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Increased Risk for Fat Loss in HIV+ Women Observed in WIHS Study
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"Incidence of Lipoatrophy and Lipohypertrophy in the Women's Interagency HIV Study"
JAIDS Journal of Acquired Immune Deficiency Syndromes 2003; 34(5):461-466
Phyllis C. Tien, MD; Stephen R. Cole, PhD; Carolyn Masters Williams, PhD; Rui Li, MS; Jessica E. Justman, MD; Mardge H. Cohen, MD; Mary Young, MD; Nancy Rubin, DO; Michael Augenbraun, MD; Carl Grunfeld, MD, PhD
The WIHS is funded by the National Institute of Allergy and Infectious Diseases, with supplemental funding from the National Cancer Institute, the National Institute of Child Health & Human Development, the National Institute on Drug Abuse, the National Institute of Dental and Craniofacial Research, the Agency for Health Care Policy and Research, and the Centers for Disease Control and Prevention
"...Studies on fat redistribution in HIV-infected women are few and imprecise due to small samples…..the simultaneous occurrence of peripheral lipoatrophy and central lipohypertrophy was uncommon (in WIHS)…….the incidence of peripheral and central lipoatrophy was about double that among HIV-uninfected women…..the 30-month cumulative incidences of peripheral lipoatrophy were 27% (162/605) among HIV-infected women and 13% (27/210) among HIV-uninfected women. The relative hazard for HIV-infected women compared with HIV-negative women was 2.1……. the cumulative incidences of central lipoatrophy were 23% (139/605) among HIV-infected women and 13% (27/210) among HIV-uninfected women. The adjusted relative hazard was 1.8”. As you can see from data below, the incidence of developing fat accumulation in belly was not greater in HIV-infected women (18% vs 25%). HIV-uninfected women were just as likely to develop body changes, but lipoatrophy (fat loss) in both periphery and belly predominates among HIV-infected women in WIHS. I think this data supports findings from FRAM that fat loss is predominant feature of body change rather than fat accumulation.
Author comments: HIV-infected women had a lower mean body weight and a lower percent total body fat than did HIV-uninfected women. The mean body weight and percent total body fat did not change for HIV-infected women over the 30-month follow-up period. HIV-uninfected women, on the other hand, had increases in both mean body weight and total percent body fat. The findings for HIV-uninfected women are expected with aging, especially among this middle-aged cohort. However, this same increase in mean weight and percent total body fat was not found for HIV-infected women, which suggests an effect of HIV infection on weight and total body fat. The differences in weight and percent total body fat between HIV-infected and HIV-negative women may be explained by our findings of the incident analysis of lipoatrophy and lipohypertrophy.
Over the 30-month follow-up period, a marked increase in the incidence of both peripheral and central lipoatrophy among HIV-infected women compared with HIV-uninfected women in the WIHS was observed, suggesting that subcutaneous lipoatrophy may predominate in HIV-infected women. There was no difference between HIV-infected and HIV-negative women in the risk of central lipohypertrophy, and the risk of peripheral lipohypertrophy appeared lower for HIV-positive women than for HIV-uninfected women. To our knowledge, these findings have not previously been reported. Most previous studies presumed an association between peripheral lipoatrophy and central lipohypertrophy associated with HIV infection and only investigated lipoatrophy in peripheral sites and lipohypertrophy in central sites. In addition, most studies did not include an HIV-uninfected comparison group.
The simultaneous presence of peripheral lipoatrophy and central lipohypertrophy in HIV-infected women was uncommon in our study. Using the classification of having peripheral lipoatrophy, central lipoatrophy, central lipohypertrophy, and/or peripheral lipohypertrophy, most women who could be classified into 2 of the 4 groups had either both peripheral and central lipoatrophy or both peripheral and central lipohypertrophy. This suggests that lipoatrophy and lipohypertrophy should be assessed separately when describing the prevalence or incidence, or exploring the etiology of lipodystrophy syndrome. In addition, both fat loss and fat gain should be assessed in both peripheral and central sites.
ABSTRACT. The purpose of this study was to estimate the incidence of lipoatrophy and lipohypertrophy among HIV-infected and HIV-uninfected women from the Women's Interagency HIV Study.
Eight hundred fifteen women were studied looking at semiannual data on self-report by women of bidirectional change in body fat, anthropometric measurements, weight, and bioelectric impedance analysis were included in a 30-month incidence analysis.
