Sex differences in HAART-associated dyslipidaemia
Pernerstorfer-Schoen, Heidemarie; Jilma, Bernda; Perschler, Alina; Wichlas, Sibylle; Schindler, Karinb; Schindl, Andreasc; Rieger, Armin; Wagner, Oswald F.d; Quehenberger, Peterd
From the From the Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, the aDepartment of Clinical Pharmacology, the bInstitute of Nutritional Sciences, the cDivision of Special and Environmental Dermatology and the dDepartment of Medical and Chemical Laboratory Diagnostics, University of Vienna Medical School, Vienna General Hospital, Vienna, Austria.
Received: 5 June 2000;
revised: 12 October 2000; accepted: 1 February 2001.
Requests for reprints to: P. Quehenberger, Department of Medical and Chemical Laboratory Diagnostics, University of Vienna Medical School, Waehringer Guertel 18–20, A-1090 Vienna, Austria.
Objectives: Because female sex protects against dyslipidaemia and atherosclerosis in normal subjects, we aimed to reveal potential sex differences in metabolic side-effects of a newly initiated highly active antiretroviral therapy (HAART) regimen, and to relate these changes to endothelial cell activation as measured by levels of circulating E-selectin (cE-selectin).
Design: Prospective longitudinal cohort study.
Setting: Tertiary care centre at a University Hospital.
Methods: HIV-seropositive male (n = 27) and female patients (n = 13) with a plasma viral load of ≥ 10 000 copies/ml and 35 healthy controls were enrolled in the study. All participants were weight stable, free of acute opportunistic infections, and had not taken any protease inhibitors before. Serum levels of lipids, insulin, leptin, and cE-selectin were measured before initiation of HAART, and at 3 and 6 months thereafter.
Results: HAART increased serum levels of triglycerides, leptin, and low-density lipoprotein (LDL) cholesterol; these effects were more distinct in women. Fasting insulin levels and the LDL : high density lipoprotein (HDL) ratio increased only in female HIV-infected patients (P < 0.02 versus men). In contrast, endothelial activation, as measured by cE-selectin, decreased more in men (P < 0.02) than in women. As a consequence, women had higher triglycerides and leptin levels after therapy than did men, and the LDL : HDL ratio and cE-selectin levels, which were initially higher in men, were no longer different between the sexes.
Conclusions: Metabolic adverse effects during HAART are more pronounced in women than in men. Hence, female HIV-infected patients seem to loose part of their natural protection from atherosclerosis during antiretroviral therapy.
The HIV epidemic has entered a new phase in the industrialized countries. Human HIV infection has moved off the list of the 15 leading causes of death for the first time since 1987  because an increasing number of effective antiretroviral agents has become available. The use of combinations of these drugs delays disease progression and extends life expectancy in HIV-infected individuals .
The current mainstay in HIV therapy usually consists of a combination of at least three drugs, and frequently includes a protease inhibitor (PI) in addition to two nucleoside analogue reverse transcriptase inhibitors (NRTI) . However, a variety of metabolic disturbances have recently been reported to be associated with antiretroviral treatment [4–8]. Whether these changes occur as a result of therapy containing PI or other components, or whether these changes occur because effective treatment has allowed the patients to survive to the point in time at which this syndrome would develop naturally, has not yet been elucidated.
Amongst the reported side-effects of highly active antiretroviral therapy (HAART) regimens are increases in serum triglycerides, low-density lipoproteins (LDL), total cholesterol and insulin levels. These changes in lipid profiles have raised clinical concern with respect to the atherogenic risk.
It is well known that female sex exerts anti-atherogenic–cardioprotective effects which can be explained in part by the effect of oestrogens on lipoprotein subfractions [i.e. decreasing LDL levels and increasing high-density lipoprotein (HDL) levels] [9,10]. However, it is not known whether female sex provides any protection against the negative effects of PI on lipid metabolism. Furthermore, it is unclear whether antiretroviral therapy may affect variables of lipid metabolism differently in male and female patients. This is of interest because HIV infection in the industrialized countries is no longer a problem afflicting primarily men; because of heterosexual transmission the number and proportion of HIV-infected women has increased constantly throughout the past decade .
Data on sex-specific metabolic effects of long-term HIV therapy are scarce because most studies have had a cross-sectional design. To the best of our knowledge, no such longitudinal data are available to date. Most of the recent reports dealing with drug-associated adverse effects are limited to men [6,12], or address mixed populations [5,7,8,13], and only a few reports focus on metabolic disturbances in women treated for HIV infection .
