Poorer Muscle Quality and Quantity With ART Initiation Is Associated With Greater Inflammation and Immune Activation : JAIDS Journal of Acquired Immune Deficiency Syndromes

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Clinical Science

Poorer Muscle Quality and Quantity With ART Initiation Is Associated With Greater Inflammation and Immune Activation

Kousari, Arianna MDa; Moser, Carlee PhDb; Olefsky, Maxine MSb; Brown, Todd T. MD, PhDc; Currier, Judith S. MDd; McComsey, Grace A. MDe; Scherzinger, Ann PhDf; Stein, James H. MDg; Lake, Jordan E. MD, MSch; Erlandson, Kristine M. MD, MSa

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: December 1, 2021 - Volume 88 - Issue 4 - p 399-405
doi: 10.1097/QAI.0000000000002776
  • Free

Abstract

INTRODUCTION

Both HIV infection and antiretroviral therapy (ART) for the treatment of HIV are associated with alterations in adipose tissue and skeletal muscle. Before the advent of ART, weight loss and wasting were common AIDS-defining illnesses1; however, newer generations of ART are now associated with weight gain.2,3 Studies suggest that this weight gain is associated with negative metabolic consequences, including increased risk for diabetes.4 Less is known about the effects of newer ART on extravisceral sites of fat deposition, such as skeletal muscle.

Visceral adipose tissue (VAT) accumulation and accumulation of adipose tissue in other extravisceral sites have been associated with increased inflammation5 and immune activation6 and likely contribute to the higher levels of inflammation observed among people with HIV (PWH) even with a suppressed HIV-1 viral load, in comparison with HIV-uninfected controls.7,8 Whether accumulation of extravisceral fat in skeletal muscle is similarly associated with greater inflammation, particularly in the setting of weight gain experienced with ART initiation, is unknown.

In addition to fat within muscle, PWH may have a greater loss of muscle mass and function or sarcopenia.9–11 Sarcopenia has been described in HIV infection, either as a result of HIV infection itself or because of effects of ART on muscle.12 Inflammation has been implicated in the development of sarcopenia in PWH.13 Thus, sarcopenia remains a clinical target of interest given its associated risk for accelerated aging in PWH and subsequent morbidity.

In the AIDS Clinical Trials Group study, A5260s, we have previously shown that ART initiation is associated with decreases in visceral and subcutaneous adipose tissue density, regardless of the initial ART regimen.14 Furthermore, we have shown that weight gain with ART initiation attenuates a decrease in markers of inflammation and immune activation, particularly among women,15 and that lower adipose tissue density after ART correlates with higher inflammatory markers, even with effective viral suppression.14 We similarly found that ART initiation was associated with an increase in lean mass (an estimate of skeletal muscle mass by dual-energy X-ray absorptiometry) and psoas muscle volume [by computed tomography (CT)], but with lower muscle density, suggesting that gains were primarily of lower quality, fatty skeletal muscle.16 Here, our goal was to explore the relationships between inflammation and immune activation and changes in psoas muscle density and area after ART initiation. We hypothesized that after 96 weeks of ART, those with persistent inflammation and immune activation would have poorer muscle quality (less fat within the muscle) and smaller muscle area, changes that may have longer-term effects on physical function.

METHODS

Study Design

AIDS Clinical Trials Group A5260s was the observational metabolic substudy of A5257.17,18 In A5257, ART-naive PWH were randomized to tenofovir disoproxil fumarate-emtricitabine (TDF/FTC) plus atazanavir (ATV)/ritonavir(r), darunavir (DRV)/r, or raltegravir (RAL) for at least 96 weeks.17 The A5260s primary objectives were to compare atherosclerosis progression and endothelial function between the randomized regimens.18 Secondary objectives included assessing changes in cardiovascular disease burden, fat composition [as measured by abdominal CT scans for subcutaneous AT and VAT quantity assessment (ie, AT area)], soluble inflammation and cellular immune activation biomarkers, and bone mineral density. All participants provided written, informed consent, and the institutional review boards at each institution provided approvals for the studies.