Lipoatrophy and lipohypertrophy in both peripheral (arms, legs, and buttocks) and central (waist, chest, and upper back) sites were defined by self-report of either a decrease or an increase in a body fat region over the previous 6 months that was confirmed by a corresponding change in anthropometric measurement.
Weight and total body fat increased in HIV-uninfected women but remained stable in HIV-infected women over 30 months.
Among HIV-infected women, the incidence of peripheral (relative hazard, 2.1; 95% confidence interval [CI], 1.4-3.3) and central (relative hazard, 1.9; 95% CI, 1.2-2.8) lipoatrophy was about double that among HIV-uninfected women, after adjustment for age and race.
The incidence of peripheral lipohypertrophy appeared lower among HIV-infected women than among HIV-uninfected women (relative hazard, 0.8; 95% CI, 0.6-1.1), while the incidence of central lipohypertrophy did not differ by HIV status.
Of HIV-infected women with 2 of 4 lipodystrophy outcomes, most (81%) had combined peripheral and central lipoatrophy or combined peripheral and central lipohypertrophy. Only 14% of these women had both peripheral lipoatrophy and central lipohypertrophy.
The 30-month cumulative incidences of peripheral lipoatrophy were 27% (162/605) among HIV-infected women and 13% (27/210) among HIV-uninfected women. The relative hazard for HIV-infected women compared with HIV-negative women was 2.1 (95% CI, 1.4-3.2) after adjustment for age and race group. The cumulative incidences of central lipoatrophy were 23% (139/605) among HIV-infected women and 13% (27/210) among HIV-uninfected women. The adjusted relative hazard was 1.8 (95% CI, 1.2-2.8) when HIV-infected women were compared with HIV-uninfected women. The cumulative incidences of central lipohypertrophy were 28% (169/605) among HIV-infected women and 31% (65/210) among HIV-uninfected women. The adjusted relative hazard was 1.0 (95% CI, 0.7-1.3) when HIV-infected women were compared with HIV-uninfected women. Finally, the cumulative incidences of peripheral lipohypertrophy were 18% (109/605) among HIV-infected women and 25% (53/210) among HIV-negative women. The adjusted relative hazard was 0.8 (95% CI, 0.6-1.1) when HIV-infected women were compared with HIV-uninfected women. All relative hazards were essentially the same in analyses further adjusting for height, weight, and percent body fat. Results were similar when an alternative definition of body fat changes was used based primarily upon skinfold measurements rather than circumference. The risk of lipoatrophy or lipohypertrophy was not substantially increased between women with 10-unit increases in body weight or total percent body fat at baseline when stratified by HIV status (data not shown).
Two hundred fifty-one of the 605 HIV-infected women and 47 of 210 HIV-uninfected women reported loss of fat in the periphery over the 6 study visits, and the proportion of these women with a confirmed change of [ge]0.7 cm in the circumference measurement between visits was similar (53% [134/251] vs. 51% [24/47], respectively; [chi]2 test, P = 0.87). Two hundred twenty HIV-infected and 45 HIV-uninfected women reported loss of fat in central body sites, and the proportion of women with a confirmed change was similar (54% [118/220] vs. 56% [25/45], respectively; [chi]2 test, P = 0.87). Two hundred two HIV-infected and 78 HIV-uninfected women reported gain of fat in the periphery, and the proportion of women with a confirmed change was similar (46% [93/202] vs. 53% [41/78], respectively; [chi]2 test, P = 0.35). Three hundred twenty-one HIV-infected and 91 HIV-uninfected women reported gain of fat in central sites, and the proportion of women with a confirmed change was lower among the HIV-infected women than among the HIV-uninfected women (38% [121/321] vs. 55% [50/91], respectively; [chi]2 test, P < 0.01). The median change in anthropometric measurements between visits for both HIV-infected and HIV-uninfected women exceeded the standardized cutoff values of 0.7 cm for circumference measurements and 0.2 cm for the subscapular skinfold measurement by >2-fold for every site except the arm, where the average median circumference change was 1.0 cm (data not shown).