We therefore studied prospectively the effects of a newly initiated HAART regimen firstly to reveal potential sex differences in changes of serum levels of lipids, insulin, and leptin and secondly to determine their relationship to endothelial cell (EC) activation as measured by circulating E-selectin (cE-selectin).
Materials and methods
Prospective longitudinal cohort study in clinically stable HIV-infected male and female patients and healthy controls at a tertiary care centre of a University Hospital. As it is currently considered inappropriate to withhold HAART from HIV-infected individuals at high risk of progression , we did not assign an additional placebo-controlled group of patients to single out the effects of a PI-containing HAART on metabolic disturbances.
Patients and controls gave written informed consent after approval of the study protocol by the Ethics Committee of the Vienna University Hospital.
Forty clinically stable outpatients (27 men, 13 pre-menopausal women; mean age, 36 years; range, 22–51 years) with HIV infection documented by enzyme-linked immunosorbent assay and confirmatory immunoassay, were recruited from the HIV outpatient clinic of the Vienna University Hospital.
Body composition and resting energy expenditure data of a subset of the patients have been reported previously .
An additional group of 35 HIV-seronegative, healthy volunteers, who were matched for age, sex and body mass index, served as controls and underwent metabolic and adhesion molecule assessment in the same setting.
After a screening examination and recording of the Centers for Disease Control and Prevention (CDC) status , patients were enrolled in the study if they had never been treated with any HIV-1 PI before. All patients had to fulfil the criteria for initiation or intensification of antiretroviral therapy according to the guidelines of the International AIDS Society 
The following exclusion criteria were defined to isolate direct or indirect effects of HAART on parameters of lipid and glucose metabolism and EC activation: opportunistic infection within 12 weeks of screening, persisting fever (> 37.8°C), night sweat and/or elevation of C-reactive protein (CRP > 1 mg/dl) 6 weeks prior to the beginning of the study ; malignancy; pre-existing endocrinological and/or cardiovascular disease ; and therapy with or intake of substances known to influence lipid or glucose metabolism.
Patients who developed opportunistic infections during the course of the study or who did not adhere to the study protocol were excluded from final evaluation.
A uniform triple combination therapy was administered to all patients according to the current guidelines for antiretroviral treatment  : (i) one PI [nelfinavir (Roche, Vienna, Austria), 750 mg three times per day]; and (ii) two NRTI, [didanosine (Bristol-Myers Squibb, Vienna, Austria) 400 mg four times per day (250 mg for body weight < 60 kg) and stavudine (Bristol-Myers Squibb, Vienna, Austria) 40 mg twice per day (30 mg for body weight < 60 kg)]. The choice of this triple regimen was based on practical issues such as regimen complexity, drug interactions and tolerance, to maximize therapeutic benefit over time, and finally, on financial aspects concerning the reimbursement for medication by health insurance companies. To rule out substance-specific effects  all patients were treated uniformly with the same antiretroviral regimen.
Patients were evaluated shortly before the initiation of HAART and at 12 and 24 weeks thereafter.
Venous blood samples were obtained by atraumatic venipuncture after an overnight fast to measure fasting serum triglycerides, total cholesterol, LDL, HDL, serum insulin, leptin, cE-selectin, peripheral blood CD4 lymphocyte subset count and plasma viral load. Urine and stool cultures were performed for analysis of urogenital and gastrointestinal pathogens.
The occurrence of side-effects, the patients’ clinical course, and their adherence to HAART were controlled every 4 weeks during interviews performed routinely at the outpatient clinic.
Body composition was assessed as described previously  after an overnight fast, and after voiding, within the first 5 min of resting in the supine position. A bioimpedance apparatus operating at 50 kHz (Bioelectrical Impedance Analyzer Model BIA-101; RJL Systems, Florence, Italy) was used with standardized procedures [20,21]. Body composition parameters were evaluated using the software BODYGRAM2 Version 2.2 (Akern, Florence, Italy). Fat-free mass was calculated by Kotler's corrected sex-specific predictive equation for fat-free mass, using parallel impedance, height, and weight , and fat mass was calculated as follows: fat mass = kg body weight − free fat mass.
After venipuncture with a 21-gauge needle, blood was collected into Vacutainer tubes (Becton Dickinson; Meylan Cedex, France) and centrifuged at 2000 g for 15 min at 4°C, aspirated and stored at −80°C until analysis; all samples were assayed in duplicate.
