Lipoatrophy among HIV-infected patients is associated with higher levels of depression than lipohypertrophy

Abstract

Objectives

We sought to determine the association between body morphology abnormalities and depression examining lipoatrophy and lipohypertrophy separately.

Methods

Observational cross-sectional study of 250 patients from the University of Washington HIV Cohort. Patients completed an assessment including depression and body morphology. We used linear regression analysis to examine the association between lipoatrophy, lipohypertrophy, and depression. ANOVA was used to examine the relationship between mean depression scores and lipoatrophy and lipohypertrophy in 10 body regions.

Results

Of 250 patients, 76 had lipoatrophy, and 128 had lipohypertrophy. Mean depression scores were highest among patients with moderate-to-severe lipoatrophy (16.4), intermediate among those with moderate-to-severe lipohypertrophy (11.7), mild lipohypertrophy (9.9), and mild lipoatrophy (8.5), and lowest among those without body morphology abnormalities (7.7) (p=0.002). After adjustment, mean depression scores for subjects reporting moderate-to-severe lipoatrophy were 9.2 points higher (p<0.001), scores for subjects with moderate-to-severe lipohypertrophy were 4.8 points higher (p=0.02), and scores for subjects with mild lipohypertrophy were 2.8 points higher (p=0.03) than patients without body morphology abnormalities. Facial lipoatrophy was the body region associated with the most severe depression scores (15.5 versus 8.9 for controls, p=0.03).

Conclusions

In addition to long-term cardiovascular implications, body morphology has a more immediate effect on depression severity.

INTRODUCTION

The dramatic decline in HIV-related mortality due to combination antiretroviral therapy (cART) has led to unexpected abnormalities in fat distribution such as lipoatrophy and lipohypertrophy (8, 34), commonly grouped under the term lipodystrophy. Studies suggest that lipodystrophy may have a detrimental impact on sexual behavior, self-esteem, and general well-being (12, 15, 28). The few studies that assessed lipodystrophy and depression reported mixed results; some found an association between lipodystrophy and depression (22, 28), others did not (7, 31). Although lipoatrophy and lipohypertrophy are often conceptualized as a single disorder, they are distinct entities with different etiologies (3, 13). Prior studies have not examined the independent association between lipoatrophy or lipohypertrophy with depression severity among patients in clinical care. We conducted this study to examine the associations between lipoatrophy, lipohypertrophy, and depression.

METHODS

Study setting

This cross-sectional study was conducted among a convenience sample of patients in the University of Washington (UW) HIV Cohort, a longitudinal observational study of HIV-infected patients who receive primary care in the UW Harborview Medical Center HIV Clinic. This study was approved by the UW Institutional Review Board.

Study participants

HIV-infected patients over 18 years of age who attended the clinic between 9/26/2005 and 6/01/2006 were eligible for the study. We did not exclude patients who were receiving antidepressant medications.

Data sources

Patients used tablet PCs with touch screens to complete an assessment including measures of depression (Patient Health Questionnaire from the PRIME-MD) (18, 29), drug use (Alcohol, Smoking, and Substance Involvement Screening Test) (26, 35), and lipoatrophy and lipohypertrophy (based on the Study of Fat Redistribution and Metabolic Change instrument) (3, 13, 14, 33). As previously described (10), we used web-based survey software developed specifically for patient-based measures.

Data were also obtained from the UW HIV Information System (UWHIS). UWHIS integrates comprehensive clinical data on the UW HIV cohort from all outpatient and inpatient encounters including demographic, clinical, laboratory, medication, and socioeconomic information.

Instrument Scoring

For the depression instrument, patients indicate for each of 9 depressive symptoms whether, during the prior 2 weeks, the symptom bothered them “not at all,” “several days,” “more than half the days,” or “nearly every day.” We scored it as a severity measure with scores ranging from 0 to 27. We also categorized depression severity as: none (0-4 points), mild (5-9 points), moderate (10-19 points), and severe (≥20 points) (18, 29).

There are several ways of scoring the Alcohol, Smoking, and Substance Involvement Screening Test (26, 35). Because of the association between drug use and depression (5, 32), we were interested in current drug use (within 3 months).

