Hypertension
The prevalence of hypertension in HIV disease has been
estimated to be about 20-25% before the introduction of
HAART [3]. Hypertension is currently considered part of
HAART-associated metabolic syndrome [24]. It appears to
be related to PIs-induced lipodystrophy and metabolic
disorders, especially to elevated fasting triglyceride and
insulin resistance, with a prevalence of up to 74% in patients
with HAART-associated metabolic syndrome [24,46]. When
treating hypertension in HIV-infected patients with HAART-
associated metabolic syndrome, it should be noted that beta-
blockers and diuretics might worsen the metabolic profiles
of these patients. In addition, calcium-channel blockers
should be used with caution, since they may interact with
PIs. No interactions between NRTIs and nucleotide reverse
transcriptase inhibitors and antiarrhythmics, statins or
anticoagulants diseases have, however, been documented.
Angiotensin-converting-enzyme inhibitors and angiotensin
II-receptor blockers might be considered, but data from
controlled clinical trials assessing these drugs in this subset
of patients are lacking.
HAART AND RISK OF CARDIOVASCULAR
DISEASE
Coronary heart disease. HIV-infected patients with pre-
existing additional risk factors (e.g. hypertension, diabetes
or increased plasma homocysteine levels) might be at raised
risk of developing coronary heart disease because of
accelerated atherosclerosis. Cardiovascular risk stratification
of HIV-infected patients receiving HAART according to the
Pavia Consensus Statement [54] has been reported in Table
1. Conflicting data exist, however, on the relationship
between HAART and the incidence of acute coronary
syndromes, such as unstable angina or myocardial infarction,
among HIV-infected patients receiving PIs-containing
HAART [4,6,22,32,37]. Differences in the study design,
selection of the patients and statistical analyses might
explain this disparity. However, longer exposure to HAART
and/or PIs seem to increase the risk of myocardial infarction.
The results of the Data Collection on Adverse Events of
Anti-HIV Drugs study showed that HAART therapy is
associated with a 26% relative risk increase in the rate of
myocardial infarction per year of HAART exposure [22].
Peripheral vascular disease. Also the issue of surrogate
markers of subclinical atherosclerosis has been addressed. A
study was performed on a cohort of 168 HIV-infected
patients to measure the intima-media thickness (IMT) and

Metabolic and Cardiovascular Complications of HAART Current HIV Research, 2006, Vol. 4, No. 1 83
assess indirectly the cardiovascular risk. In this population a
high prevalence of atherosclerotic plaques within the femoral
or carotid arteries was observed, but their presence was not
associated with the use of PIs [17]. Similar results were
reported also by Hsue et al. [33] and by Currier et al. [16] in
case-control studies suggesting that traditional risk factors
may contribute to atherosclerosis in HIV-infected patients
independently of PIs exposure.Different results were reported
by Maggi et al. who observed a higher than expected
prevalence of premature carotid lesions in PIs-treated patients
compared to PIs-naive patients [36]. The impact of
individual measures to reduce the cardiovascular risk and the
progression of atherosclerosis has been addressed by
Thiebault et al. [50]. According to these authors, the
increased use of lipi-lowering agents, of PIs-free HAART
regimes and the reduction of smoking may decrease the IMT
in HIV-infected patients over time [50]. In spite of these
different results, markers of subclinical atherosclerosis
should be carefully assessed in HIV-infected patients
receiving HAART, especially in those with lipodystrophy
[54].
Vasculitis
Drug-induced hypersensitivity vasculitis is common in
HIV-infected patients receiving HAART. The vasculitis
associated with drug reactions typically involves small
vessels and has a lymphocytic or leukocytoclastic
histopathology. The pathologic mechanisms include T-cell
recognition of haptenated proteins or the deposition of
immune complexes in blood-vessel walls. Medical
practitioners need to be especially aware of abacavir
hypersensitivity reactions because of the potential for fatal
outcomes. Hypersensitivity reactions of this type should
always be considered as a possible etiology for a vasculitic
syndrome in an HIV-infected patient [34].
Coagulation Disorders
HIV-infected patients, especially those with fat
redistribution, might develop coagulation abnormalities,
including increased levels of fibrinogen, D-dimer,
plasminogen activator inhibitor-1, and tissue-type
plasminogen activator antigen, or deficiency of protein S
[29,55]. For instance, protein S deficiency has been reported
in up to 73% of HIV-infected men [29,55]. These
abnormalities have been associated with thromboses
involving veins and arteries and seem to be related to
HAART regimens that include PIs [49]. Thrombocytosis has
been reported in 9% of patients receiving HAART, with
cardiovascular complications in up to 25% of cases [39].
CONCLUSIONS
HAART-associated metabolic syndrome is an
increasingly recognized clinical entity. A better
understanding of the molecular mechanisms responsible for
this syndrome will enable the development of new drugs
with reduced metabolic and cardiovascular side effects.
Careful cardiac screening is warranted for patients who are
being evaluated for, or who are receiving, HAART regimens,
particularly for those with known underlying cardiovascular
risk factors. The atherogenic effects of PIs-containing
HAART might synergistically promote the development of
coronary or cerebrovascular disease and increase the risk of
death from myocardial infarction or stroke even in young
HIV-infected people. A close collaboration between
cardiologists and infectious disease specialists is needed for
management decisions regarding the use of antiretrovirals
and other therapies, for a careful stratification of the
cardiovascular risk and cardiovascular monitoring according
to the most recent clinical guidelines.
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Received: August 3, 2005 Revised: August 26, 2005 Accepted: August 30, 2005