Body Composition Measures

CT has been validated as a tool to measure skeletal muscle area (quantity) and fatty infiltration (quality).19,20 A cross-sectional measure of the psoas muscle area at the L4-L5 level21 or at midthigh22 has been used to estimate total body skeletal muscle volume. CT can also provide a measure of skeletal muscle quality through the density, or intramuscular fat, as measured by Hounsfield units (HUs), a radiographic distinction between tissues densities such as water, muscle, fat, or bone.23 CT estimates of muscle density are strongly associated with increased muscle fiber lipid content in vivo23 and with clinical measures of physical function.24 For this study, CTs at week 0 and 96 were reinterpreted for psoas density (HU), psoas lean density (HU), psoas area (square centimeter), and psoas lean area (square centimeter) at the University of Colorado's Anschutz Medical Center by a reader blinded to clinical data using specialized body composition software (Excelis Visual Information Systems, Boulder, CO). The lean density and lean area were determined by excluding muscle with a density <30 HU.

Laboratory Assessment

Blood samples (fasting for > 8 hours) were collected at the study entry before ART initiation and at 96 weeks. All blood samples were sent to core laboratories without prior thaw for processing. Biomarkers were measured at the University of Vermont Laboratory for Clinical Biochemistry Research (Burlington, VA) on batched plasma stored at −70°C. Tests included high-sensitivity C-reactive protein (hs-CRP) by nephelometry (Siemens BNII Nephelometer; Siemens Healthcare, Indianapolis, IN) and interleukin-6 (IL-6) using enzyme-linked immunosorbent assay. Measures of immune activation were measured including soluble CD14, soluble CD163, %CD4+:CD38+HLADR+, and %CD8+:CD38+HLADR+.25

Statistical Methods

This exploratory, retrospective analysis included all participants enrolled in A5260s, who had paired CT scans (at week 0 and 96), who were virologically suppressed at week 96, and who had inflammation or immune activation biomarker data available.

Total psoas density and area were calculated as the sum of the right and left psoas measures. All biomarker outcomes were log-10 transformed before analysis. Percent change in psoas density and area and absolute change in biomarker levels were calculated from baseline to week 96.

Spearman rank-based correlations were used to assess associations between psoas density and psoas lean area and biomarkers cross-sectionally at baseline and week 96 and as change from baseline. Partial Spearman correlations were used to evaluate associations adjusting for body mass index (BMI), psoas area, and ART regimen. Spearman rho and P-values are used to describe all associations, with P-values compared with a 5% type I error rate. No adjustments for multiple comparisons were made; however, interpretations emphasized magnitudes and consistency of effect sizes (Spearman rho). All analyses were performed in SAS 9.4.

RESULTS

Baseline Characteristics

Of the 328 participants enrolled in A5260s, 239 (73%) had paired CT scans that could be reread for muscle endpoints and were virologically suppressed at week 96, and among those, 222 (67%) had available inflammation or immune activation marker data. As shown in Table 1, the median baseline age of participants was 36 years (interquartile range 28–45); most were male (90%). Forty-four were White non-Hispanic, 30% were Black non-Hispanic, and 21% were Hispanic. Baseline median (interquartile range) CD4 was 345 (185–454) cells/μL, HIV-1 RNA was 4.6 (4.1–5.1) log10 copies/mL, and BMI was 24.5 (22.3–27.8) kg/m2.

