Are all of these problems connected?

For several years, beginning with the widespread use of HIV drug combination therapy, the different types of body-shape changes (lipohypertrophy and lipoatrophy) have been reported by numerous HIV-positive people and their healthcare providers. In turn, they were both unofficially lumped together as being a part of the same syndrome, likely caused by antiretroviral (ARV) drug treatment. However, it's still not clear if these two different types of body-shape changes are really related. Some HIV-positive people don't have any signs of lipoatrophy or lipohypertrophy, some experience one or the other, whereas others experience both. Because different HIV-positive people seem to experience different problems, it has been difficult to establish an official "case definition" of lipodystrophy. And for researchers to really understand the cause(s), prevention, and treatment of lipodystrophy, an official case definition needs to be determined.

To better understand how these problems are connected, and to help come up with an official case definition of lipodystrophy, researchers have been conducting important studies involving HIV-positive people with these symptoms. The first study to come up with a case definition was headed by Dr. Andrew Carr of St. Vincent's Hospital in Sydney, Australia. Results from the Lipodystrophy Case Definition (LDCD) study, an international effort involving 32 clinical research centers and 1,081 HIV-positive patients worldwide, were reported in 2003. In short, the study indicated that both lipohypertrophy and lipoatrophy are features of lipodystrophy. The study also suggested that the two features are linked to each other—where there is an increase in visceral fat there will most likely be a decrease in subcutaneous fat (and vice versa).

The connection between lipoatrophy and lipohypertrophy was questioned, however, with the publication of data from the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study. The study was headed by Dr. Carl Grunfeld of the University of California, San Francisco. Unlike the LDCD study, which only enrolled HIV-positive people, the FRAM study compared HIV-positive with HIV-negative volunteers. It enrolled 825 HIV-positive men, 350 HIV-positive women, and 338 HIV-negative people. Results focusing on men enrolled in FRAM were published in October 2005. Results focusing on women enrolled in FRAM were published in August 2006.

The study demonstrated that lipoatrophy was much more common in the HIV-positive volunteers than in the HIV-negative study participants. Approximately 38 percent of the HIV-positive men had "clinical" lipoatrophy of at least one part of the body—fat loss that was reported by the study participants and confirmed by the researchers during a physical examination—compared with approximately 4 percent of the HIV-negative men. Clinical lipoatrophy was also documented in 28 percent of the HIV-positive women compared with 4 percent of the HIV-negative women.

The study also demonstrated that HIV-positive people do experience lipohypertrophy. However, this buildup of fat—which was confirmed using MRI scans—was actually more common in the HIV-negative men than in the HIV-positive men. Approximately 40 percent of the HIV-positive men had lipohypertrophy, compared with approximately 56 percent of the HIV-negative men. Among women, reported lipohypertrophy was similar in both groups. Approximately 62 percent of the HIV-positive women had lipohypertrophy of at least one part of the body, compared with 63 percent of the HIV-negative women.

These study results indicate that lipoatrophy is a unique complication caused by HIV and/or HIV medications, whereas lipohypertrophy is not, given that visceral fat increases were similar among the HIV-positive and HIV-negative women and even more common in the HIV-negative men. The study also suggested that lipoatrophy and lipohypertrophy are not linked—patients who had increased visceral fat were more likely to have increased (not decreased) subcutaneous fat. In other words, FRAM suggests that visceral fat and subcutaneous fat either increase together or decrease together; one doesn't go up while the other goes down.

The FRAM results don't say that lipohypertrophy isn't a problem for HIV-positive people. Quite the opposite—they confirm that significant numbers of people with HIV suffer with this condition. What the FRAM results do say, is that the problem is no more common in people with HIV than uninfected people. Some have proposed that the problem may be more obvious, or visible in people with HIV, because so many people also have lipoatrophy. Most HIV-negative people with lipohypertrophy also carry extra weight in their faces, buttocks and limbs, so gut or breast fat isn't always as noticeable as it is for HIV-positive people. Subsequent analysis of the FRAM data have also confirmed that lipohypertrophy can have serious health consequences. The FRAM study isn't perfect. It only looked at people across a single time point. It's possible, therefore, that more people with HIV may have developed lipohypertrophy over time. It remains, however, one of the largest and most rigorously controlled studies on the topic thus far.

The additional studies using FRAM data have confirmed that changes in how the body processes sugar—and increases in cholesterol and triglycerides—are strongly associated with increased gut fat accumulation, but researchers don't know for certain how much one causes the other. Do blood sugar and blood fat changes lead to lipohypertrophy, or does lipohypertrophy lead to blood fat and blood sugar changes? This is one of the big unanswered questions.

Based on the results of FRAM (and other studies that reported similar findings), it is clear that we are still a ways off from an official case definition for lipodystrophy. Is it lipohypertrophy and lipoatrophy, or is it just lipoatrophy? How are high levels of fats and sugar in the blood related to body-shape changes? Hopefully additional studies will settle this once and for all.

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