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Fat & ART Effects in HIV, Comorbidities: Initiating ART Is Associated With Decreased Fat Density in People Living With HIV
 
 
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In a prospective randomized clinical trial of ART initiation, L4-L5 abdominal CT scans measured subcutaneous AT (SAT) and visceral AT (VAT) area and density in treatment-naive PLWH randomized to tenofovir-emtricitabine plus ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or raltegravir. Linear regression models compared week 0 and week 96 levels, and 96-week changes, in SAT and VAT density (in Hounsfield units [HU]). Spearman correlations assessed relationships between AT density and immunometabolic parameters.
 
In this study, we aimed to assess the effects of modern ART initiation on VAT and SAT density, and to determine relationships between AT density and circulating inflammatory and metabolic biomarkers. Adipose tissue (AT) alterations are common in people living with human immunodeficiency virus (PLWH). Decreases in AT density suggest disrupted adipocyte function/hypertrophy. We assessed changes in AT density after antiretroviral therapy (ART) initiation and associations with immunometabolic parameters.
 
Fat changes are common in people living with HIV. When people gain fat, their bodies can either make new fat cells (hyperplasia), or their existing fat cells can take up more fat (hypertrophy). Hypertrophy results in fat cells becoming less dense, and is associated with inflammation, poorer fat cell function, and metabolic diseases such as diabetes and cardiovascular disease. This study assessed changes in fat density after antiretroviral therapy (ART) initiation among participants enrolled in A5260s, in which ART-na├»ve people living with HIV were randomized to start tenofovir-emtricitabine plus either ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or raltegravir. Fat in and around the organs (visceral fat) and underneath the skin (subcutaneous fat) were measured using abdominal CT scans. Of the 228 participants, 89 percent were male and 44 percent were white non-Hispanic. The median age was 36 years old, baseline HIV-1 RNA was 4.6 log10 copies/mL, and CD4+ T-cell count was 344 cells/μL. Over 96 weeks, visceral and subcutaneous fat cells became less dense on all three ART regimens, suggesting that people living with HIV who initiate ART experience fat cell hypertrophy. Following virologic suppression, lower visceral and subcutaneous fat density were associated with more inflammation, more insulin resistance (a precursor to diabetes), and worse cholesterol, independent of how much fat the person had, suggesting that changes in fat density with ART may contribute to adverse health outcomes in people living with HIV.
 
In this large, prospective, randomized trial of ART initiation, both SAT and VAT density decreased after 96 weeks of ART, with women having larger decreases in VAT and SAT density in all models. The greatest declines in VAT density occurred with RAL, followed by darunavir then atazanavir, though variability was high, and these between-arm subset comparisons did not reach statistical significance (nor were they powered to do so). Importantly, both pre- and post-ART, lower AT density correlated with greater disruptions of lipid and insulin-glucose metabolism. Lower AT density on suppressive ART was also associated with higher markers of systemic inflammation (hs-CRP and IL-6) and lower adiponectin and higher leptin levels, indicating poorer adipose tissue function and worse cardiometabolic and inflammatory profiles.
 
Adipose tissue (AT) disturbances including lipohypertrophy and obesity are common in the setting of treated and untreated human immunodeficiency virus (HIV). Lipohypertrophy or visceral fat accumulation in the abdomen is well described following antiretroviral therapy (ART) initiation, with changes not limited to older ART regimens [1-3]. Abdominal subcutaneous AT (SAT) and visceral AT (VAT) quantities are closely associated with the development of cardiometabolic abnormalities [4, 5], and increases in visceral fat are associated with greater mortality in people living with HIV (PLWH) [6].
 
Greater quantity of abdominal AT is associated with greater metabolic dysregulation, including hyperglycemia, hypertriglyceridemia, and low HDL cholesterol [4, 19], and elevated risk of CVD and all-cause mortality among PLWH, even after adjustment for additional risk factors [6, 20]. However, assessments of AT quality/function (including noninvasive assessment of AT quality via CT, as presented here) are fairly novel, with few prior studies reporting results [7, 14, 21-23] and the implications of changes in AT density less well understood. Data from PLWH are particularly scant. We previously reported, using data from an older ACTG ART initiation trial, A5224s, that CT-measured SAT and VAT density decreased following ART initiation, while AT areas increased [12]. Additionally, CT SAT density correlated with biopsy-quantified SAT adipocyte size [12], validating CT AT density as an accurate, noninvasive measure of adipocyte size in PLWH, and opening the door for explorations of clinical implications similar to those explored in this analysis.
 