TABLE 1. - Baseline Characteristics
Characteristics N = 222
Age (yr) 36 (28–45)
Baseline CD4+ T-cell count (cells/μL) 345 (185–454)
HIV-1 RNA (log10 copies/mL) 4.6 (4.1–5.1)
BMI (kg/m2) 24.5 (22.3–27.8)
Race/ethnicity
 White, non-Hispanic 97 (44%)
 Black, non-Hispanic 67 (30%)
 Hispanic (regardless of race) 46 (21%)
 Others 12 (5%)
Female sex 23 (10%)
ART regimen
 Atazanavir/ritonavir 74 (33%)
 Raltegravir 76 (34%)
 Darunavir/ritonavir 72 (32%)
Psoas measures
 Total psoas area (cm2) 37.36 (32.17–41.77)
 Total psoas density (HU) 94.79 (88.40–101.59)
 Lean psoas area (cm2) 31.79 (26.74–36.20)
 Lean psoas density (HU) 108.41 (103.83–113.16)
Biomarkers
 IL-6 (pg/mL) 1.61 (1.12–2.75)
 hs-CRP (μg/mL) 1.29 (0.66–2.81)
 sCD14 (ng/mL) 1684.01 (1453.88–1977.13)
 sCD163 (ng/mL) 1078.11 (770.87–1563.83)
 %CD4+: CD38+HLADR+ 19.1 (11.9–31.4)
 %CD8+: CD38+HLADR+ 42.5 (34–54.8)
Values reported represent median (first and third quartile) or frequency (percentage).

Cross-Sectional Inflammation and Immune Activation and Psoas Muscle Density and Area

Correlations between markers of inflammation with psoas density and area were first examined at baseline. As shown in Figure 1, panel A, we found weak-to-moderate associations (r = −0.15 to −0.30). The strongest associations were observed between IL-6 and psoas density, psoas lean density, psoas area, and psoas lean area (r = −0.23 to −0.30, P < 0.001), and soluble CD14 (sCD14) and psoas area and psoas lean area (r = −0.26 to −0.30, P < 0.001). Modest associations were observed between soluble CD163 (sCD163) and %CD4:CD38+HLADR+ with psoas area and psoas lean area (r = −0.18 to −0.21, P < 0.01). In analyses adjusting for baseline BMI, IL-6 and sCD163 remained independently associated with psoas density and higher levels of inflammation and immune activation remained independently correlated with the lower baseline psoas lean area (Table 2).

F1
FIGURE 1.:
Changes in psoas density, lean density, area, and lean area at week 0 baseline (panel A), week 96 post-ART initiation (panel B), and percent change (panel C) and correlations with inflammatory and immune activation markers. Partial Spearman correlations are represented by color gradients indicating the strength of correlation. Significant correlations are indicated with * or **.
TABLE 2. - Partial Spearman Correlations: Baseline Psoas Density (HU) and Psoas Lean Area (cm2) With Baseline Biomarker Levels
Biomarker Adjusted for Baseline BMI P Adjusted for Baseline Psoas Area P
Correlation Correlation
Baseline psoas density (HU)
 IL-6 (log10 pg/mL) −0.27 <0.001 −0.17 0.01
 hs-CRP (log10 μg/mL) −0.09 0.18 −0.08 0.24
 sCD14 (log10 ng/mL) −0.08 0.22 0.08 0.21
 sCD163 (log10 ng/mL) −0.14 0.04 −0.09 0.19
 %CD4:CD38+HLADR+ (log10) −0.15 0.029 −0.04 0.52
 %CD8:CD38+HLADR+ (log10) −0.01 0.89 0.03 0.61
Baseline psoas lean area (cm2)
 IL-6 (log10 pg/mL) −0.29 <0.001
 hs-CRP (log10 μg/mL) −0.15 0.02
 sCD14 (log10 ng/mL) −0.23 0.0005
 sCD163 (log10 ng/mL) −0.18 0.0073
 %CD4:CD38+HLADR+ (log10) −0.16 0.02
 %CD8:CD38+HLADR+ (log10) −0.08 0.24
Bold numbers indicate P <0.05.