Serum triglycerides (Triglyceride GPO-PAP Test; Roche Diagnostics, Vienna, Austria), serum cholesterol (Cholesterol CHOD-PAP Test; Roche Diagnostics, Vienna, Austria) and direct measurement of HDL-cholesterol (HDL-C Plus; Roche Diagnostics, Vienna, Austria) were performed on a Hitachi 747 analyser (Roche Diagnostics, Vienna, Austria). LDL cholesterol was calculated according to the Friedewald formula.
Concentrations of cE-selectin and of human leptin were determined by commercially available enzyme immune assay kits (R & D Systems, Biomedica, Vienna, Austria and R & D Systems, BioVendor, Brno, Czech Republic respectively) . Serum insulin was measured by radioimmune assay (RIA) (Serono, Freiburg, Germany) .
Plasma HIV RNA quantification
Plasma HIV-RNA levels were determined using an in vitro nucleic acid amplification test, lower limit of detection: 50 copies/ml (Roche Ultrasensitive Assay®, Roche Diagnostics, Vienna, Austria).
CD4 cell counts
Peripheral blood CD4 lymphocyte subset counts were determined by FACScan flow cytometer using monoclonal antibodies, and the Cellquest software (Becton-Dickinson, Mountain View, California, USA) .
Data is expressed as mean and the range, unless stated otherwise. Statistical calculations were carried out by using the StatView 5.0 Power PC Version software package (SAS Institute, Cary, North Carolina, USA), using non-parametric methods because data was distributed non-normally. Comparisons between groups were carried out by using the Mann–Whitney U test. Changes within the treatment groups were tested using the Friedman ANOVA and the Wilcoxon signed ranks test for post hoc comparisons. Correlations between parameters within each group were calculated with the non-parametric Spearman test. A two-tailed P value of < 0.05 was considered significant.
Forty HIV-seropositive patients were included in the study (27 men, 13 women). Recruitment of consecutive patients resulted in a male : female sex distribution of approximately 2 : 1, which reflects the current sex distribution of newly HIV-infected patients in industrialized countries.
Seventeen of the patients (43%) had AIDS as defined by the CDC classification  (eight men, nine women); no patient was suffering from HIV-associated wasting. Baseline levels of measured outcome parameters were not different between HIV-infected and AIDS patients (all P values > 0.05).
Demographics of patients and healthy controls are given in Table 1, and final outcome values for lipids, insulin, leptin, and cE-selectin are presented in Table 2.
Five participants (three men, two women) dropped out of the study before final evaluation. Reasons for exclusion were discontinuation of therapy (one patient), switch to different (reverse transcriptase inhibitor only) antiretroviral regimens (two patients), lost to follow-up (two patients).
One female patient developed subjective symptoms of incipient lipodystrophy after 5 months of therapy. As she decided to leave the study on her own will and to discontinue medication (see above) she was not evaluated further.
Lipids, insulin and leptin
Baseline fasting serum triglycerides, levels of insulin, leptin, and LDL were similar in patients and controls (P values > 0.05 versus control). However, the LDL : HDL ratio was > 25% higher in HIV-infected patients than in matched controls (P < 0.02, Table 1), which was due mainly to the 25% lower serum HDL levels in HIV-positive patients.
Influence of sex
Levels of triglycerides, insulin, leptin, and LDL were similar in both sexes (P > 0.05 between groups). Yet, serum HDL was approximately 20% lower in men, and hence, the LDL : HDL ratio was more than 40% higher in male than in female patients (P < 0.02 between groups, Table 1).
Body weight and body composition
Baseline and influence of sex
Baseline body weight, total body fat mass, and body fat as a percentage of body weight were similar in patients and controls (P values > 0.05 versus control).
Despite the 20% weight difference between HIV-infected men and women (P < 0.02, Table 1), baseline fat mass was similar in both sexes (P > 0.05, Table 1).
Accordingly, percentage body fat for men averaged 17% and for women, 24% (Table 1). The fact that our female patients had almost 30% greater relative fat mass than our male patients corresponds to the usual sex difference in body composition.
Effects of antiretroviral therapy on lipids, insulin leptin and fat mass
HAART increased serum levels of triglycerides, leptin, LDL and HDL, in both sexes (P < 0.05, Table 2, Fig. 2). However, insulin and the LDL : HDL ratio increased significantly only in female patients (P < 0.02 in females), and trend-wise in male patients (Table 2, Fig. 1, Fig. 2).
After therapy, triglyceride and leptin levels were higher in female patients (P < 0.02 between sexes), and LDL and the LDL : HDL ratio were no longer different from those in men (P > 0.05 between sexes).
