There are a number of theories with some data to support that NRTIs AZT & d4T lead to fat loss. We still are unsure if PIs lead to fat loss as there are mixed reports but no conclusive evidence. My thinking is that HIV accelerates metabolism & aging process through mitochondria toxicity, inflammation and other unidentified means. HIV appears to cause mitochondrial toxicity. Starting ART with low nadir CD4, advanced HIV appears assoiated with fat loss, thus my theory that HIV accelerated aging is associated with lipoatrophy. But I think these potential causes may vary by individual. For example, some individuals have a genetically lower mitochondria count or perhaps enviobnmentally caused. Familial genetics ma also present a propensity for some of these develoments. In HIV-negatives with diabetes many men experiences belly fat and limb fat loss but I don;t think we fully understand how this connection might work in HIV.
On Jan 4, 2009, at 10:56:15 AM, livingthelava <livingthelava@
From: livingthelava <livingthelava@ gmail.com> Subject: Re: [PozHealth] NATAP: Lipoatrophy & Depression Date: January 4, 2009 10:56:15 AM EST To: julev <JuLev@aol.com> Cc: "new lipidlist" <PozHealth@yahoogrou ps.com> Hi Julev, commenting about item (4) below, I never read anything that discusses what other processes are interruptedin our bodies by taking the meds we take, I only see the charts of this is how Combivir interrupts the HIV replication, and obviously, these drugs are interrupting other processes, important ones I will assume, because I have about 50 pounds of tummy and shoulder fat, that came on so very quickly and now fighting and working out like a demon to get rid of it. Do you ever read something that speaks to exactly what other processes are affected in the body? larry On Jan 1, 2009, at 8:50 AM, julev wrote:from Jules: body changes and in particular lipoatrophy have lost attention from the research community and thought leaders as other health issues have taken center stage including aging, bone disease, heart disease etc, and in particular as newer HIV drugs apppear to be less causative of body changes than the older HIV drugs which were more associated with body changes. It's important to remember several points: (1) a significant number of older patients who took the older HIV drugs experienced body changes and still suffer with them, they have not gone away, although they may have improved after switching to less offensive NRTIs tenofovir and abacavir. (2) this article raises important health concerns for patients who experience body changes, concerns that are very relevant to aging issues--for one, depression affects the immune system which is already taking hits just because of the aging process and another hit when an HIV+ person ages. (3) aging & HIV studies should include looking at the effects of body changes on the aging process and its effects. (4) we still have not developed an adequate understanding of how lipoatrophy develops and how to treat lipoatrophy and it is crucial to develop treatment. The risk for lipodystrophy in younger patients who only use newer drugs has not been well studied but I think there appears to still be body changes occurring. For example, research has shown that low nadir CD4 predicts risk for lipodystrophy and we know that many individuals are initially diagnosed with HIV with low CD4s and advanced disease. So we have not studied the incidence of body changes in this group and we should.
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From: "NATAP HIV mailing list" <hiv@natap.org> Subject: NATAP: Lipodystrophy Causes Depression Date: January 1, 2009 11:33:00 AM EST To: hiv@natap.org, nataphcvhiv@ natap.org , natapindustry@natap.org , natapdoctors@natap.org NATAP http://natap.org/ ____________ _________ _________ _________ ________
Portions of the data were presented at the 44th Annual Meeting of the Infectious Diseases Society of America, 2006, Toronto, ON.
KEYWORDSdepression • HIV • lipoatrophy • lipodystrophy • lipohypertrophyABSTRACT
Objectives
We sought to determine the association between body morphology abnormalities and depression, examining lipoatrophy and lipohypertrophy separately.
Methods
An observational cross-sectional study of 250 patients from the University of Washington HIV Cohort was carried out. Patients completed an assessment including measures of depression and body morphology. We used linear regression analysis to examine the association between lipoatrophy or lipohypertrophy and depression. Analysis of variance 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 those for patients without body morphology abnormalities. Facial lipoatrophy was the body region associated with the most severe depression scores (15.5 vs. 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.
Received: 15 January 2008, accepted 27 May 2008
Introduction
The dramatic decline in HIV-related mortality as a consequence of combination antiretroviral therapy (cART) has led to unexpected abnormalities in fat distribution such as lipoatrophy and lipohypertrophy [1,2], commonly grouped under the term 'lipodystrophy'
. Studies suggest that lipodystrophy may have a detrimental impact on sexual behaviour, self-esteem, and general wellbeing [3–5]. The few studies that assessed lipodystrophy and depression reported mixed results; some found an association between lipodystrophy and depression [5,6], and others did not [7,8]. Although lipoatrophy and lipohypertrophy are often conceptualized as a single disorder, they are distinct entities with different aetiologies [9,10]. Prior studies have not examined the independent association between lipoatrophy or lipohypertrophy and depression severity among patients in clinical care. We conducted this study to examine the associations between lipoatrophy or lipohypertrophy and depression. Methods
Study setting
This cross-sectional study was conducted on 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 26 September 2005 and 1 June 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 Primary Care Evaluation of Mental Disorders (PRIME-MD)] [11,12], drug use (Alcohol, Smoking and Substance Involvement Screening Test) [13,14], and lipoatrophy and lipohypertrophy (based on the Study of Fat Redistribution and Metabolic Change in HIV instrument] [9,10,15,16]. As previously described [17], 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 out-patient and in-patient encounters, including demographic, clinical, laboratory, medication and socioeconomic information.