We next examined associations between inflammation and immune activation biomarkers with psoas density or area at week 96 (post-ART initiation) (Fig. 1, panel B). The strongest associations were observed between IL-6 and hs-CRP and psoas density and lean density (r = −0.22 to −0.28, P < 0.001), with higher levels of inflammatory markers associated with lower density. We found modest correlations (r = −0.24 to r = −0.28, P < 0.001) between higher IL-6 and hs-CRP with lower psoas total and lean density (Fig. 1, panel B). In analyses adjusting for baseline BMI, baseline psoas area ,and ART regimen, IL-6 and hs-CRP remained independently correlated with the psoas density; adjusting for baseline BMI and ART, hs-CRP remained correlated with the psoas lean area (Table 3).

TABLE 3. - Partial Spearman Correlations Between Week 96 Psoas Density (HU) and Psoas Lean Area (cm2) and Week 96 Biomarker Levels
Biomarker Adjusted for Baseline BMI P Adjusted for Baseline Psoas Area P Adjusted for ART Regimen* P
Correlation Correlation Correlation
Week 96 psoas density (HU)
 IL-6 (log10 pg/mL) −0.22 0.0008 −0.22 0.0012 −0.25 0.0002
 hs-CRP (log10 μg/mL) −0.25 0.0002 −0.24 0.0003 −0.29 <0.0001
 sCD14 (log10 ng/mL) −0.06 0.42 0.02 0.81 −0.04 0.52
 sCD163 (log10 ng/mL) −0.11 0.09 −0.08 0.26 −0.12 0.078
 %CD4:CD38+HLADR+ (log10) −0.06 0.37 −0.01 0.87 −0.04 0.55
 %CD8:CD38+HLADR+ (log10) −0.002 0.98 0.08 0.24 0.02 0.76
Week 96 psoas lean area (cm2)
 IL-6 (log10 pg/mL) −0.11 0.12 −0.10 0.13
 hs-CRP (log10 μg/mL) −0.17 0.011 −0.16 0.019
 sCD14 (log10 ng/mL) −0.08 0.25 −0.10 0.13
 sCD163 (log10 ng/mL) −0.07 0.27 −0.07 0.31
 %CD4:CD38+HLADR+ (log10) −0.02 0.82 −0.03 0.71
 %CD8:CD38+HLADR+ (log10) −0.02 0.80 −0.03 0.62
Bold numbers indicate P <0.05.
*Protease inhibitors were pooled together.

Change in Inflammation and Immune Activation and Psoas Density and Area

Correlations between absolute change in inflammatory and immune activation biomarkers with percent change in psoas density and area are shown in Figure 1, panel C. The strongest associations were observed for IL-6, sCD14, and sCD163, with a greater decrease in these markers associated with a greater increase in psoas density, psoas area, and psoas lean area (r = −0.07 to −0.18). %CD8+:CD38+HLADR+ was weakly correlated with the psoas lean area (r = 0.17, P = 0.015), whereas no significant associations were observed between psoas density or area and %CD4+:CD38+HLADR+.

In partial correlations adjusted for change in BMI, change in psoas area, or ART regimen (Table 4), greater decreases in IL-6 remained independently associated with greater increase in the psoas density. Similarly, in partial correlations adjusted for change in BMI and ART, greater decrease in IL-6, %CD8+:CD38+HLADR+, sCD14, and sCD163 all remained independently associated with greater increase in the psoas lean area.