Adipose tissue (AT) disturbances including lipohypertrophy and obesity are common in the setting of treated and untreated human immunodeficiency virus (HIV). Lipohypertrophy or visceral fat accumulation in the abdomen is well described following antiretroviral therapy (ART) initiation, with changes not limited to older ART regimens [1-3]. Abdominal subcutaneous AT (SAT) and visceral AT (VAT) quantities are closely associated with the development of cardiometabolic abnormalities [4, 5], and increases in visceral fat are associated with greater mortality in people living with HIV (PLWH) [6].
 
Obesity is associated with changes in AT quality that arise from alterations in tissue vascularity, lipid content, and fibrosis [7]. During weight gain, adipocytes become larger, engorged with lipids, and less dense [8, 9]. With continued adipocyte expansion, inflammation occurs and compensatory mechanisms such as fibrosis are employed to limit further expansion [10]. AT fibrosis and inflammation may be triggered by multiple processes, including infection or tissue injury, and are associated with increased AT density and altered adipocyte function [11]. AT quality can be indirectly assessed by quantifying AT density (in Hounsfield units [HU]) on computed tomography (CT). We have previously shown in PLWH that density from SAT on abdominal CT scans correlates with biopsy-quantified adipocyte size, the gold standard for assessment of AT quality [12]. Importantly, decreases in AT density may be associated with cardiovascular risk independent of AT quantity [7, 13], and longitudinal decreases in AT density have been independently associated with increased incidence of and adverse changes in cardiovascular disease (CVD) risk factors [14].
 
Although AT disturbances have been linked to the use of thymidine analogue nucleoside reverse transcriptase inhibitors (NRTIs) and older protease inhibitors (PIs), weight gain and metabolic complications may be a side effect of all ART, including integrase strand transfer inhibitors (INSTIs) [1, 15]. Limited studies have explored the relationship between AT quality (density) and ART [12]. In this study, we aimed to assess the effects of modern ART initiation on VAT and SAT density, and to determine relationships between AT density and circulating inflammatory and metabolic biomarkers.
 
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Antiretroviral Therapy Initiation Is Associated With Decreased Visceral and Subcutaneous Adipose Tissue Density in People Living With Human Immunodeficiency Virus
 
Clinical Infectious Diseases 28 February 2020 - Paula Debroy,1,a Jordan E. Lake,1,a Carlee Moser,2 Maxine Olefsky,2 Kristine M. Erlandson,3 Ann Scherzinger,3 James H. Stein,4 Judith S. Currier,5 Todd T. Brown,6 and Grace A. McComsey7 1University of Texas Health Science Center at Houston, Houston, Texas, USA, 2Harvard University, Boston, Massachusetts, USA, 3University of Colorado, Aurora, Colorado, USA, 4University of Wisconsin, Madison, Wisconsin, USA, 5University of California, Los Angeles, California, USA, 6Johns Hopkins University, Baltimore, Maryland, USA, and 7University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio, USA
 
Abstract
 
Background

 
Adipose tissue (AT) alterations are common in people living with human immunodeficiency virus (PLWH). Decreases in AT density suggest disrupted adipocyte function/hypertrophy. We assessed changes in AT density after antiretroviral therapy (ART) initiation and associations with immunometabolic parameters.
 
Methods
 
In a prospective randomized clinical trial of ART initiation, L4-L5 abdominal CT scans measured subcutaneous AT (SAT) and visceral AT (VAT) area and density in treatment-naive PLWH randomized to tenofovir-emtricitabine plus ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or raltegravir. Linear regression models compared week 0 and week 96 levels, and 96-week changes, in SAT and VAT density (in Hounsfield units [HU]). Spearman correlations assessed relationships between AT density and immunometabolic parameters.
 
Results
 
Of the 228 participants, 89% were male and 44% were white non-Hispanic. Median age was 36 years, baseline HIV-1 RNA was 4.6 log10 copies/mL, and CD4+ T-cell count was 344 cells/μL. Over 96 weeks, SAT and VAT HU decreased significantly in all arms. Less dense week 96 SAT and VAT density correlated with higher high-density lipoprotein (HDL) cholesterol and adiponectin (r = 0.19-0.30) levels and lower interleukin 6, non-HDL cholesterol, triglyceride, leptin, and homeostatic model assessment of insulin resistance (r = -0.23 to -0.68) levels at week 96 after adjusting for baseline CD4+ T-cell count, HIV-1 RNA, and baseline AT area.
 