Of the 605 HIV-infected women, 311 ended the 30-month follow-up without any incident lipoatrophy or lipohypertrophy. Of the 294 women who did develop changes, 99 developed peripheral lipoatrophy alone, central lipoatrophy alone, central lipohypertrophy alone, or peripheral lipohypertrophy alone. One hundred forty-six women had 2 of the 4 outcomes (81% had either combined peripheral and central lipoatrophy or combined peripheral and central lipohypertrophy, whereas only 14% had peripheral lipoatrophy and central lipohypertrophy). Thirty-two HIV-infected women had 3 of the 4 outcomes, and 17 had all 4 outcomes.
Of the 210 HIV-uninfected women, 121 ended the 30-month follow-up without any incident lipoatrophy or lipohypertrophy. Of the 89 women who did develop changes, 32 developed peripheral lipoatrophy alone, central lipoatrophy alone, central lipohypertrophy alone, or peripheral lipohypertrophy alone. Forty-eight women had 2 of the 4 outcomes (94% had either combined peripheral and central lipoatrophy or combined peripheral and central lipohypertrophy, and 4% had peripheral lipoatrophy and central lipohypertrophy). Four HIV-uninfected women had 3 of the 4 outcomes, and 5 had all 4 outcomes.
The authors conclude that these prospective data suggest that lipoatrophy, affecting both peripheral and central sites, predominates in HIV-infected women. The simultaneous occurrence of peripheral lipoatrophy and central lipohypertrophy was uncommon.
There are a number of limitations to our study. First, measurements of regional fat by dual-energy x-ray absorptiometry, computed tomography, or magnetic resonance imaging were not performed. Therefore, it is unclear whether there was a preferential increase in visceral fat in HIV-infected women compared with HIV-uninfected women, as was suggested in a case series of HIV-infected men. However, the description of the clinical syndrome of lipoatrophy and lipohypertrophy was based upon self-report and examination changes in abdomen size and not on measured visceral fat when assessing central body regions. Second, as demonstrated, regardless of the presence or absence of lipoatrophy or lipohypertrophy, HIV-infected women had lower mean weight and percent total body fat at the index visit, which on average did not change in the 30-month follow-up period. Therefore, using a dichotomous clinical classification of having either lipoatrophy or lipohypertrophy may be limited; continuous measurements of regional fat using dual-energy x-ray absorptiometry or other imaging modalities are needed. Third, women who may have had lipoatrophy or lipohypertrophy at some more distant time in the past were not captured in the analysis using our definition of a report of body fat change confirmed by a measured change in fat in the previous 6 months beginning in 1999.
Our findings suggest that studies of women need to use a more rigorous definition of clinical lipoatrophy and lipohypertrophy. The direct measurement of fat should be considered. Analyses of determinants of lipoatrophy and lipohypertrophy, particularly antiretroviral therapies, can be misleading in the absence of the use of a more rigorous definition of lipoatrophy and lipohypertrophy and the use of a HIV-uninfected comparison group. Therefore, we did not include data on the determinants of antiretroviral therapy on lipoatrophy and lipohypertrophy in this analysis to emphasize the importance of defining the outcomes of lipoatrophy and lipohypertrophy using confirmation with objective measures. Future research efforts should be focused on the contributions of antiretroviral therapy and other factors to the development of lipoatrophy in HIV-infected women.
BACKGROUND
There is increasing concern regarding changes in fat distribution associated with HIV infection, including the development of a buffalo hump, increased breast size, and abdominal girth as well as fat loss in the face, limbs, and buttocks. These changes are often referred to as "lipodystrophy syndrome."9 Previous studies have used different definitions of the syndrome including a combination of peripheral lipoatrophy and central lipohypertrophy, isolated peripheral lipoatrophy, and isolated central lipohypertrophy. The lack of a consensus definition may partly explain the varying prevalence of lipodystrophy syndrome, between 2% and 84% in previous reports.
Studies on fat redistribution in HIV-infected women are few and imprecise due to small samples. A case definition of lipodystrophy has recently been proposed, but only 15% of the cohort studied were women.16 Increases in breast size and abdominal girth and decreases in lower limb fat are most commonly reported in case series and studies of HIV-infected women. Two studies of HIV-infected women have described the prevalence of lipodystrophy syndrome as 18% and 11%. In the first study, the occurrence of a body habitus change was defined as any report of an increase in abdominal girth, breast size, or peripheral wasting. In the second study, the syndrome was defined as self-report of an increase in abdominal girth or breast size accompanied by wasting of the buttocks, legs, and thighs, confirmed by physical examination.
