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La Presse Médicale
Volume 37, numéro 4P1
pages 579-584 (avril 2008)
Doi : 10.1016/j.lpm.2007.09.022
Reçu le : 15 novembre 2006 ;  accepté le : 26 septembre 2007
Articles originaux
Metabolic syndrome: A major risk factor for atherosclerosis in HIV-infected patients (SHIVA study)
Le syndrome métabolique : un risque cardiovasculaire majeur chez les patients séropositifs pour le VIH
 

Luc de Saint Martin 1, , Elisabeth Pasquier 1, Nathalie Roudaut 2, Olivier Vandhuick 3, Sophie Vallet 4, Véronique Bellein 1, Luc Bressollette 3
1 Internal medicine department (EA 3878), University Hospital, F-29609 Brest Cedex, France 
2 Department of endocrinology, University Hospital, F-29609 Brest Cedex, France 
3 LATIM (Inserm U680), University Hospital, F-29609 Brest Cedex, France 
4 Department of microbiology (EA 388), University Hospital, F-29609 Brest Cedex, France 

 Luc de Saint Martin, Département de médecine interne, CHU de La Cavale Blanche, F-29609 Brest Cedex, France. Tel.: +33 2 98 34 73 36 Fax: +33 2 98 34 79 44
Summary
Objective

Metabolic syndrome (MetS) is directly related to a high incidence of cardiovascular disease in the general population. The association is more doubtful among HIV-infected patients, although MetS has an elevated prevalence in this population. We explored the impact of MetS on early atherosclerosis markers.

Research design and methods

All HIV-infected outpatients followed at the Brest University Hospital were included in this cross-sectional hospital-based study (SHIVA study, France) (n=154). The MetS status (NCEP ATPIII definition, at least three of these five criteria: fasting glucose, triglycerides, HDL-C, waist circumference and hypertension.) of each patient was analyzed (Mann-Whitney test) according to carotid intima-media thickness, number of plaques, and a combined cardiovascular score.

Results

After exclusion of 6 patients treated with statins or insulin or both, MetS status was available for 140 (90.9%) patients and positive for 10 (7.1%). MetS status was due predominantly to blood glucose and triglyceride levels and was strongly correlated with all atherosclerosis markers (p≤0.01).

Conclusion

The MetS prevalence in this population is low for a group with HIV infection, even after inclusion of the statin-treated patients (11.4%), but remains higher than among the general population. MetS in this population is probably a heterogeneous cluster of side effects of antiretroviral therapy (high triglycerides, lower HDL-C, and hypertension) and direct effects of HIV (glucose disturbances). Because it is strongly linked to the presence of plaque and intimal thickness, it is a pertinent criterion for deciding about cardiovascular prevention.

Résumé
Objectif

S’il est admis que le syndrome métabolique représente un facteur de risque cardiovasculaire, sa responsabilité dans l’athérosclérose précoce des patients séropositifs pour le VIH est moins claire. Sa forte prévalence dans cette population justifie d’explorer son impact sur les marqueurs précoces d’athérosclérose.

Matériel et méthodes

Tous les patients séropositifs pour le VIH de plus de 18 ans inclus dans l’étude transversale Shiva (n=154), à l’exclusion de 6 patients sous hypolipémiant et/ou hypoglycémiant, ont été classés, selon la définition de la NCEP ATPIII, avec ou sans syndrome métabolique. Les données échographiques carotidiennes (l’épaisseur intima-média, la présence et le nombre de plaque) et un score cardiovasculaire combiné, ont été comparés entre les 2 groupes par Mann-Whitney test.

Résultats

Parmi les 140 patients dont les données sont exploitables, 10 (7,1 %) présentent un syndrome métabolique, dont l’hyperglycémie et l’hypertriglycéridémie sont les composantes les plus fréquentes. Ces patients ont des marqueurs d’athérosclérose statistiquement (p≤0,01) plus élevés.

Discussion

La prévalence du syndrome métabolique, si elle reste supérieure à celle de la population générale, est inférieure aux données antérieures de la littérature, même après inclusion des 6 patients en prophylaxie (11,4 %). Ce syndrome métabolique, qui est probablement un agrégat hétérogène de complication des traitements antirétroviraux (hypertriglycéridémie, hypertension, hypoHDLc) et de la pathologie VIH (hyperglycémie), représente, comme dans la population générale, un facteur de risque cardiovasculaire majeur qui justifie son dépistage et sa prévention.

