The worldwide implementation of highly active antiretroviral therapy (HAART) for HIV infection resulted in a drastic reduction in morbidity and mortality, as well as in an increase in life expectancy of people living with HIV (PLHIV). HIV infection has acquired characteristics of a controllable chronic disease.1–3 With the prolonged longevity, the risk of aging-related diseases in PLHIV is higher, even for those individuals with well controlled infection.2,3

Metabolic syndrome (MetS) is a useful construct to identify patients in whom there is a greater overall risk of mortality and, specifically, a greater risk of dying from cardiovascular-related causes or diabetes.4 Increased rates of MetS (33–45%) among PLHIV have been reported by some investigators, while other studies showed rates comparable to those found in the general population (11–26%).5–16 These differences are due to population heterogeneity across the studies regarding clinical and demographic features, and factors related to HIV infection itself, as well as to the set of criteria used to diagnose MetS.

Factors previously reported to be associated with MetS in HIV-infected populations are high body mass index (BMI), high proportion of central body fat, older age, and reported high calorie, high carbohydrate and high overall sugar intake. With respect to HIV-related factors, high viral load and use of protease inhibitors (PI) have been associated with greater prevalence of MetS.5–16 In the general population, postmenopausal women are at a greater risk of developing MetS compared to premenopausal women.17–21 Regarding diagnosis criteria for MetS in a study of PLHIV, low high-density lipoprotein (HDL)-cholesterol was found in 68.5%, and the common profile of MetS was high waist circumference, low HDL-cholesterol and abnormal blood pressure (29.6%).15

Nevertheless, the mechanisms underlying MetS and cardiovascular disease in PLHIV remain poorly understood, as is the role of each pathogenic factor and the complex interactions between traditional factors for MetS, HIV infection and its treatment.5–14 The toxicity profile of antiretroviral drugs has improved immensely over the past 10 years and their efficacy in suppressing the virus is more enduring. Recent data suggest that the immunological recovery and viral suppression promoted by modern antiretroviral therapy (ART) have a favorable cardiovascular effect, approximating the cardiovascular risk of PLHIV to that of the general population.22,23

One consequence of the increased life expectancy of PLHIV is the growing number of women living with HIV going through the physical changes of menopausal transition.17 Despite the viral suppression and immune recovery promoted by modern treatment, aging, together with prolonged exposure to antiretroviral drugs, may increase the risk of MetS in this emerging population.3 Evaluating the prevalence and particularities of MetS in the population of aging women under modern ART according to their reproductive phase may contribute significantly toward managing cardiovascular risk in this population, a challenge that is increasingly central in the care of PLHIV.

Two hundred seventy-three HIV-infected climacteric women were included in the study. Detailed demographics and behavioral characteristics and data on general health are shown in Table 1. The mean age was 47.7 years, with most women (64.1%) being between 40 to 50 years old. The majority was premenopausal (59.1%). Only 25.5% had previous diagnosis of AIDS, while 91% were on ART. The mean time since HIV diagnosis was 9.9 years, with a mean of 9.4 years of exposure to ART. The response to treatment was excellent in the majority of cases, as shown by the rate of undetectable viral load in 76.9% and CD4 count over 500cells/mm3 in 61.7% of cases.

According to the IDF criteria, 120 of 256 participants were diagnosed with MetS, resulting in a prevalence of 46.9%.

With respect to the factors related to the presence of MetS, the univariate analysis (Table 2) showed a statistically significant association with age ≥50 years (p=0.002), schooling <8 years (p=0.003), post-menopause (p<0.001), BMI >25kg/m2 (p<0.001) and FSH ≥40mIU/mL (p=0.002). However, only BMI >25kg/m2 (PR=1.09; 95% CI: 1.05–1.13; p<0.001), and FSH level ≥40mIU/mL (PR=1.66; 95% CI: 1.14–2.40; p=0.008) remained independently associated with MetS in the multivariate analysis (Table 3). There was no association between the presence of the MetS and use of protease inhibitors or any other factor related to HIV-infection in any of the analyses performed.

Table 4 shows the prevalence of the different diagnostic criteria for MetS according to the 2006 IDF definitions. Waist circumference ≥80cm was present in 100% of cases, since that is an essential diagnostic criterion. Other criteria present in this population, in order of frequency, were: HDL <50mg/dL (56.7%), blood pressure ≥130/85mmHg (51.3%), triglycerides ≥150mg/dL (42.8%), and glucose ≥100mg/dL (24.6%).