Because central lipohypertrophy and peripheral lipoatrophy have been seen in HIV-infected individuals, it has been proposed that the 2 conditions are associated with HIV infection. However, some of these changes, particularly an increase in abdominal girth, are also commonly seen in healthy aging adults. Examination of the findings of small studies of HIV-infected women shows that women reporting body changes tend to be older than women not reporting such changes. For example, Engelson et al found that women infected with HIV who reported truncal enlargement were on average 4 years older than those without truncal enlargement (44 vs. 40 years, respectively).
The definition of lipodystrophy syndrome must be explored in a large cohort including HIV-uninfected controls and, specifically, women must be studied independently before contributing factors including antiretroviral therapy can be examined. We report findings of the prevalence and incidence of lipoatrophy and lipohypertrophy separately, using self-report of bidirectional changes in body fat confirmed by anthropometric measurements over a 30-month period between April 1999 and March 2002 among HIV-infected and -uninfected women from a large longitudinal cohort study.
Women's Interagency HIV Study
The Women's Interagency HIV Study (WIHS) is a prospective multisite study (New York, Chicago, Los Angeles, San Francisco, and Washington, D.C.) of the history of HIV infection in women with or at risk for HIV infection that has been conducted since 1994. At each semiannual WIHS visit, participants complete an extensive interviewer-administered questionnaire covering sexual practices, HIV-related symptoms, and demographic and psychosocial characteristics. In addition, participants are asked about changes in body fat in the face, neck, upper back, chest, arms, legs, buttocks, and waist since their last visit; if a change is reported, they are asked whether the change was a gain or a loss in fat. Blood specimens are obtained for determination of CD4 cell count, plasma HIV-1 RNA level, and other laboratory parameters, and physical examination is also performed.
Anthropometric measurements, including circumferences of the triceps, thigh, hip, chest, and waist region and skinfolds of the triceps, thigh, subscapular and suprailiac regions, were performed by trained clinicians beginning at the 10th semiannual WIHS visit (April to October 1999). Anthropometric measurements were performed using the techniques described by the Third National Health and Examination Survey procedures. Examiners completed an intense standardized training and certification program before collection of anthropometric data. A single exercise physiologist conducted training and certification of all examiners at each site. Skinfolds were measured using Harpenden calipers. The percent total body fat was determined semiannually by bioelectric impedance analysis ("Quantum" [BIA-101Q]; RJL Systems, Inc., Detroit, MI).
Appropriate informed consent was obtained from all participants. Guidelines for human experimentation in accordance with the US Department of Health and Human Services and the institutional review board of each participating institution were followed in the conduct of the study.
Definitions of Lipoatrophy and Lipohypertrophy
Incident body fat changes were classified as peripheral (ie, arms, legs, and buttocks) or central (ie, abdomen, chest, and upper back) and as either lipoatrophy (fat loss) or lipohypertrophy (fat gain). The body fat regions that comprise the classification of central and peripheral fat are consistent with those used in previous studies of lipodystrophy. A change in body fat was defined as lipoatrophy or lipohypertrophy when self-report of any change in body fat in the arms, legs, buttocks, abdomen, or chest was confirmed by a measured change in circumference measurements of >0.7 cm in the same direction in the corresponding body region (ie, triceps, thigh, hip, waist, or chest) over the prior 6 months. We selected the criterion of 0.7 cm because this is the limit for accepted differences between repeated circumference measurements used in the WIHS. This limit is based on the standardized values for reproducibility of circumference measurements used in the Third National Health and Examination Survey.
Circumference measurements rather than skinfold measurements were used when both circumference and skinfold measurements were available for a given body site, because in our data we found that circumference measurements were more strongly correlated with self-reported changes in body fat for the corresponding body site at each visit than skinfold measurements. Circumference measurements were rarely missing; however, subscapular skinfold measurements were used for the upper back because no circumference measurements corresponded to that body site. Results were similar when an alternative definition of body fat changes was used based primarily upon skinfold measurements rather than circumference (data not shown). Self-report of a change in body fat in the upper back was confirmed by a measured change of 0.2 cm in the subscapular skinfold in the same direction. We used the criterion of 0.2 cm because this is the standard cutoff value for reproducibility of the subscapular skinfold measurement.
