In this five year follow-up study of regional adipose tissue volumes, we found that HIV-infected participants in the FRAM study gained less or similar AT on the average than control participants. Many HIV-infected participants started at lower levels due to HIV-associated lipoatrophy, and the results indicate that those with lipoatrophy had little recovery regardless of whether they discontinued the implicated antiretroviral drugs.
The diminished recovery was most obvious in leg SAT, the depot most affected by HIV-associated lipoatrophy. Over five years, control men and women gained on average 0.8L of SAT in the leg, whereas HIV-infected men gained only 0.4 L and HIV-infected women showed no average gain. Thus HIV-infected participants had even less leg SAT on average relative to controls at the year-five exam. In the Multicenter AIDS Cohort Study, thigh circumference increased more over four years in control than HIV-infected men[15
]. In the Women’s Interagency HIV Study, over four years thigh circumference increased in control women and decreased in HIV-infected women[14
Some studies of the change in AT after switching antiretroviral therapy report mean percent change, with longer-term switch studies finding 10–42% increases after switching off NRTI[8
]. However, the absolute gains were typically small in these switch studies. In the study with the largest percent gain (42%), mean leg fat by DEXA increased from 1.6 to 2.2 kg[11
]. Indeed, it may be that past papers reporting percentage increases led readers to believe there was more significant recovery. In our study, the geometric mean relative change in leg SAT was 28% in HIV-infected men compared to 3.9% in controls, which might suggest that substantial recovery was made in HIV-infected men. The percent changes should be contrasted with the baseline and absolute changes. HIV infected men started with a baseline average leg SAT of 3.3 L, while control men started with a baseline of 4.9 L. Despite starting lower, in HIV-infected men the actual mean gain in leg SAT was 0.47L vs. 0.65L in controls, which clearly conveys that HIV-infected men were not catching up. HIV-infected women started with less leg SAT than control women (8.7L vs. 10.4L). On average HIV-infected women did not gain leg SAT (−.03L), whereas control women did gain (0.69L). Furthermore, in the two AT depots that were higher in HIV-infected women than controls at baseline (upper trunk SAT and VAT), controls gained more AT; therefore, at five year follow-up these depots were virtually the same in HIV-infected and control women.
Many of the longer-term switch studies did not require the presence of lipoatrophy for entry[11
]. When we examined HIV-infected subjects who had lipoatrophy defined as having leg SAT below the cutoff of the lowest control decile, the HIV-infected subjects had a 40% gain in leg SAT. However, the HIV-infected gained 0.96L, while the comparative controls gained 1.23L; the net result is that there is no relative recovery from lipoatrophy when HIV-infected participants are compared to controls.
In further support of this concept, multivariable modeling found that little gain could be attributed to years off stavudine or other antiretroviral drugs including zidovudine. Yet in the HIV-infected cohort, duration of exposure to stavudine was associated with lower leg SAT at both FRAM exams. In the WIHS study, women who discontinued stavudine had smaller annual decreases in thigh circumference than those who continued stavudine[14
The results with leg SAT should be contrasted to those with VAT, where HIV-infected and control men saw similar gains, while HIV-infected women no longer had greater VAT than control women. These data, along with our previous studies of SAT and VAT in HIV-infection[2
], add additional support for the concept that these depots are independent and are not affected by the same factors.
There are several limitations to our study. We did not require lipoatrophy as an entry criterion, because our study was originally designed to be representative of the spectrum of HIV infection. However, we found little recovery in those HIV-infected who started with the lowest baseline SAT relative to controls. Likewise, several of the longer term switch studies did not require lipoatrophy as an entry criterion[11
]. While our HIV-infected participants span a wide age range (19–76 years at baseline), comparisons with controls were restricted to a narrower age range (baseline 33–45 years), which limits our ability to generalize these results to older populations. Our study is observational. While a randomized study of discontinuation vs. continuation of relevant NRTI would be optimal, a five-year randomized study is neither feasible nor ethical. The longest NRTI switch study was 144 weeks. Finally, we cannot rule out accelerated gain of SAT after an even greater time off the drugs associated with lipoatrophy. However, in multivariable analyses the average 3.6 years of exposure to stavudine was associated with dramatically lower amounts of SAT, while in those who had been off of stavudine for an average of 4.3 years, little of the AT gain could be attributed to the time off drug.
A major strength of our study is the comparison of change in AT in HIV-infected persons over five years to that of controls in order to account for the normal changes in aging. Our controls come from the VIM substudy[29
] of the CARDIA cohort, where the average BMI is similar to that of the nationally representative sample of NHANES.
In conclusion, five years after the first exam in the FRAM study, gain in AT was similar in HIV-infected and control participants. HIV-infected participants had significant subcutaneous lipoatrophy at the baseline exam and, five years later, relative lipoatrophy persisted compared to controls, even in those who discontinued antiretroviral drugs associated with lipoatrophy, such as stavudine, during this period. These data must be considered when studying the potential mechanisms underlying HIV-associated lipoatrophy. It remains to be determined whether there was destruction of adipose cells and precursors as proposed by some[30
], or whether other factors continue to contribute to the persistence of lipoatrophy in HIV infection. Finally, as the presence of lipoatrophy has been associated with adverse metabolic effects[31
] and with depression[33
], the long-term consequences and treatment of persistent lipoatrophy need additional study.