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Does Lipoatrophy Persist ? - Regional adipose tissue measured by MRI over 5 years in HIV-infected and control participants indicates persistence of HIV-associated lipoatrophy - pdf attached (I suggest reading the pdf closely)
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Grunfeld, Carl; Saag, Michael; Cofrancesco, Joseph Jr; Lewis, Cora Elizabeth; Kronmal, Richard; Heymsfield, Steven; Tien, Phyllis C; Bacchetti, Peter; Shlipak, Michael; Scherzer, Rebecca; for the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM)
Objective: Peripheral fat loss and visceral fat gain have been reported in HIV infection. There are limited data on long-term change in adipose tissue in HIV-infected patients vs. controls. Therefore, we determined change in regional adipose tissue from baseline examination to 5 years later among participants in the study of Fat Redistribution and Metabolic Change in HIV Infection.
Methods: Regional adipose tissue volume was measured using MRI at both examinations in 477 HIV-infected and 214 control men and women. Lipoatrophy was defined as leg subcutaneous adipose tissue (SAT) below the cutoff point marking the lowest decile (10%) of controls at each examination.
Results: HIV-infected and control participants showed similar adipose tissue gains. In men, all SAT depots and visceral adipose tissue started lower and remained lower on average in HIV-infected vs. controls. In women, leg and arm SAT also started lower and remained lower in HIV-infected vs. controls. Mean leg SAT of HIV-infected men was 67% of control men at baseline and 65% at follow-up; for women 83% and 77%. At baseline, 48% of HIV-infected participants had lipoatrophy; on average those with baseline lipoatrophy gained 0.96L of leg SAT compared with 1.23L gain for controls in the lowest decile (P = 0.16). At follow-up, 53% of HIV-infected participants had lipoatrophy. In multivariable models, discontinuation of stavudine appeared to produce little gain in leg SAT (~1.1%/year).
Conclusion: HIV-infected participants did not substantially recover SAT compared with controls, although both showed average gains. HIV-associated lipoatrophy persisted after 5 years of follow-up.
The introduction of combination antiretroviral therapy (ART) was followed by changes in fat distribution and metabolic abnormalities in HIV-infected individuals that may contribute to cardiovascular disease [1]. Both peripheral fat loss (lipoatrophy) and central fat gain (lipohypertrophy) have been reported in HIV infection. A major finding of the first study of Fat Redistribution and Metabolic Change in HIV infection (FRAM) was that HIV-infected participants differed from controls in terms of lipoatrophy, but not lipohypertrophy, as defined by self-report confirmed by examination, as well as by direct measurement using total body regional MRI [2,3].
Participants with clinical lipoatrophy had less subcutaneous adipose tissue (SAT) in all depots than those without clinical lipoatrophy and controls. HIV-infected men without clinical lipoatrophy also had less SAT than healthy controls. Less SAT was associated with use of specific antiretroviral drugs. In contrast, the amount of visceral adipose tissue (VAT) was independent of SATand not associated with specific antiretroviral drugs.
Little is known about what happens to adipose tissue over the long term in HIV-infected patients. Previous studies in uninfected individuals have found that younger and middle-aged adults gain 0.5- 1.0 kg/year [4]. Total body fat is known to increase with age (until age 55 in men and age 65 in women) [5].
Many studies have assessed the effects of switching antiretroviral drug regimens on adipose tissue in HIVinfected participants, butmost lasted 1 year or less and those studies varied in results [6,7]. When participants were switched off protease inhibitors, loss of adipose tissue often continued. When participantswere switched off stavudine or thymidine analogues, increases in leg or limb adipose tissue were usually small. In the few studies lasting up to 96- 144 weeks, in which participants were switched off nucleoside reverse transcriptase inhibitors(NRTIs), gain in fat was more consistently found, ranging from 10 to 42% [8- 13]. However, none of these studies compared changes in fat with the changes found in healthy controls. Furthermore, these studies mostly used dual-energy X-ray absorptiometry or computed tomography scans, hence were limited in the regional depots studied. In the large observational studies that studied fat changes in HIV infection and included controls, measures were limited to the use of anthropometry [14,15]. Thus, no large study has compared changes over several years in whole body regional adipose tissue depots including VAT in a nationally representative, multiethnic cohort of both HIV-infected participants, and controls. A primary aim of the second FRAM study was to determine the changes in SAT and VAT using whole body MRI in both HIVinfected and control participants after 5 years of follow-up [16]. We hypothesized that a well treated cohort of HIVinfected participants in the HAARTera would not resolve their HIV-associated lipoatrophy over 5 years. We also sought to investigate the associations of ART use and discontinuation with changes in fat.
