Existing metabolic syndrome predicts cardiovascular disease and diabetes in HIV-positive people starting anti-HIV treatment

In a large-scale trial of treatment-naïve HIV-positive adults about to begin antiretroviral therapy, metabolic syndrome was found in a surprisingly low 8%. However, the syndrome developed in a significant number over the first three years of therapy, and such development was a risk factor for cardiovascular disease and diabetes. The study, an analysis of data from the INITIO trial, was published in the November 30^th edition of AIDS.

Metabolic syndrome is a group of conditions including insulin resistance, high lipid levels, high blood pressure and abdominal obesity. It is not synonymous with HIV-associated lipodystrophy and metabolic abnormalities, although many of the features are markedly similar.

The INITIO trial was a large, international, prospective clinical trial which compared three initial antiretroviral regimens: didanosine (ddI, Videx) and stavudine (d4T, Zerit) plus either efavirenz (Sustiva), nelfinavir (Viracept), or both. (A study limitation is that few of these are now preferred initial agents.) A post hoc analysis of 881 participants in the INITIO trial evaluated the prevalence and incidence of metabolic syndrome and subsequent cardiovascular disease (CVD) and diabetes, over a three-year period after starting anti-HIV therapy. (NB: all references to 'diabetes' in this report refer to type 2 diabetes mellitus).

The two most widely-used definitions of metabolic syndrome (MS) are those of the (US) National Cholesterol Education Program Adult Treatment Panel III (ATP-III), and the International Diabetes Federation (IDF). This study analysis used both of these definitions. ATP-III defines MS as three or more of the following: fasting plasma glucose ≥ 6.1 mmol/l, fasting serum triglycerides ≥ 1.7 mmol/l, serum HDL cholesterol 102 cm (40 inches) for men or 88 cm (35 inches) for women. The IDF definition requires a waist circumference > 94 cm (37 inches) for men or 80 cm (31.5 inches) for women, and, in addition, two or more of the following: fasting plasma glucose ≥ 5.6 mmol/l, fasting serum triglycerides ≥ 1.7 mmol/l, serum HDL cholesterol

All participants were treatment-naïve at baseline. Of the 881 included in analysis, 21% were female, the mean age was 38.7 years, and the mean body mass index (BMI) was 23.0 kg/m². Seven hundred and forty-one remained to follow-up after three years; the split between treatment arms was roughly equal throughout.

Prior to starting antiretrovirals, 8.5% of the participants had MS using the ATP-III criteria, and 7.8% by the IDF criteria. This is considerably lower than the estimated 25% prevalence rate in the general US population and 26% in British males found in other studies. It is also lower than other reported estimates of MS in the HIV-positive population, which range from 14% to 26%. The researchers suggest that the higher rates of other reports could be due to the cross-sectional nature of the studies and the fact that their cohorts were already largely on anti-HIV treatment, as opposed to the purely treatment-naïve population of INITIO: "the lower rates … in this population suggest… that HIV infection per se probably does not contribute to MS".

Despite low baseline prevalence, incidence rates were high. Over the three years following initiation of therapy, 234 (12/100 patient-years) and 178 (8/100 patient-years) developed MS according to ATP-III and IDF definitions, respectively. The authors note that their incidence estimates are "substantially higher" than those of other recent studies, again noting that most participants in other studies were already on anti-HIV drugs.

In HIV-negative populations, the most common features of MS are obesity and high blood pressure (hypertension). The study participants who developed MS tended to develop elevated triglycerides in combination with increased blood pressure and glucose. This particular pattern of MS-associated features has been seen in other studies.

Developing MS during therapy was a significant risk factor for developing cardiovascular disease (CVD) or diabetes; having MS at baseline was also a significant risk factor for CVD but only marginally associated with CVD. Hazard ratios and confidence intervals were as follows:

(*not significant / borderline significant)

Despite the well-defined differences between the metabolic effects of antiretroviral drug classes, no significant differences were observed in rates of progression to MS between the randomised treatment arms.

The researchers note the following caveats: although this was a prospective trial, these published analyses were post hoc; CVD endpoints were assessed from study site reports and not independently validated; blood measurements could be confirmed as fasting values for only a minority of site visits; the regimens used would no longer be recommended as initial therapy; and no reliable race or ethnicity data was available. While "urg[ing] caution against overinterpretation of these findings," the authors believe that their data show MS to be "less prevalent in HIV-infected individuals who are ART-naïve compared with… the general population," that "substantial progression to MS occurs within three years following initiation of ART," and that "MS possibly identifies those at increased risk of CVD and [type 2 diabetes mellitus]" and hence "may be of value for selecting patients for risk assessment and possibly preventative strategies."

Significantly, the combined predictive value for MS overall was better than that of any of its components: the authors state that this study "is one of the first to use prospective data to support the multiplicative effects of the combined risk factors over the assessment of individual risk factors."