The body morphology instrument asks patients to rate changes in the amount of fat in specific body regions graded on a 7-point scale ranging from -3 to +3 for each region. No change was scored as 0; mild, moderate, and severe increases were scored as +1, +2, and +3; and mild, moderate, and severe decreases were scored as -1, -2, and -3. An overall lipohypertrophy score was calculated totaling all positive responses (indicating increases in size of body regions). An overall lipoatrophy score was calculated totaling all negative responses (indicating decreases in size). Severity of each condition was defined as none (0 points), mild (1-12 points), and moderate-to-severe (>12 points). Patients with both lipoatrophy and lipohypertrophy were categorized by the more severe abnormality.

Statistical analyses

We performed bivariate analyses comparing study participant characteristics to the overall UW HIV cohort using chi-squared tests and t-tests. Among subjects, we examined associations between depression, body morphology abnormalities, demographic characteristics (age, race, sex, risk factor for HIV transmission), and clinical characteristics (CD4⁺ cell count nadir, current CD4⁺ cell count, peak HIV-1 RNA level, current cART use, BMI category, and current illicit drug use). We calculated BMI using the traditional Quetelet index: weight divided by height squared (kg/m²) (1). BMI was categorized as underweight (<18.5 kg/m²), normal (18.5-24.9 kg/m²), overweight (25-29.9 kg/m²), and obese (≥30 kg/m²). We performed bivariate analyses of associations with depression scores using t-tests. We used one-way analysis of variance (ANOVA) to examine the relationship between mean depression scores and any lipoatrophy or lipohypertrophy compared with no abnormality in each of 10 body regions, and moderate-to-severe abnormalities compared with no abnormality. Pairwise comparisons were performed for statistically significant factors. We used multivariate linear regression with depression scores as the dependent variable to examine associations between depression and lipoatrophy and lipohypertrophy in adjusted analyses. We determined the amount of variance explained by lipoatrophy and lipohypertrophy by subtracting the adjusted R² from models excluding them from the adjusted R² of the full model. Two-tailed p values <0.05 were considered statistically significant.

RESULTS

The assessment was completed by 250 patients. Mean age of subjects was 43 years, 86% were men, and mean CD4⁺ count nadir was 169 cells/mm³ (Table 1). Demographic and clinical characteristics of subjects were similar to those of all UW HIV cohort patients in the study period (data not shown).

Table 1.

Demographic and clinical characteristics of study patients (N=250)

Characteristic	No body morphology abnormalities N=46	Mild lipohypertrophy N=106	Mild lipoatrophy N=65	Moderate-to-severe lipohypertrophy N=22	Moderate-to-severe lipoatrophy N=11	p Value
	N (%)	N (%)	N (%)	N (%)	N (%)
Sex
Male	41 (89)	93 (88)	56 (86)	15 (68)	10 (91)
Female	5 (11)	13 (12)	9 (14)	7 (32)	1 (9)	0.15
Race
White	30 (65)	68 (64)	46 (71)	14 (64)	10 (91)
Black	11 (24)	23 (22)	13 (20)	8 (36)	1 (9)
Hispanic	4 (9)	9 (8)	4 (6)	0	0
Other/Unknown	1 (2)	6 (6)	2 (3)	0	0	0.6
Age (years)
< 30	9 (20)	4 (4)	6 (9)	0	0
30-39	14 (30)	34 (32)	13 (20)	7 (32)	2 (18)
40-49	18 (39)	43 (41)	26 (40)	12 (55)	6 (55)
≥50	5 (11)	25 (24)	20 (31)	3 (14)	3 (27)	0.03
Risk factor for HIV transmission
Male sex-with-male	28 (61)	58 (55)	36 (55)	12 (55)	6 (55)
Injection drug use	12 (26)	30 (28)	14 (22)	3 (14)	3 (27)
Heterosexual	6 (13)	17 (16)	10 (15)	6 (27)	1 (9)
Other/unknown	0	1 (1)	5 (8)	1 (5)	1 (9)	0.4
Current CD4R+cell count (cells/mm3)
0-200	12 (26)	22 (21)	15 (23)	2 (9)	6 (55)
201-350	16 (35)	27 (25)	12 (18)	7 (32)	3 (27)
351 or greater	18 (39)	57 (54)	38 (58)	13 (59)	2 (18)	0.06
Currently receiving HAART
Yes	27 (59)	79 (75)	54 (83)	21 (95)	9 (82)
No	19 (41)	27 (25)	11 (17)	1 (5)	2 (18)	0.007