PlanMasquer le plan
What was already known
What this article adds
Introduction
Methods
Results
Discussion
Conflicts of Interest
Funding
Remarks
What was already known

•
The high incidence of cardiovascular disease among people with HIV infection.
•
The high prevalence of metabolic syndrome in people with HIV infection.
•
The direct relation between metabolic syndrome and cardiovascular disease in the general population.

What this article adds

•
The prevalence of MetS (10.9%) was much lower than previously reported in patients with HIV but remained higher than among the general population (4.8%).
•
Metabolic syndrome status depends on a combination of adverse events due to antiretroviral treatment and HIV-associated dysfunctions.
•
MetS status was strongly linked to cardiovascular disease markers and can be used for determining the need for primary cardiovascular prevention.

Introduction

Metabolic abnormalities are prevalent among HIV-infected patients [1] and are frequently related to antiretroviral therapy (ART) [2]. These abnormalities, which combine glucose metabolism disturbances and dyslipidemia, often meet the definition of the metabolic syndrome (MetS) [3]. In the general population, this syndrome is directly associated with a high incidence of cardiovascular disease (CVD) and specifically, atherosclerosis [4]. This relation is more doubtful in ART-induced MetS because the time of exposure is relatively short, indeed, usually less than three years. We conducted a cross-sectional study (Study of HIV and atherosclerosis : SHIVA) to explore the impact of this cluster of atherosclerosis risk factors on subclinical and clinical markers of atherosclerosis.

Methods

The cross-sectional SHIVA study [5], which was approved by the local ethics committee, enrolled 154 (96.5%) patients from a cohort of HIV outpatients under follow-up at Brest University Hospital (Figure 1). This study took place from January through April 2003. After patients provided informed consent, the following information was collected:

•
blood levels (after overnight fast, > 12hours) of triglycerides, glucose, total cholesterol, HDL cholesterol [HDL-C]
•
anthropometric and other clinical data: waist circumference, body mass index (BMI), clinical lipodystrophy status, bicipital and tricipital skinfold thickness (Harpenderʼs caliper), and blood pressure (after 10 minutes seated, with the elbow flexed at the heart)
•
demographic data: age, sex, percentage of CVD among first-degree relatives, smoking status (in pack-years), and previous CVD history
•
HIV status: duration of current ART exposure, duration of HIV infection, CD4 cell count and viral load.



Figure 1


Figure 1.

Study design and NCEP criteria results

CVD: cardiovascular disease; IMT: carotid intima-media thickness; p: Chi test (alpha risk: 5%); r: Pearson product-moment correlation coefficient (measure of association that can range from -1 [perfect negative correlation] to 1 [perfect positive correlation], usually considered as strong if < −0.8 or > 0.8; and good if < −0.6 or > 0.6).

Zoom

We used the working definition suggested by the National Cholesterol Education Program (NCEP) guidelines [6] to determine MetS status, that is, three of the five criteria for fasting glucose, triglycerides, HDL-C, waist circumference, and hypertension. Symptomatic CVD patients receiving antihypertensive, antidiabetic, or hypolipidemic agents that interfered with these criteria were excluded from the analysis.

Atherosclerosis was assessed with two criteria: intima-media thickness (IMT) and number of plaques, both collected by two-dimensional carotid ultrasonography on an ATL HDI 5000 apparatus (Philips, Eindhoven, the Netherlands), with a linear broadband transducer (L 12-7) and Metris software (Metris, Argenteuil, France). Exercise myocardial scintigraphy was performed for patients with IMT>0.75mm [7] or Framingham scores>3. A combined cardiovascular score (CVS) was calculated by assigning 5 points for symptomatic CVD, 2 for each necrosis, 1 for each ischemic scintigraphic area, and 0.5 point for each carotid plaque.

The statistical analysis was conducted with SPSS 11 software (SPSS Inc, Chicago IL USA). For the atherosclerosis markers, which were mostly not normally distributed, the comparisons of subjects with or without MetS used a nonparametric Mann-Whitney U test. Comparisons of the categorical variables used Fisherʼs exact test. Variables with a univariate association (p≤0.05) were included in the logistic regression analysis to assess the effect after adjustment for age and BMI.

Results

MetS status was available for 140 patients (86.9%). Ten patients (7.1%) met the NCEP definition. Positive status for MetS was strongly correlated with all atherosclerosis markers (p≤0.01). Only age, total cholesterol, and BMI, of the MetS-independent atherosclerosis risk factors, and viral load, of the HIV parameters, were correlated with MetS status (Table I). An interaction (p>0.05) was observed between the variables correlated with MetS status. Moreover, MetS status was not associated with current or cumulative ART class exposure or with lipodystrophy status.

