July 15, 2003
The early enthusiasm for highly active antiretroviral therapy (HAART) has been tempered by an awareness of the chronic toxicities associated with these regimens. Several of these toxicities have been grouped under the term lipodystrophy, which encompasses lipoatrophy (loss of subcutaneous fat), central fat gain, insulin resistance, diabetes mellitus and hyperlipidemia. Lipodystrophy is most often a complication of combination therapy, and many of the different toxicities of lipodystrophy can occur as adverse effects together in one person. However, these toxicities are probably best viewed as separate complications with separate causes, and the term "lipodystrophy" should be avoided. The FRAM study was undertaken to help define these various metabolic complications of HIV and antiretroviral therapy.
An overview of the FRAM study was provided by Carl Grunfeld. FRAM (Fat Redistribution and Metabolic Change in HIV Infection Study) is a multi-site cross-sectional study sponsored by the National Institutes of Health. It enrolled 825 HIV-positive men, 350 HIV-positive women and 338 HIV-negative controls. The HIV-positive participants were randomly chosen from the databases at the participating sites. The HIV-negative controls were recruited from the Coronary Artery Risk Development in Young Adults (CARDIA) program, and simulated a random sample of U.S. adults. Both the HIV-positive and HIV-negative participants were between 33 and 45 years old.
All of the participants answered a questionnaire on perceived fat loss or gain at several sites around the body (i.e., legs, arms, cheeks, lower trunk and upper trunk). All participants underwent a physical exam for clinical evidence of fat loss. The study collected an objective measure (whole body MRI) of fat distribution to evaluate total body fat, subcutaneous fat and visceral abdominal fat. The study also collected fasting lipid profiles and other metabolic laboratories.
Michael Saag presented data on the body composition in men. Overall, self-reported fat loss was much more common among HIV-positive men than HIV-negative men. Fat gain was reported more often by HIV-negative men than by HIV-positive men. Participants were classified as having lipoatrophy when they reported fat loss and this was confirmed by physical exam. Lipoatrophy among HIV-negative men was not associated with central fat gain.
The researchers found that HIV-positive men with lipoatrophy actually had less central fat (visceral abdominal fat) than did men without lipoatrophy. HIV-positive men had a lower body mass index (BMI, i.e., weight adjusted for height) than did HIV-negative men.
Among men with HIV, researchers discovered that those with lipoatrophy had a lower BMI than did men without lipoatrophy. The same results were seen for total body fat -- men who were HIV-positive had less total body fat than men who were HIV-negative, HIV-positive participants with lipoatrophy had less total body fat than HIV-positive participants without lipoatrophy. The legs were the most prominent sites of subcutaneous fat loss for HIV-positive men. Upper chest and central fat loss was less pronounced.
Abby Shevitz presented data on body fat composition in women. Overall, the BMI of HIV-positive women was not different than that of HIV-negative women. HIV-positive women with lipoatrophy had a lower BMI and total body fat than did HIV-positive women without lipoatrophy. As was seen in men, lipoatrophy was not associated with central fat gain. HIV-positive women with lipoatrophy actually had less central fat (visceral abdominal fat) than did women without lipoatrophy. Women with HIV lost the most fat in the legs.
Charles van der Horst presented data on lipids and insulin resistance in men. Overall, HIV-positive men had a lower total cholesterol, a lower low-density lipoprotein (LDL), a lower high-density lipoprotein (HDL) and higher triglycerides than did HIV-negative men. The average lipid profile of the HIV-positive men was associated with a higher risk for coronary artery disease than was the average lipid profile for HIV-negative men. HIV-positive men with lipoatrophy had higher triglycerides than both HIV-positive men without lipoatrophy and HIV-negative controls. HIV-positive men and HIV-negative men had similar fasting blood glucose, but the insulin levels and insulin/glucose ratios (markers for early diabetes mellitus) were higher in HIV-positive men than in HIV-negative men.
Judith Currier presented data on lipids and insulin resistance in women. Overall, HIV-positive women had lower LDL and HDL, higher triglycerides and a similar total cholesterol than did HIV-negative women. As was the case for men, the average lipid profile for HIV-positive women was associated with a higher risk for coronary artery disease than was the average lipid profile for HIV-negative women. The lipid profile was not different between HIV-positive women with lipoatrophy and HIV-positive women without lipoatrophy. HIV-positive women and HIV-negative women had similar fasting blood glucose, but the insulin levels and insulin/glucose ratios (markers for early diabetes mellitus) were higher in HIV-positive women than in HIV-negative women.
The most important information from this session and probably the most controversial finding of the FRAM study is the lack of an association between lipoatrophy (loss of subcutaneous fat) and central fat gain. In fact, people with lipoatrophy actually had less central fat. This implies that fat is not redistributing; it doesn't move from the periphery to the abdominal cavity. Many members of the audience were quite reticent to accept this finding. There is much analysis left to conduct on this study. For example, no information on participants' antiretroviral use or medical history has been analyzed to date. The FRAM study should continue to clarify the vexing problem of metabolic complications from HIV and antiretroviral therapy.
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