Only 46 subjects (18%) reported no lipoatrophy or lipohypertrophy, 106 (42%) reported mild lipohypertrophy, 65 (26%) reported mild lipoatrophy, 22 (9%) reported moderate-to-severe lipohypertrophy, and 11 (4%) reported moderate-to-severe lipoatrophy. There were 4 subjects who had moderate-to-severe lipoatrophy concurrent with mild lipohypertrophy, and 8 who had moderate-to-severe lipohypertrophy concurrent with mild lipoatrophy. These 12 subjects are classified according to their more severe body morphology abnormality. In addition, 75 subjects had both mild lipohypertrophy and mild lipoatrophy. These individuals are classified according to which mild abnormality was more severe. The mean depression score was 9.6, corresponding to mild-to-moderate depression: 72 (29%) had no depression, 70 (28%) mild depression, 82 (33%) moderate depression, and 26 (10%) severe depression.

Patients reporting any body morphology abnormality (lipoatrophy or lipohypertrophy) had higher mean depression scores than patients without body morphology abnormalities (10.0 versus 7.7, p=0.046 t-test). Mean depression scores varied among patients reporting different body morphology abnormalities (Figure 1), with the highest values among patients with moderate-to-severe lipoatrophy (16.4), intermediate values among those with moderate-to-severe lipohypertrophy (11.7), mild lipohypertrophy (9.9), and mild lipoatrophy (8.5), and the lowest values among those without body morphology abnormalities (7.7) (p=0.002, ANOVA).

Figure 1.

Mean depression score by body morphology

Overall p value for one-way analysis of variance examining the relationship between mean depression scores and body morphology abnormalities was 0.002.

* p values for pairwise comparisons for each body morphology abnormality versus None (no reported body morphology abnormalities).

Multivariate analyses

The relationship between body morphology abnormalities and depression remained after controlling for age, race, sex, cART use, BMI category, current drug use, and current CD4⁺ cell count. After adjustment, mean depression scores for subjects reporting moderate-to-severe lipoatrophy were 9.2 points higher (p<0.001, linear regression), while scores for subjects with moderate-to-severe lipohypertrophy were 4.8 points higher (p=0.02) than those without body morphology abnormalities. Scores for subjects with mild lipohypertrophy were only 2.8 points higher (p=0.03) than those without abnormalities. Scores for those with mild lipoatrophy were not significantly different from those without abnormalities.

Overall, the fully adjusted model, including lipoatrophy and lipohypertrophy severity scores, explained 7.3% of the variance in depression. Lipohypertrophy and lipoatrophy scores explained 5.4% of the variance, thus 74% of the variance explained by the full model was attributable to lipoatrophy and lipohypertrophy. In contrast, current CD4⁺ cell count accounted for only 2.3% of the variance of depression.

Individual body regions

We examined depression scores associated with regional body morphology abnormalities for patients reporting moderate-to-severe lipoatrophy or lipohypertrophy for each region compared with patients reporting no changes (Figure 2). We found mean depression scores for patients with moderate-to-severe lipoatrophy or lipohypertrophy were higher compared with those without changes, and these differences were statistically significant by overall one-way ANOVA (p values 0.001-0.04) for all regions except cheeks (p=0.09) and legs (p=0.08).

Figure 2.

Mean depression scores by body region

**Overall p values from one-way analysis of variance (ANOVA) for patients with moderate-to-severe lipohypertrophy, moderate-to-severe lipoatrophy, or no body morphology abnormality for each body region

* Significant pairwise comparisons for moderate-to-severe lipohypertrophy versus no abnormality

† Significant pairwise comparisons for moderate-to-severe lipoatrophy versus no abnormality Patients who reported central changes (chest, back, waist and belly) were more likely to report moderate-to-severe lipohypertrophy than lipoatrophy. In contrast, patients reporting peripheral changes (face, cheeks, buttocks, arms, and legs) were more likely to report moderate-to-severe lipoatrophy than lipohypertrophy. No significant differences were found among the number of patients reporting moderate-to-severe lipoatrophy (N=23) versus lipohypertrophy (N=21) of the neck Mild abnormalities excluded from figure for simplicity

The highest depression scores were found for patients with moderate-to-severe facial lipoatrophy (15.5 versus 8.8 for patients without facial lipoatrophy or lipohypertrophy, pairwise comparison p=0.01) (note that this instrument distinguishes face and cheeks as 2 regions).