Discussion

Despite the inclusion of 6 patients with a history of CVD (10.9%), the prevalence of MetS (7.4%) was much lower than those previously reported in HIV-infected patients — ranging from 17% to 45% [8, 9 and 10]. Nevertheless it is higher than MetS prevalence in the French general population, reported to be 4.8% [11] for a population of the same age and using the same definition as the Spanish HIV patient cohort with a prevalence of 17% [10].

This low prevalence is not explained by a high rate of drug users (14.3%) or by the low number of women (27.9%). The hypothesis of that these results are due to the high quality of the samples, due to the strict 12-h overnight fast, was improbable because triglyceride levels were higher than the NECP cut-off in almost 29% of the patients without MetS (Table I). The lower prevalence was probably due to the HDL-C and waist circumference criteria (Figure 1), as in the Spanish study [10].

MetS, more frequent in HIV-infected patients than in the general population, is a powerful independent risk factor for CDV. It is highly associated with IMT and with plaque formation in our HIV cohort as well as in the general population.

The role of ART exposure in this HIV-associated MetS is not clear. Although the SHIVA study previously reported the effect on IMT of exposure to protease inhibitors [5], no relation between HAART class and MetS was seen here. However, the period of ART exposure is short, an average of 6.1 years.

The same is true for lipodystrophy status, which is usually linked to exposure to nucleoside reverse transcriptase inhibitors [12]: no association was found in our study.

We conducted an analysis for each criterion of MetS and found that the use of protease inhibitors (p<0.001), especially lopinavir (p=0.001), was associated with elevated triglyceride levels, as usually reported [13], and with high blood pressure (p=0.05), in contrast to a previous study [14]. On the other hand, thymidine analogs (p=0.004) – stavudine (p<0.001) and zidovudine (p=0.02) – were linked to abdominal obesity. This relation is currently the object of debate [15 and 16], and abdominal obesity itself is associated with high triglyceride levels (p=0.02) [15].

A final ART affecting the MetS criteria is nevirapine, a non-nucleoside reverse transcriptase inhibitor that decreases HDL-C values (p=0.001) [17]. This does not affect any MetS diagnosis, since all patients positive for the HDL-C criterion satisfied the MetS criteria independently of their HDL-C status.

In contrast to a prior study [18], an elevated blood glucose level, the most significant criterion for MetS in our study, was not associated with any ART class; it was, however, inversely correlated with viral load (p=0.03), but not with CD4 cell count (p=0.6), as previously reported [19].

MetS is a cluster of risk factors for atherosclerosis without, at least among HIV-infected populations, a single pathophysiological mechanism. Our hypothesis is that MetS in these patients results from the independent association of various side effects of ART (high triglycerides, lower HDL-C and hypertension) and direct effects of HIV disease (glucose intolerance disappears with the weight loss induced by uncontrolled infection) (Figure 2). Nonetheless, use of other definitions for MetS (i.e ., IDF or WHO criteria [20]) would have led to different results. Moreover, while the NCEP definition is generally considered to have the best predictive value for CVD, this value does not persist for patients with high triglyceride levels [21] — that is, most HIV-infected patients.



Figure 2


Figure 2.

Putative mechanisms of HIV-associated metabolic syndrome (MetS)

Based on associations (the heavier the bolding of the arrow, the stronger the association is estimated) in the Shiva cohort, between HAART class and NCEP criteria of MetS, between this criteria and MetS status and between MetS status and other cardiovascular risk factors.

BMI: body mass index; NNRTI: non-nucleoside reverse transcriptase inhibitors; NRTI: nucleoside reverse transcriptase inhibitors; PI: protease inhibitors.

Zoom

In this context, the arbitrary aggregation of cardiovascular risk factors should be avoided: it leads to confusion and presents no pathophysiological interest. Nevertheless, MetS status is strongly linked to CVD markers and can be used to decide about primary CVD prevention.

Conflicts of Interest

none

Funding

This project received funding from a PHRC 2003 grant.

Remarks

The SHIVA study was approved by the Brest institutional review board (CCPPRB). The database has been reported to the French Data Protection Authority (CNIL), as required by statute.

Luc de Saint Martin designed the study, analyzed the data and participated in writing the paper

Elisabeth Pasquier analyzed the data and participated in writing the paper

Nathalie Roudaut participated in writing the paper.

Olivier Vandhuick (IMT), Sophie Vallet (HIV status), Véronique Bellein (lipodystrophy) and Luc Bressollette (IMT) conducted the laboratory tests.



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