Because self-report of bidirectional changes-that is, increase, decrease, or no change in body fat at each of the body regions-was obtained, both lipoatrophy and lipohypertrophy could be separately assessed. A report of any decrease in a peripheral site confirmed by anthropometric measurement was classified as peripheral lipoatrophy. A report of any peripheral increase confirmed by examination was classified as peripheral lipohypertrophy. Likewise, a confirmed report of any increase at a central site was classified as central lipohypertrophy, and a confirmed report of any central decrease was classified as central lipoatrophy. Therefore, a participant may have completed the 30-month follow-up without any body fat changes or could have had confirmed reports of 1 to all 4 of the possible changes.
Of the 2628 women enrolled in the WIHS, 1656 were seen at the 10th semiannual WIHS visit; 43 were excluded due to pregnancy in the prior 2 years, leaving a sample of 1613 women, of whom 1266 were HIV positive and 347 were HIV negative. Analyses of incident lipoatrophy and lipohypertrophy were restricted to the 815 women (605 HIV-infected and 210 HIV-uninfected women) who remained after exclusion of 760 (643 HIV-infected and 117 HIV-uninfected women) who reported any prevalent body fat change during the 6 months before the baseline (ie, 10th semiannual) WIHS visit, 37 (18 HIV-infected and 19 HIV-uninfected women) without follow-up, and 1 who seroconverted at visit 11. Seventeen women became pregnant during follow-up and were censored at the visit before the reported pregnancy. For the 605 HIV-infected and 210 HIV-uninfected women included in the incidence analyses, changes in body weight and percent total body fat (over the 6 semiannual study visits [visits 10-15]) were analyzed by HIV status using a generalized linear model with robust variance estimates to account for repeated measurements.
Characteristics at Baseline Visit
Race: 60% Black in HIV-infected, 63% Black in HIV-uninfected; 23% Hispanic in HIV-infected vs 29% Hispanic in HIVuninfected; 17% White in HIV-infected vs 9% in HIV-uninfected. Age: 41 in HIV-infected vs 40 in uninfected. Height: 163 cm vs 163 cm. Weight: 68 kg in HIV-infected vs 75 kg in HIV-unifected (p<0.01). Percent of body fat: 26 in HIV-infected vs 31 in HIV-unifected (p<0.01). CD4 count: 366 in HIV-infected vs 984 in uninfected. 44% had clinical AIDS in infected and HIV RNA was 3.3 log.
RESULTS and AUTHOR COMMENTS
Of the 1613 women seen at the 10th semiannual WIHS visit, 18% (230/1266) of HIV-infected women and 20% (68/347) of HIV-uninfected women (Fisher exact test, P = 0.53) reported a decrease in peripheral body fat in the prior 6 months. Seventeen percent (214/1266) of HIV-infected women versus 11% (38/347) of HIV-uninfected women (Fisher exact test, P < 0.01) reported a decrease in central body fat, 35% (442/1266) versus 24% (83/347) (Fisher exact test, P< 0.01) reported an increase in central body fat, and 22% (276/1266) versus 7% (24/347) (Fisher exact test, P < 0.01) reported an increase in peripheral body fat, respectively. A change in body fat during the 6 months before the baseline visit was reported by 760 women (643 HIV-infected and 117 HIV-negative women); these women were excluded from the incident analyses.
Interestingly, when the 1613 women seen at the 10th semiannual WIHS visit were studied in a cross-sectional analysis using self-reported data of body fat change since the prior WIHS visit 6 months earlier, we did not find that HIV-positive women reported more peripheral fat loss in the prior 6 months than HIV-uninfected women. This clearly demonstrates the difficulty in interpreting data on clinical lipoatrophy and lipohypertrophy across studies of women given differences in study design, varying definitions of lipoatrophy and lipohypertrophy, and the lack of a HIV-uninfected comparison group in most other previous studies. The use of subjective measures, especially self-report of body fat change alone, may not be adequate in studies of lipoatrophy and lipohypertrophy, especially cross-sectional studies. Our use of a more rigorous definition in the incidence analyses, not previously done in other studies, of a report of body fat change confirmed by an anthropometric measurement in the same direction for a given body site, rather than confirmation by subjective examination, may provide a more accurate reflection of the incidence of lipoatrophy and lipohypertrophy among women. The comparison of HIV-infected and HIV-uninfected women is also important to understanding what changes are pathologic.
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