Mean depression scores were higher for patients reporting any lipoatrophy or lipohypertrophy in each body region compared to patients who did not report an abnormality. Differences in depression scores for patients reporting no abnormalities compared with any degree of lipoatrophy or any lipohypertrophy were statistically significant by overall one-way ANOVA for every region except the waist (data not shown).

DISCUSSION

In this study of 250 HIV-infected patients attending the clinic for routine visits we found a high prevalence of body morphology abnormalities: 82% of patients had at least some degree of lipoatrophy or lipohypertrophy. Most abnormalities were mild, with 13% of patients reporting moderate-to-severe lipoatrophy or lipohypertrophy. Mean depression scores were significantly higher among patients with lipoatrophy or lipohypertrophy. Moderate-to-severe lipoatrophy was associated with dramatically higher depression scores: over double that of patients reporting no abnormalities in adjusted analyses. The depression instrument has a previously established minimal clinically important different of 4.8 (21). The definition of a minimal clinically important difference varies but is typically the smallest difference in a score considered to be clinically worthwhile or important (4). In adjusted analyses, the increase in depression scores associated with moderate-to-severe lipoatrophy was approximately 2 MCIDs, compared with an increase of just over one MCID for moderate-to-severe lipohypertrophy.

Prior studies have suggested a possible association between lipodystrophy and depression. However, these small studies did not differentiate between lipoatrophy and lipohypertrophy (7, 22, 28). One study found that lipodystrophy was more common among patients taking psychotropic medications such as antidepressants (34). A qualitative study suggested an association between lipodystrophy and depression (28), however only 14 patients were included. To our knowledge, no prior studies have assessed the association between body morphology abnormality severity and depression adjusting for other key factors associated with depression such as sex, age, and current CD4⁺ cell count.

We adjusted for BMI category in the multivariate analysis because of concerns that lipohypertrophy may in part be measuring obesity. However, findings were not significantly different when BMI category was not included in the analysis.

The highest depression scores were seen among patients reporting facial lipoatrophy which may be due to social stigma and the potential for facial lipoatrophy to identify a person as HIV-infected. Depression is known to have detrimental effects on medication adherence, immune function, disease progression, and survival (6, 9, 16, 24, 27). The association between facial lipoatrophy and depression suggest a simple way for providers to identify patients at increased risk for depression and that treatment of facial lipoatrophy may be an important part of care for HIV-infected patients.

Strengths and limitations

A key strength of our study is the use of the self-report body morphology measure from the Study of Fat Redistribution and Metabolic Change which allows separate examination of lipoatrophy and lipohypertrophy severity and their association with depression. In addition, we examined lipoatrophy and lipohypertrophy in individual body regions. Advantages of self-report over DEXA scans or single-cut CT scans are that patients’ perception of their fat changes may have a larger impact on depression than objective measures. In addition, the association with facial lipoatrophy, a clinically significant finding of this study, can be assessed with self-report. Another strength of this study is use of the Patient Health Questionnaire depression measure which has been extensively studied including its validity, responsiveness, and internal consistency among outpatient, inpatient, clinical trial, and HIV-infected populations (11, 17-21, 23, 29, 30). At 9 items, it is half the length of many other depression measures, has comparable sensitivity and specificity, and encompasses the 9 criteria upon which the diagnosis of DSM-IV (2) depressive disorders are based (18).

A limitation of this observational non-randomized study is that while the cross-sectional design demonstrates a significant association between lipoatrophy, lipohypertrophy, and depression, it does not allow conclusions to be drawn regarding the direction of association. This association may be bi-directional. Patients who are depressed may be more likely to report body morphology abnormalities. More importantly, however, we suspect that lipoatrophy and lipohypertrophy lead to higher depression scores. This hypothesis is supported by a clinical trial of poly-L-lactic acid for facial lipoatrophy which found improvement in depression after lipoatrophy treatment (25). Longitudinal follow-up of patients in the UW HIV cohort will allow us to examine the time course and strengthen conclusions regarding the direction of the association. Our study may be generalizable only to patients with similar characteristics. Further studies are needed to examine the impact of differences in body morphology perception by sex or race.

Conclusions

Lipoatrophy and lipohypertrophy are significantly associated with higher depression scores among HIV-infected patients. Lipoatrophy is associated with more severe depression than lipohypertrophy. Our results suggest that facial lipoatrophy, in particular, has a profound impact on depression severity.

Abbreviations

cART

combination antiretroviral therapy

ANOVA

one-way analysis of variance

UW

University of Washington

UWHIS

UW HIV Information System