A high prevalence of MetS was found in these middle-aged women living with HIV on ART at two referral services in Brazil between 2010 and 2012. Nevertheless, although high, the MetS rate of 46.9% in the present study is similar to those found in other studies including middle-aged HIV-negative women. Figueiredo Neto et al., using the same IDF criteria, diagnosed MetS in 49.9% of pre- and post-menopausal Brazilian women aged 40–65 years.24 Oliveira also reported an even higher rate (56.9%) in women over 45 years of age in a rural area of Bahia, a state in northeastern Brazil.25 Based on the same diagnostic criteria used in the present study, Ford identified MetS in 33% of women in the general population in the United States and in 49% of women aged 50–59 years old.26 On the other hand, in Austria, Ponholzer et al. reported a lower prevalence: 8.6% in premenopausal women with a median age of 38 years and 32.6% in menopausal women.27 However, data specifically on MetS in middle aged HIV-infected women are scarce. The population of the present study consisted predominantly of women of 40–50 years of age who had not yet reached menopause, were not at an advanced stage of HIV infection, were under modern ART, and whose immunological status was excellent. In other words, the profile of these women's general and immunological health nears that of the general population. Our finding of a prevalence rate of MetS similar to that reported for the general population in publications both in Brazil and worldwide is in agreement with recent evidence suggesting a “normalization” of health in PLHIV who begin treatment early, have access to adequate treatment and achieve satisfactory immune recovery.23,28,29

In our study, the most common diagnostic parameters for MetS were low HDL cholesterol levels and hypertriglyceridemia, whereas abnormal glucose levels were present in only 24.6% of the women with the MetS. Likewise, a relatively higher frequency of hypertriglyceridemia, and low levels of HDL cholesterol have been reported by other investigators in PLHIV in relation to the frequency of the MetS in the general population.30 The direct effects of the infection in reducing the HDL fraction of cholesterol and increasing triglyceride levels and the effect of ART on triglycerides are well known and explain the present findings. It is possible that in years to come the progressive improvement in treatment, involving more timely interventions and drugs with little effect on lipids, may change the profile of the diagnostic parameters of the MetS in PLHIV.

In this population of HIV-infected women, those with MetS, compared to those without it, were relatively older, more obese, had poorer education level, and were more likely to be climacteric and to have FSH levels >40mIU/mL, reflecting estrogen deprivation. Only BMI >25kg/m2 and FSH ≥40mIU/mL remained as predictors of MetS in the multivariate analysis. Each unit of kg/m2 above 25 added to the BMI was associated with a 9% increase in the risk of MetS. Women with FSH ≥40mIU/mL had a 66% greater risk of having MetS compared to women with FSH <40mIU/mL. None of the HIV-related characteristics such as disease staging and the duration of infection, exposure to any ART or to PI, immune status, and viral suppression were associated with the presence of MetS in this population.

In the present study, only traditional risk factors were predictors of MetS. The effect of menopause and BMI on the risk of MetS has already been shown in various previous studies and there is strong evidence for the role of these factors as independent predictors of MetS.17–21,31 In other studies involving PLHIV, traditional risk factors such as age, BMI, weight gain, and dietary patterns were also strong predictors of MetS.6–11,15,30,32,33

With respect to HIV-related factors, PI use was found to be marginally associated with MetS in a study conducted by Samaras et al.33 In that study, however, over 57% of the patients had a clinical diagnosis of lipodystrophy. In this respect, the combination of advanced infection and exposure to more toxic and less effective ARV drugs may have contributed to the development of metabolic alterations that define MetS. The same could be said with respect to the findings of Jericó et al. who reported an increased risk of MetS in patients on ART and on PI compared to treatment-naïve patients. It should also be taken into consideration that the comparison between treatment-naïve patients and patients under ART was not controlled for various confounders associated with HIV infection. In general, in the past observational studies, patients who had not initiated treatment were those in the earliest phase of infection, whose clinical and immune status were better. In the study conducted by Mondy et al., type of ART and time on treatment were not predictors of MetS.30

Studies relating ART MetS could be grouped into two phases. Early studies showed an association between ART and dyslipidemia, insulin resistance, and fat redistribution, an association attributed particularly to PIs. On the contrary, more recent studies, beginning with the Strategies for Management of ARV Therapy (SMART) trial, suggested a positive effect of the treatment on metabolism.34 On the other hand, in the present study, the protective or harmful role of ART could not be investigated adequately because the number of treatment-naïve women was very small (<9%), which limited the statistical power of the analysis. Likewise, the possible influence of other aspects of the infection such as stage of the disease, nadir CD4 count and the patient's current immune and viral status was not confirmed by these results, since the sub-groups of women with advanced uncontrolled disease were small. This limited the statistical power to identify the role of these factors as predictors of MetS. This study was limited by its cross-sectional nature, the scarcity of information concerning the cumulative exposure of the patients to each antiretroviral drug, and the heterogeneity of their therapeutic history. It is still a great challenge to assess the complex effect of ART on metabolic syndrome. Larger prospective studies shall clarify these issues.

The results of the present study show a high prevalence of MetS in middle-aged HIV-infected women; however, the prevalence is similar to that of the general population. The predictive factors of MetS in this population were elevated FSH levels and high BMI, both of which are traditional risk factors for the syndrome. Factors related to HIV infection and its treatment were not associated with MetS in this group of women with access to effective and timely treatment, and whose immune and general health status was good. The present results are in agreement with recent evidence showing that, with access to modern ARV treatment, morbidity and mortality of the HIV-infected patients is similar to that of the general population.

The high prevalence of MetS found in middle-aged HIV-infected women and the current profile of the epidemic, with PLHIV aging, indicate that MetS is indeed an increasingly common problem within the context of clinical management of HIV. In this new phase of the epidemic, it is essential to develop specific strategies for prevention, diagnosis, and treatment of MetS in PLHIV.

Funded by the São Paulo Foundation for the Support of Research – FAPESP, Grant 2010/06037-5.

The authors declare no conflicts of interest.