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Positron Emission Tomography to Characterize Dorsocervical Fat Pad Hypertrophy in People With Treated HIV Infection

Janus, Scott E. MDa; Sullivan, Claire MDa,b,c; Morrison, Justin MDa; McComsey, Grace A. MDa,b,c,d; Longenecker, Chris T. MDa,b,c

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JAIDS Journal of Acquired Immune Deficiency Syndromes: March 1, 2020 - Volume 83 - Issue 3 - p e23-e25
doi: 10.1097/QAI.0000000000002273

To the Editors:

In the era of combination antiretroviral therapy (ART), HIV-associated lipodystrophy has historically been characterized by peripheral/subcutaneous fat loss (lipoatrophy of limbs and face) with or without lipohypertrophy, the latter manifesting as dorsocervical fat pad hypertrophy (“buffalo hump”) and abdominal fat accumulation.1 The underlying mechanism of lipodystrophy—especially with more modern ART regimens, where lipohypertrophy predominates—is not clear, but may involve an inflammation-induced stress response in adipocytes causing dysregulation of thermoregulatory brown fat genes such as UCP-1 or DIO2.2,3 Noninvasive imaging of brown fat with 18-fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET-CT) is well-validated, but small studies in People with HIV (PWH) with clinical lipodystrophy have been inconclusive and have not evaluated associations with vascular disease.3

We conducted a prospective study of 55 PWH on stable ART with HIV-1 RNA <400 copies/mL and 19 age-matched HIV-uninfected controls without clinical evidence of cardiovascular disease who underwent an FDG PET-CT vascular imaging protocol as previously reported.4 Briefly, all subjects fasted for a minimum of 4 hours before 18-FDG injection. Delayed PET-CT imaging occurred 3 hours ± 10 minutes after injection. All images were analyzed offline by 2 readers blinded to HIV status and other clinical variables. In a secondary analysis of these scans, we measured dorsocervical fat pad volumes, which we defined on the coregistered PET-CT using a 3-dimensional region of interest tool (MIM Software, Inc; Cleveland, OH). We manually traced the borders of the subcutaneous dorsocervical fat from C3 to C7, taking care to exclude skin and underlying muscle or connective tissue. From this single volume of interest, we then measured the radiodensity in average Hounsfield Units (HU) from the CT data and the mean standardized uptake value (SUV) from the PET data. We measured target to background ratio (TBR) of the ascending aorta and spleen SUV as previously described.4 Unadjusted and multivariable adjusted linear regression was used to examine associations of dorsocervical fat pad size with other PET-CT variables of interest.

Overall, the population consisted of 81% men with a mean (SD) age of 48 (11) years (see Table, Supplemental Digital Content, PWH and HIV-negative control subjects were well-matched for demographics and clinical variables (P > 0.2), with the only exceptions being PWH were more likely to be African American (73% vs. 47%) and to have hypertension (56 vs. 16%). For PWH, median CD4+ was 690 cells/mL, and 88% had HIV-1 RNA <20 c/mL; 43% were on a protease inhibitor.

Overall, median (Q1, Q3) dorsocervical fat pad volume was 99 (29–224) cc. Visual inspection of the histogram of dorsocervical fat pad volumes revealed 6 PWH and no controls with excessive dorsocervical fat pad volumes >1000 cc. Subsequent analyses compared subjects with large fat pads to all others (both PWH and controls). Large fat pads tended to be more prevalent among women compared with men (21% of women vs. 5% of men, P = 0.08). Median BMI was higher in those with large fat pads [median (interquartile range) 41 (35–45) vs. 26 (24–29), P < 0.001]. Among PWH, there were no associations of large fat pad with HIV-specific variables such as current or nadir CD4+ count, detectable HIV viral load, duration of ART, or current/cumulative duration of protease inhibitors. Interestingly, large dorsocervical fat pads were associated with less FDG uptake [fat pad SUV 0.20 (0.15–0.27) vs. 0.35 (0.28–0.46); P < 0.001] and lower mean radiodensity [−109 (−111 to −106) vs. −72 (−91 to −39) HU; P < 0.001]. Large dorsocervical fat pads were also associated with higher mean aortic TBR [1.73 (1.58–1.79) vs. 1.48 (1.38–1.59); P = 0.05] and mean splenic SUV [1.93 (1.75–2.00) vs. 1.36 (1.21–1.63); P = 0.001]. As shown in the Table 1, associations with fat pad SUV (P = 0.025), mean aortic TBR (P = 0.020), and mean splenic SUV (P = 0.009) remained statistically significant after adjustment for multiple potential confounders including age, sex, race, BMI, HIV status, and traditional risk factors (diabetes mellitus, family history, smoking, dyslipidemia, and hypertension).

Multivariable Models of the Relationship of Dorsocervical Fat Hypertrophy to Selected PET/CT Measures Among HIV+ and Control Subjects

In our cohort of well-treated PWH and controls, those with dorsocervical fat pad hypertrophy had significantly less FDG uptake and lower radiodensity of the fat. These data are consistent with a previous small study of 13 PWH with clinical lipodystrophy3 and offer imaging evidence that hypertrophied dorsocervical fat pads of PWH on modern ART may have less metabolically active and less radiodense fat cells, consistent with a loss of brown fat function. Interestingly, the 6 subjects with hypertrophied dorsocervical fat pads also had increased aortic TBR—a marker of aortic inflammation and early atherosclerotic vascular disease—and increased splenic SUV—a marker of immune activation. Previous studies have demonstrated HIV infection is associated with increased aortic FDG uptake and splenic SUV.4,5 This study extends those findings to suggest that the size, density, and metabolic activity of the dorsocervical fat pad may relate to aortic inflammation and immune activation, thus providing a mechanistic link between HIV lipohypertrophy and cardiovascular risk in the modern ART treatment era. The association between obesity and cardiovascular disease is partially mediated by inflammation, and previous studies suggest the “quality” and not just the “quantity” of fat may explain this association.6 In addition to our current findings in support of this concept, our previous work suggests that for PWH, imaging characteristics such as fat radiodensity are associated with inflammation, cardiometabolic risk, and subclinical disease.7,8 Finally, although the parent study was one of the largest PET-CT studies of PWH to date, our current secondary analysis was limited by the lack of a cooling protocol in the parent study to fully assess the presence of brown fat and by the lack of biopsies to assess metabolic activity of the fat. Future studies are needed to determine whether tissue-specific FDG uptake is associated with clinical cardiovascular outcomes in this population.


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