Percentage body fat was 30% higher in women than in men not only at baseline, but also at final evaluation, due to the similar gain in fat mass in both sexes during HAART (Fig. 2).
There was a moderate correlation between serum leptin levels and body fat mass in both HIV-infected men and women at baseline (r = 0.64 and r = 0.68, respectively, P < 0.02 for both sexes). Positive correlations between the gain in serum leptin levels and in fat mass were noted only in women during HAART (r = 0.63, P < 0.03).
In contrast, baseline serum insulin levels did not correlate with baseline fat mass (r = 0.34 in men, r = 0.24 in women, P > 0.05 for both sexes), and the increase in serum insulin did not correlate with the gain in fat mass during therapy (r = 0.35 in men, r = 0.25 in women, P > 0.05 for both sexes).
Baseline and influence of sex
Baseline levels of cE-selectin were > 50% higher in patients than in controls (P < 0.02), and they were approximately 50% higher in HIV-infected males than in HIV-infected females (P < 0.02 between groups, Table 1).
Effects of antiretroviral therapy
During antiretroviral treatment, cE-selectin decreased significantly in males (P < 0.02) and only trend-wise in females (Table 2). As a consequence, cE-selectin was no longer different between male and female patients after 6 months of HAART (P > 0.05 between sexes).
Viral load and CD4 lymphocytes
Baseline and influence of sex
Levels of plasma viral load and CD4 lymphocytes did not differ between sexes (P > 0.05).
Antiviral effectiveness is similar between sexes
As shown by Table 2, HIV RNA plasma levels decreased to < 200 copies/ml after 24 weeks of PI-containing HAART irrespective of sex (P > 0.05 between groups). Twenty-three out of 40 patients even reached the lower level of detectability, i.e. 50 copies/ml after 8 weeks (two patients), after 12 weeks (seven patients), and after 24 weeks (14 patients) of PI treatment. CD4 lymphocytes increased equally in both sexes during therapy (P > 0.05 between groups, Table 2).
Dyslipidaemia and asymptomatic atherosclerotic lesions are more frequent in HIV-positive patients than in healthy controls [17,26,27]. The risk to these patients of developing cardiovascular complications may increase further during long-term use of antiviral therapy .
As female sex protects from cardiovascular disease in HIV-seronegative subjects, we set out to study prospectively sex-differences in metabolic side-effects of a newly initiated HAART regimen, in particular to evaluate whether female sex is protective in this setting.
In good agreement with previous findings, HIV-infected patients had lower baseline levels of HDL than healthy age-matched controls  (Table 1), whereas levels of LDL (Table 1) and total cholesterol were not different from control values. The latter finding is possibly due to the relatively good immune and the adequate nutritional status of our HIV-patients, who were also free of opportunistic infections or wasting.
Hence, the baseline LDL : HDL ratio, an established indicator of cardiovascular risk, was higher in HIV-patients than in controls, and higher in HIV-infected men than HIV-infected women (Fig. 1). The less favourable lipid profiles in our male patients before the start of HAART mirror nicely what is seen in the general population, i.e. the well-known increased risk for cardiovascular disease in men as compared with women [9,29]. Thus, HIV-infected women seem to be naturally better ‘protected’ from the pro-atherogenic effects of HIV-infection per se than are men.
However, after initiation of a combined antiretroviral therapy, LDL : HDL ratios increased only in our female HIV patients (Fig. 1) due to increases in LDL (Table 2). As a consequence, the baseline sex difference in the LDL : HDL ratio finally disappeared (Fig. 1). Hence, women seemed to have ‘lost’ part of their natural protection from cardiovascular disease.
Triglycerides, insulin, leptin, and fat mass
Baseline levels of serum triglycerides and insulin were similar between sexes as in a normal population, whereas serum leptin concentrations were trend-wise (> 30%) higher in female than in male patients. Although the magnitude of this sex difference was not significant, it was comparable to the degree of sex differences in leptin levels in a healthy population.
Antiretroviral therapy increased serum triglycerides, insulin and leptin levels predominantly in our female, and to a lesser extent in our male HIV patients (Fig. 2, Table 2). Even though we were not surprised to find rising leptin levels during HAART [30,31], we had not necessarily expected sharper increases in the female patients as compared with the male HIV-infected patients. Of note, the twofold increase in serum leptin levels in women (Fig. 2) is rather pronounced in view of animal studies, showing that induction of inflammation by lethal doses of endotoxin increased leptin levels only 2.5-fold .