Instrument scoring
For the depression instrument, patients indicated for each of nine depressive symptoms whether, during the prior 2 weeks, the symptom bothered them 'not at all,' on 'several days,' on 'more than half the days,' or 'nearly every day'. We scored the depression instrument 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) [11,12].
There are several ways of scoring the Alcohol, Smoking and Substance Involvement Screening Test [13,14]. Because of the association between drug use and depression [18,19], 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 seven-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, respectively; and mild, moderate and severe decreases were scored as −1, −2 and −3, respectively. An overall lipohypertrophy score was calculated by totalling all positive responses (indicating increases in size of body regions). An overall lipoatrophy score was calculated by totalling all negative responses (indicating decreases in size). The 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 the characteristics of study participants with those of the overall UW HIV Cohort using χ
2 tests and t-tests. In subjects, we examined associations among depression, body morphology abnormalities, demographic characteristics (age, race, sex and risk factor for HIV transmission) and clinical characteristics [CD4 cell count nadir, current CD4 cell count, peak HIV-1 RNA level, current cART use, body mass index (BMI) category and current illicit drug use]. We calculated BMI using the traditional Quetelet index: weight divided by height squared (kg/m2 ) [20]. 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 score 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 R 2 of 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. The mean age of subjects was 43 years, 86% were men, and the mean CD4 count nadir was 169 cells/μL (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 Men having sex with men 28 (61) 58 (55) 36 (55) 12 (55) 6 (55) Injecting 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 CD4 count (cells/μL) 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 cART Yes 27 (59) 79 (75) 54 (83) 21 (95) 9 (82) No 19 (41) 27 (25) 11 (17) 1 (5) 2 (18) 0.007 HAART, highly active antiretroviral therapy. 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 four subjects who had moderate-to- severe lipoatrophy concurrent with mild lipohypertrophy, and eight 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 vs. 7.7; P=0.046 in t-test). Mean depression scores varied among patients reporting different body morphology abnormalities (Fig. 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 in anova).
Fig. 1 Mean depression score by body morphology. The 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 vs. no abnormality.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 in linear regression), while scores for subjects with moderate-to- severe lipohypertrophy were 4.8 points higher (P=0.02) than those for subjects without body morphology abnormalities. Scores for subjects with mild lipohypertrophy were only 2.8 points higher (P=0.03) than those for subjects without abnormalities. Scores for those with mild lipoatrophy were not significantly different from scores for 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 (Fig. 2). We found mean depression scores for patients with moderate-to- severe lipoatrophy or lipohypertrophy were higher compared with those for patients 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).
Fig. 2 Mean depression score by body region. Patients who reported central changes (in the chest, back, waist and belly) were more likely to report moderate-to-
severe lipohypertrophy than lipoatrophy. In contrast, patients reporting peripheral changes (in the face, cheeks, buttocks, arms and legs) were more likely to report moderate-to- severe lipoatrophy than lipohypertrophy. No significant differences were found in the number of patients reporting moderate-to- severe lipoatrophy (n=23) vs. lipohypertrophy (n=21) of the neck. Mild abnormalities are excluded from the figure for simplicity. ** Overall P-values from one-way analysis of variance 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 vs. no abnormality. † Significant pairwise comparisons for moderate-to-severe lipoatrophy vs. no abnormality. The highest depression scores were found for patients with moderate-to-
severe facial lipoatrophy (15.5 vs. 8.8 for patients without facial lipoatrophy or lipohypertrophy; pairwise comparison P=0.01) (note that this instrument distinguishes face and cheeks as two regions). Mean depression scores were higher for patients reporting any lipoatrophy or lipohypertrophy in each body region compared with patients who did not report an abnormality. Differences in depression scores for patients reporting no abnormalities compared with those reporting 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 those of patients reporting no abnormalities in adjusted analyses. The depression instrument has a previously established minimal clinically important difference (MCID) of 4.8 [21]. The definition of MCID varies but is typically the smallest difference in a score considered to be clinically worthwhile or important [22]. 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 1 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 [5–7]. One study found that lipodystrophy was more common among patients taking psychotropic medications such as antidepressants [2]. A qualitative study suggested an association between lipodystrophy and depression [5]; 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 a result of 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 [23–27]. The association between facial lipoatrophy and depression suggests a simple way for providers to identify patients at increased risk for depression and suggests 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 in HIV Infection which allows separate examination of lipoatrophy and lipohypertrophy severities and their association with depression. In addition, we examined lipoatrophy and lipohypertrophy in individual body regions. Advantages of self-report over dual-energy X-ray absorptiometry scans or single-cut computed tomography 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 in terms of, for example, its validity, responsiveness and internal consistency among out-patient, in-patient, clinical trial and HIV-infected populations [11,12,21,28–33]. At nine items, it is half the length of many other depression measures, has comparable sensitivity and specificity, and encompasses the nine criteria upon which the diagnosis of Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) [34] depressive disorders are based [11].
A limitation of this observational nonrandomized study is that, while the cross-sectional design demonstrates a significant association between lipoatrophy or lipohypertrophy and depression, it does not allow conclusions to be drawn regarding the direction of association. This association may be bidirectional. 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 [35]. 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.
Acknowledgement
The questionnaires for self-report of fat distribution were developed under the auspices of NIH R01 DK 57508. We also wish to thank the patients and providers of the University of Washington Madison HIV clinic. This work was supported by grants from the Mentored Patient-Oriented Research Career Development Award NIAID Grant (AI-60464), and the University of Washington Center for AIDS Research NIAID Grant (AI-27757).
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