TABLE 4. - Partial Spearman Correlations Between Percent Change in Psoas Density (HU) and Psoas Lean Area (cm2) and Absolute Change in Biomarker Levels (Changes From Baseline to Week 96)
Biomarker Adjusted for Change in BMI P Adjusted for Change in Psoas Area P Adjusted for ART Regimen* P
Correlation Correlation Correlation
Percent change in psoas density (HU)
 IL-6 (log10 pg/mL) −0.13 0.06 −0.15 0.02 −0.14 0.04
 hs-CRP (log10 μg/mL) −0.04 0.57 −0.04 0.55 −0.05 0.49
 sCD14 (log10 ng/mL) −0.07 0.31 −0.09 0.17 −0.08 0.24
 sCD163 (log10 ng/mL) −0.07 0.31 −0.08 0.27 −0.07 0.29
 %CD4:CD38+HLADR+ (log10) −0.02 0.77 −0.05 0.48 −0.03 0.67
 %CD8:CD38+HLADR+ (log10) 0.04 0.61 0.06 0.42 0.05 0.49
Percent change in psoas lean area (cm2)
 IL-6 (log10 pg/mL) −0.14 0.043 −0.17 0.0121
 hs-CRP (log10 μg/mL) −0.008 0.90 −0.04 0.5384
 sCD14 (log10 ng/mL) −0.16 0.019 −0.2 0.0033
 sCD163 (log10 ng/mL) −0.14 0.04 −0.14 0.038
 %CD4:CD38+HLADR+ (log10) −0.09 0.19 −0.11 0.10
 %CD8:CD38+HLADR+ (log10) 0.14 0.044 0.17 0.016
Bold numbers indicate P <0.05.
*Protease inhibitors were pooled together.

DISCUSSION

In the setting of ART initiation, we observed that before ART initiation, higher inflammation (IL-6 and hs-CRP) was associated (albeit weakly) with lower psoas density and area, whereas higher immune activation correlated only with the lower psoas area. With 96 weeks of ART, greater decreases in inflammation were associated with greater increases in psoas density and area and decreases in immune activation associated only with increases in the psoas muscle area, most prominently with the lean muscle area.

We observed that higher baseline levels of IL-6 were associated with decreased psoas area and lean area. In HIV-uninfected populations, high levels of inflammation are associated with muscle atrophy because of signaling pathways resulting in decreased protein synthesis or increased muscle degradation. These effects are particularly prominent in cancer, where high systemic inflammation is associated with cancer-associated cachexia.26 Notably, the median serum IL-6 level in cancer patients from 72 separate studies was 6.95 pg/mL (range: 0.23–78.5 pg/mL)27 compared with the median value (1.6 pg/mL) in our study, emphasizing the comparatively low level of inflammation even before ART. In murine models, increased IL-6 levels activate the STAT3 pathway with subsequent downstream activation of the ubiquitin proteasome system.28 This creates muscle degradation by breaking down myofibrillar proteins.29 In addition, in murine models, higher systemic IL-6 induced skeletal muscle protein degradation and skeletal muscle atrophy.30 Among adults with cancer, higher IL-6 is associated with increased ubiquitin protein levels (ubiquitin proteasome system activity) in skeletal muscle.31 In older adults, higher IL-6 was associated with smaller muscle area and less appendicular muscle mass.32

IL-6 also influences muscle through modulation of the insulin-like growth factor (IGF)-1 pathway. IGF-1 activates a common signaling pathway with the end result of activation of mechanistic target of rapamycin, resulting in protein synthesis and inhibition of muscle degradation.33,34 IL-6 has several effects on this pathway that can lead to muscle atrophy. First, in a rat model, treatment with IL-6 resulted in skeletal muscle atrophy.35 IL-6 inhibits mechanistic target of rapamycin, the main transcriptional regulator of protein synthesis.36 In a mouse model, overexpression of IL-6 decreases IGF-1 levels.37 We have previously shown that in PWH, administration of tesamorelin, a growth hormone analog, resulted in increases in muscle density and lean area. The increases in lean area seen with tesamorelin were suggested to be due to IGF-1 effects rather than the reduction in VAT.38