In this 5-year follow-up study of regional adipose tissue volumes, we found that HIV-infected participants in the FRAM study gained less or similar adipose tissue 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 5 years, control men and women gained on average 0.7L of SAT in the leg, whereas HIV-infected men gained only 0.5L 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 5 examination. In the Multicenter AIDS Cohort Study, thigh circumference increased more over 4 years in control than HIV-infected men [15]. In the WomenÕs Interagency HIV Study, over 4 years thigh circumference increased in control women and decreased in HIVinfected women [14].
Some studies of the change in adipose tissue after switching antiretroviral therapy report mean percentage change, with longer term switch studies finding 10- 42% increases after switching off NRTI [8- 13]. However, the absolute gains were typically small in these switch studies. In the study with the largest percentage gain (42%), mean leg fat by dual-energy X-ray absorptiometry increased from 1.6 to 2.2 kg [11]. Indeed, it may be that past articles 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 with 3.9% in controls, which might suggest that substantial recovery was made in HIVinfected men. The percentage changes should be contrasted with the baseline and absolute changes.
HIV-infected men started with a baseline average leg SATof 3.3L, whereas control men started with a baseline of 4.9L. 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 [-0.03L], whereas control women did gain (0.69L). Furthermore, in the two adipose tissue depots that were higher in HIV-infected women than controls at baseline (upper trunk SAT and VAT), controls gained more adipose tissue; therefore, at 5-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- 13]. When we examined HIV-infected participants who had lipoatrophy defined as having leg SAT below the cutoff of the lowest control decile, the HIV-infected participants had a 40% gain in leg SAT. However, the HIV-infected gained 0.96L, whereas 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 examinations. 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, in which HIV-infected and control men saw similar gains, whereas HIV-infected women no longer had greater VAT than control women. These data, along with our previous studies of SAT and VAT in HIVinfection [2,3], 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- 13]. Although 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.
Although a randomized study of discontinuation vs. continuation of relevant NRTI would be optimal, a 5-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 stavudinewas associatedwith dramatically lower amounts of SAT, whereas in those who had been off stavudine for an average of 4.3 years, little of the adipose tissue gain could be attributed to the time off drug.
A major strength of our study is the comparison of change in adipose tissue in HIV-infected persons over 5 years to that of controls to account for the normal changes in aging. Our controls come from the Visceral Fat and Metabolic Rate in Young Adults Study (VIM) substudy [29] of the CARDIA cohort, in which the average BMI is similar to that of the nationally representative sample of National Health and Nutrition Examination Survey (NHANES).
In conclusion, 5 years after the first examination in the FRAM study, gain in adipose tissue was similar in HIV infected and control participants. HIV-infected participants had significant subcutaneous lipoatrophy at the baseline examination and, 5 years later, relative lipoatrophy persisted compared with 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 [31,32] and with depression [33], the long-term consequences and treatment of persistent lipoatrophy need additional study.

Body composition by MRI at baseline and follow-up were available on 691 participants whose characteristics at the follow-up examination are presented in Table 1. HIV-infected and control participants were similar in age, height, and percentage of whites and African Americans, but HIV-infected participants were more often male (68 vs. 53%) because of the design of the control study. Control participants weighed more and accordingly had higher BMI.
Comparison of fat gains in HIV-infected and control participants
Mean adipose tissue volumes at baseline and follow-up examination for each regional depot in HIV-infected and control men, restricted to the age range of controls (ages 33- 45 at baseline), are shown in Fig. 1a. Mean change in regional adipose tissue volumes between examinations is shown in Fig. 1b. Corresponding values for women are in Fig. 2a and b. Statistically significant gains were seen in nearly every depot in both HIV-infected and control men and women (with most P<0.0001, Figs 1b and 2b).
HIV-infected men had lower mean adipose tissue volumes in all depots (SAT and VAT) at the first examination than control men (Fig. 1a), although the difference in arm SAT did not reach statistical significance (P=0.14). Mean 5-year gains were somewhat smaller in all SAT depots for HIV-infected men than control men (Fig. 1b); the difference only reached statistical significance for arm SAT (P=0.0002). Hence, at the FRAM2 examination, adipose tissue volumes remained lower in HIV-infected men relative to controls in a pattern similar to the first examination. For example, mean baseline leg SAT in HIV-infected men was 3.3L and increased to 3.7L, whereas baseline leg SAT in control men was 4.9L and increased to 5.7L. Thus, mean leg SAT in these HIV-infected men was 67% that of control men at the first FRAM examination and 65% of control men at the second examination (Fig. 1a). Similar results were found for each of the other SAT depots. Average VAT gain was similar in HIV-infected and control men. As a consequence, mean VAT also remained lower in HIVinfected men at the FRAM2 examination.
HIV-infected women also had lower leg and arm SAT than control women at the first examination (Fig. 2a). Five year gains in leg SAT were somewhat smaller and in arm SAT were slightly larger in HIV-infected compared with control women, although the differences did not reach statistical significance (Fig. 2b); HIV women continued to have lower leg and arm SAT at examination 2 than control women (Fig. 2a). For example, mean baseline leg SAT was 8.6L at both examinations in HIV-infected women, whereas leg SAT in control women was 10.4L at baseline examination and 11.2L at the second examination (Fig. 2a). Thus, mean leg SAT in HIV-infected women was 83% of controls at the first examination and decreased to 77% at the second examination.