Conclusions
 
Following virologic suppression, lower SAT and VAT density was associated with greater plasma measures of systemic inflammation, lipid disturbances, and insulin resistance independent of AT area, suggesting that changes in AT density with ART may lead to adverse health outcomes independent of AT quantity.
 
DISCUSSION
 
In this large, prospective, randomized trial of ART initiation, both SAT and VAT density decreased after 96 weeks of ART, with women having larger decreases in VAT and SAT density in all models. The greatest declines in VAT density occurred with RAL, followed by darunavir then atazanavir, though variability was high, and these between-arm subset comparisons did not reach statistical significance (nor were they powered to do so).
 
Importantly, both pre- and post-ART, lower AT density correlated with greater disruptions of lipid and insulin-glucose metabolism. Lower AT density on suppressive ART was also associated with higher markers of systemic inflammation (hs-CRP and IL-6) and lower adiponectin and higher leptin levels, indicating poorer adipose tissue function and worse cardiometabolic and inflammatory profiles.
 
Greater quantity of abdominal AT is associated with greater metabolic dysregulation, including hyperglycemia, hypertriglyceridemia, and low HDL cholesterol [4, 19], and elevated risk of CVD and all-cause mortality among PLWH, even after adjustment for additional risk factors [6, 20]. However, assessments of AT quality/function (including noninvasive assessment of AT quality via CT, as presented here) are fairly novel, with few prior studies reporting results [7, 14, 21-23] and the implications of changes in AT density less well understood. Data from PLWH are particularly scant. We previously reported, using data from an older ACTG ART initiation trial, A5224s, that CT-measured SAT and VAT density decreased following ART initiation, while AT areas increased [12]. Additionally, CT SAT density correlated with biopsy-quantified SAT adipocyte size [12], validating CT AT density as an accurate, noninvasive measure of adipocyte size in PLWH, and opening the door for explorations of clinical implications similar to those explored in this analysis.
 
We have previously shown that higher baseline HIV-1 RNA levels are the main determinant of VAT gains on ART [12]. Here we extend these observations and show that higher baseline HIV-1 RNA was also associated with greater declines in SAT and VAT density, suggesting that that baseline HIV disease severity may directly and persistently affect AT function. The mechanism underlying this observed relationship cannot be definitively determined in this study, but may be due to HIV-related factors such as the presence of HIV-infected immune cells in AT, enhancing local inflammation and causing disruption of AT function (similar to other inflammatory diseases) [24, 25]. Of note, our finding is in line with prior laboratory studies showing that the circulating HIV proteins vpr, nef, and tat mediate detrimental effects on adipose tissue health [26-29]. AT may also represent an important HIV reservoir, with greater HIV-1 RNA in CD4+ T cells from AT compared to peripheral blood, and greater T-cell activation observed among AT-resident vs circulating immune cells [30]. As such, ART penetration into AT may be an important factor both in minimizing HIV AT reservoir size and optimizing AT function on suppressive ART. In vitro studies have shown that the INSTIs dolutegravir and elvitegravir penetrate AT, whereas NRTI penetration may be more limited, and RAL and bictegravir have not yet been studied in this capacity [31]. Future mechanistic studies will need to be carefully designed to unravel the complex relationship between adipocyte metabolic activity, ART penetration into AT and the impact on the AT HIV reservoir, and the subsequent effects on fat quantity and quality.
 
Women in our study had larger decreases in SAT density than men following ART initiation. Sex differences in AT density, adipocyte size, and adipokine expression have previously been reported [32, 33]. Progression to obesity is associated with adipocyte hypertrophy in both women and men, and adipocyte hyperplasia (where density remains stable) only in women [34]. Mean adipocyte size is larger in men than women, even after adjusting for BMI [33]. This may reflect reduced capacity of men to expand their SAT depots compared to women, a known sex difference believed to support pregnancy, but could have cardiometabolic implications. Supporting this is the finding that adipocyte size is a major predictor of leptin and adiponectin messenger RNA levels [33]. As the number of women in this study was small, we cannot discern whether greater decreases in AT density on ART contribute to the observed sex differences in cardiometabolic outcomes among PLWH. However, as lower AT density was associated with greater systemic inflammation and adipocytokine disturbances while on suppressive ART in this study, potentially greater cardiometabolic implications for women are suggested by our data.
 