Interestingly, HIV-infected men and women gained fat mass to comparable extents, but the increase in leptin and insulin levels was clearly more pronounced in the female patients (Fig. 2). Yet, we found a moderate correlation between the increase in leptin levels and the gain in fat mass in our female patients, but not in male patients. The moderate degree of correlation, however, indicates that the preferential increase in leptin levels in women was not solely dependent on the increase in fat mass. This is in line with previous findings indicating that circulating leptin levels do not correlate directly with weight changes in HIV-infected patients or reflect exclusively adipose tissue mass [33–35].
In view of several previous reports, peripheral insulin resistance could be an explanation for the elevations in serum insulin in these patients . Higher insulin concentrations may then have contributed to the increase in serum leptin levels, independently of body fat mass [37–39]. Finally, lower energy expenditure after successful antiretroviral treatment  may have been associated with an increase in leptin concentrations in this HIV-infected population .
It is of interest that elevated insulin  and triglyceride levels  may represent additional markers for the risk of coronary heart disease, especially in women. In addition, leptin seems to play a role in atherogenesis via different mechanisms. Leptin promotes platelet aggregation , induces plasminogen activator inhibitor-1 synthesis , up-regulates pro-inflammatory cytokines , and generates oxidative stress . Hence, it is conceivable that the elevation of leptin levels in the female HIV patients during HAART is pathophysiologically relevant and enhances the development and propagation of vascular disease . Increased insulin and triglyceride levels further support the contention that female patients are at a higher risk to develop pro-atherogenic side-effects during HAART than are male patients.
Endothelial cell damage is present early in HIV infection, but the understanding of markers and mechanisms remains incomplete . It has been reported that HIV may infect vascular EC directly , and induce shedding of adhesion molecules from the cell surface, possibly due to oxidative stress . In addition, HIV and various opportunistic pathogens may exert indirect deleterious effects on EC, conceivably via pro-inflammatory cytokines.
Serum cE-selectin is a specific endothelial activation marker, which can indicate HIV-associated vascular inflammation , and/or atherosclerosis and the consecutive development of cardiovascular disease [18,52,53].
In this study, HIV-infected patients had higher baseline levels of cE-selectin than healthy controls confirming a previous cross-sectional study . HIV-infected male patients had almost 50% higher baseline levels of cE-selectin than female patients (Fig. 1) as would be expected from healthy controls [54,55]. The preserved sex differences in baseline cE-selectin levels in HIV infection may indicate that female sex protects against endothelial activation in HIV-infected individuals.
However, during HAART, serum cE-selectin levels declined in the male, but not in the female patients (Fig. 2), despite similar reductions in viral load. As a consequence, sex differences in cE-selectin were no longer apparent 6 months after initiation of HAART (P > 0.05, Fig. 2). This may be interpreted as evidence that HAART suppressed immunological/inflammatory processes in EC less effectively in female patients than in male patients.
A limitation of this study is that the question of whether the observed metabolic disturbances were related specifically to the use of PI could not be addressed in this setting. Indeed, previous studies on the association of metabolic changes with certain components of combinational regimens have produced inconsistent data. Whereas disturbances in lipid metabolism have been reported during HIV-therapy without PI , ‘switch studies’ have indicated that cholesterol and triglyceride levels fall when PI-containing therapy is discontinued . Furthermore, PI have been shown to increase concentrations of serum triglycerides and atherogenic lipoproteins even in healthy volunteers . Only very recently, in vitro experiments have shown a direct and dose-dependent influence of PI on insulin-stimulated glucose uptake in adipocytes .
As it cannot be ruled out completely that the stage of disease also influenced metabolic changes to a certain extent, only HIV and AIDS patients who were in very good clinical condition were enrolled in the study.
However, to answer more comprehensively the question of whether there is a cause and effect relationship between the use of PI-containing HAART and metabolic disturbances would require a comparison of (at least) two groups of patients, one receiving a PI-based regimen and the other receiving a non-NRTI in combination with two NRTI.
In summary, adverse metabolic effects of a HAART regimen were more pronounced in women than in men in this study. Female patients exhibited more distinct increases in serum levels of LDL, LDL : HDL, triglycerides, insulin and leptin decreased more in men than in women. Hence, female HIV-infected patients seem to loose part of their natural protection from atherosclerosis during antiretroviral therapy.
Further studies are necessary to determine whether these pro-atherogenic effects are related specifically to PI and whether in women non-NRTI-based regimens are as effective as PI-based regimens immunologically and virologically and with fewer adverse metabolic effects.
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