We also found associations between greater decreases in immune activation (sCD14, sCD163, and %CD4+:CD38+DR+ T cells) and increased psoas lean area at week 96. After 1 year of ART, markers of inflammation and immune activation decrease; however, certain markers including sCD14 can remain elevated despite virologic suppression.8 Adipose tissue can act as a reservoir for persistent inflammation and immune activation, which may explain this occurrence in PWH with virologic suppression.39,40 Adipose tissue harbors latent HIV-infected CD4+ cells, T-cell activation, and IL-6–mediated inflammation.41,42 Adipose tissue deposits within muscle, may therefore act similarly to perpetuate systemic inflammation and immune activation, which may have negative effects on muscle function. Obesity is another well-described inflammatory state in which adipose tissue can similarly act as a reservoir for proinflammatory cells and function to secrete proinflammatory cytokines.43 In a murine obesity model, increased systemic inflammation was associated with increased deposition of extramyocellular adipose tissue in skeletal muscle; however, addition of baricitinib, a JAK1/2 inhibitor, was shown to decrease the number and expression of CD8+ T cells in skeletal muscle.44 In an uninfected population of patients on hemodialysis, higher serum sCD14 levels were associated with lower lean body mass, BMI, hand grip strength, but not with fat body mass, and higher sCD14 level correlated with more severe muscle atrophy.45 Similarly, in PWH, higher plasma levels of sCD14 were associated with greater odds of physical function impairment.46 Relatively little is known regarding the association of immune activation markers and muscle function in PWH. These adipose tissue reservoirs may act to perpetuate systemic inflammation and immune activation, and secondarily promote fat deposition within skeletal muscle, leading to overall poorer muscle quality (density). Fatty deposition within skeletal muscle can also secondarily lead to the decreased lean area (good muscle) but overall increased total muscle area because of expansion from fatty infiltrates. Therefore, overall improvement in the local inflammatory and immune activation milieu, either in AT or intramuscular AT, could explain the improvements in the psoas muscle lean area we observed.

Whether associations between muscle and ART initiation are indirect effects of inflammation or a direct result of ART penetrance into the tissue is unknown. This is in contrast to associations between ART and VAT, where variable ART penetrance into adipose tissue is described.47,48 In this same cohort, we have previously shown a greater increase in VAT density with RAL than ATV/r or DRV/r.14 In a separate cohort, we have shown that DRV/r was associated with greater visceral fat area and lower visceral fat and muscle density when compared with ATV/r and RAL.45 Variable ART penetrance into intramuscular, intermuscular, or myocellular lipid deposits could account for varying changes in the suppression of inflammation or immune activation, given these AT deposits are well known to be reservoirs of persistent inflammation despite virologic suppression.39,40 More studies examining the effects of different classes of ART on intramuscular AT and consequently changes in these inflammatory and immune activation markers could further fill in the gaps in this knowledge.

Our study had several limitations. First, this was a correlational study; thus, we cannot draw conclusions about causality or effects between the variables we studied. In addition, analyses within the ART treatment group were limited because of small sample sizes. No data were collected on physical activity, which may impact adiposity overall and in muscle. However, the study was strengthened by inclusion of both men and women with robust data before and after the initiation of ART.

In summary, we observed that decreases in inflammation and immune activation with ART initiation were associated with increases in psoas muscle area and density, largely independent of changes in BMI. These findings provide a link between ongoing, low-level inflammation and immune activation after ART initiation with poor muscle quality and quantity, which may have a long-term effect on physical function. Whether these changes have clinical implications on muscle cannot be determined from this existing study, as physical function measures were not obtained. However, we can draw inferences based on prior studies. Among older adults without HIV, lower psoas quality and/or quantity have been associated with frailty and falls.49–51 We have previously shown greater odds of lower functional status associated with the immune activation biomarker CD8+CD38/HLA-DR and increased levels of IL-6 in PWH.46 In addition, we have found that higher density (less fat) psoas and paraspinal muscle were associated with better physical function.45 Interventions to minimize inflammation and immune activation may have additional benefit on muscle area and density, which ultimately may result in improvements in physical function and mobility.

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Keywords:

inflammation; immune activation; muscle; HIV; antiretroviral therapy; ectopic fat

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