Consistent with our hypothesis, lower abdominal SAT and VAT density were associated with greater disruptions of inflammatory and metabolic biomarker levels in this cohort. Several potential mechanisms may explain this finding: lower AT density is an indicator of larger adipocytes with larger lipid droplets (reflecting impaired adipogenesis, as seen in obesity), which has been associated with disrupted metabolic activity and adipokine secretion [35-37]. We hypothesized that RAL might lead to more favorable effects on AT quality (density) compared with the PI arms, given the minimal in vitro effects of RAL on adipocyte differentiation [38]; however, we observed no statistically significant differences in AT density by treatment arm, highlighting the importance of in vivo confirmation of in vitro, hypothesis-generating data. The effects of the INSTI drug class on body composition and metabolism is an area of ongoing research, including recent reports of increased weight gain following switch to INSTI [39-41], but additional studies are needed to investigate the full cardiometabolic impact of these agents. There is a correlation between higher markers of insulin resistance (HOMA-IR and triglyceride-to-HDL ratio) and SAT density at week 96, but most participants (75%) did not have significant insulin resistance at week 96. Taken together, the adverse biomarker profile seen with lower AT density on suppressive ART may provide insight into the pathophysiological associations between hypertrophied adipocytes and cardiometabolic risk factors in PLWH.
 
Few studies in humans have previously described relationships between AT density and immunometabolic biomarkers [13, 14]. In a large, cross-sectional study from the Framingham Heart Study Third Generation cohort, lower abdominal SAT and VAT density were associated with lower adiponectin and leptin receptor levels and higher leptin levels in both women and men, consistent with greater cardiometabolic risk [21]. Our study observed similar findings, with SAT and VAT density correlating positively with adiponectin levels and negatively with leptin levels before and after virologic suppression, and negatively with IL-6 concentrations following virologic suppression. It is plausible that the imbalances in adipokine (adiponectin and leptin) production seen in correlation with changes in VAT and SAT density result from a combination of chronic immune activation in PLWH on ART [42] and altered AT function, manifested clinically by adipocyte hypertrophy and a proinflammatory state [43, 44].
 
There are several limitations to our study: First, while we have previously shown that AT density from CT scans accurately reflects adipocyte size in PWLH [12], no AT biopsy specimens were available in this study and fat density was used as a surrogate of adipocyte size/AT quality. Second, no cohort of persons without HIV was available for comparison of changes in SAT and VAT density over time, although given that this was an ART initiation trial and not a longitudinal observational of persons already suppressed on ART, a control group without HIV would not have been easily comparable. Although women had larger decreases in SAT density, our sample consisted mostly of men, limiting generalizability but highlighting the need to further explore potential sex differences in cohorts with larger numbers of women. The range of HU used to identify AT density varies in the literature, which can limit reproducibility of comparisons, though we used values standard for the CT reading center and comparable to several other large cohorts. Finally, the impact of the changes in AT quality on clinical CVD burden and other outcomes needs to be formally investigated in longer-term studies.
 
Effective ART has substantially reduced HIV-related morbidity and mortality. As PLWH live longer, an understanding of the relationship between HIV, ART, and contributors to cardiovascular risk is critical. These results help frame the potential interaction between effective ART and AT function, and suggest that earlier and aggressive cardiovascular risk assessment may need to be considered in PLWH.
 
In conclusion, these data provide a first analysis of both changes in CT-quantified AT density among PLWH initiating modern ART, and relationships between these changes and immunometabolic parameters. We demonstrated that declines in AT density occur with effective ART and are associated with adverse changes in cardiometabolic profiles.
 
Furthermore, measurement of AT density may provide additional insight into AT function beyond BMI and AT quantity alone. Given the associations between less dense AT and increased risk of cardiovascular events in people without HIV, this parameter should be further investigated as a potential risk factor in PLWH initiating ART. Better understanding of the causes of AT-associated inflammation and functional changes in AT on ART are needed to help develop interventions to attenuate cardiovascular risk in PLWH.

 
 
 
 
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