At the baseline examination, upper trunk SAT and VAT were higher in HIV-infected women than in controls (mean upper trunk SAT=6.5L vs. 5.2L, P=0.019; VAT=1.6L vs. 1.3L, P=0.023). However, the gains in upper trunk SAT and VAT were somewhat greater in control women than HIV-infected women with the differential gain in upper trunk SAT reaching statistical significance (Fig. 2b). As a consequence, at the follow-up examination (Fig. 2a), HIV-infected women had similar mean upper trunk SAT and VAT to control women (upper trunk SAT: HIV 7.1L, Control 7.0L, P=0.91; VAT: HIV 2.5L, control 2.5L; P=0.83).
We examined pooled models to determine whether the differences in 5-year change in adipose tissue between HIV-infected and control participants remained after multivariable adjustment for demographic and lifestyle factors. After adjustment, HIV-infected participants showed smaller increases than controls in all regional SAT depots and VAT (Table 2), with differences reaching statistical significance for leg SAT [-0.81L], P=0.009), arm SAT (-0.33L, P=0.0002), and upper trunk SAT (-0.85L, P.0=005). We observed statistically significant HIV by sex interactions for lower trunk (P=0.028) and arm SAT (P=0.014). In fully adjusted models, HIV infection in men was associated with smaller increases for lower trunk and arm SAT relative to controls [-098L], P=0.016; [-0.45L] P<0.0001, respectively), whereas the changes in HIV-infected women relative to controls were small and did not reach statistical significance (0.16, P=0.77; [-0.15], P=0.25).
Although HIV-infected and control participants gained adipose tissue on average, we found that the prevalence of any leg SAT loss was higher in HIV than controls (35 vs. 27%, P=0.0013). Additionally, we found that HIVinfected participants were more likely than controls to lose VAT (17 vs. 5.1%, P<0.0001).
Change in adipose tissue relative to baseline adipose tissue
In these participants, 48% of the HIV-infected had lipoatrophy at the baseline examination, defined as having leg SAT below the cutoff of the lowest 10% of controls. The HIV-infected participants in that category gained an average of 0.96L between examinations, whereas the respective controls gained 1.23L (P=0.16). At the second examination, 53% of HIV-infected had leg SAT below the 10% cutoff of second examination control values. Among those HIV-infected who had lipoatrophy by this cutoff at the baseline examination, 82% had lipoatrophy at follow-up. When we instead defined lipoatrophy using the clinical definition [2,3], 33% of the HIV-infected had lipoatrophy at the baseline examination, defined as concordance between participant report of fat loss and examination finding of less fat than a normal healthy person. The HIV-infected participants in that category gained even less, an average of 0.86L between examinations.
For leg SAT and VAT, we examined the relationship of quartiled baseline adipose tissue with change in adipose tissue, using quartile cut points based on control participants, to allow direct comparison of HIV-infected and control participants at similar baseline adipose tissue. For leg SAT (Fig. 3a), in HIV-infected participants, the median change in those with the least baseline leg SAT was similar to that of controls in the same quartile and was significantly less than controls in the third and fourth baseline quartiles. By contrast, for VAT (Fig. 3b), there was little difference between HIV-infected and control participants in change in VAT across baseline VAT quartiles.
Discontinuation of antiretroviral drugs and gain of leg subcutaneous adipose tissue in HIV-infected participants
We also evaluated repeated measures models of amount of leg SAT at the two examinations to determine whether any of the gains in leg SAT could be attributed to discontinuation of stavudine, the key antiretroviral drug responsible for leg SAT loss. Seventy-four percent of the HIV-infected participants had a history of stavudine use, but only 9.4% were still taking stavudine at the time of the second examination (see Supplemental Table, Average duration of exposure to stavudine was 3.6+/-2.7 (SD) years. Among those who had discontinued stavudine (65%), duration off stavudine was 4.3+/-2.6 yrs among the 9.4% of patients who were still on d4T at year 5, average gain in leg SAT was 0.53+/-3.0L. Somewhat smaller gains were seen in past d4T users (0.34+/-3.1L) and never d4T users (0.39+/-3.3L) although the differences did not reach statistical significance.
In multivariable models, duration of stavudine use was strongly associated with smaller absolute amounts of leg SAT (-5.6%) per year of exposure to d4T, P<0.0001). However, time off stavudine was associated with an estimated increase of only 1.1% per year in leg SAT, which did not reach statistical significance (95% CI 0.65, 2.9; P1=0.22). Likewise, little gain was associated with discontinuation of zidovudine or other antiretroviral drugs (data not shown).
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