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Antiretroviral initiation is associated
with increased skeletal muscle area and fat content
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"initiation of ART among HIV-infected persons was associated with an increase in truncal skeletal muscle area, which is likely a reflection of increased fat within the muscle rather than an increase in high-quality skeletal muscle.....Increased fatty muscle has been associated with weakness, falls, and a decline in physical activity among older adults; similar clinical significance should be established among HIV-infected middle-aged and older adults. Last, interventions such as diet and exercise should be investigated as potential therapies to limit fat accumulation within skeletal muscle and prevent long-term functional and metabolic complications."
AIDS Aug 24 2017 - Erlandson, Kristine M.a; Fiorillo, Suzannea; Masawi, Fadzaia; Scherzinger, Anna; McComsey, Grace A.b; Lake, Jordan E.c; Stein, James H.d; Currier, Judith S.e; Brown, Todd T.f
"Multiple prior studies have shown that ART initiation is associated with small increases in lean body mass and greater changes in total body weight and VAT [20-22]. The 1.5-3% gain in trunk skeletal muscle area measured by CT scan in the current analysis is comparable to the previously published dual-energy X-ray absorptiometry measured increase of 1.8% in total body lean mass from this study population [13].Although observed gains in lean body mass with ART initiation are often assumed to represent a return to health, the findings of our current study suggest that the increase in muscle area is explained by an increase in fat content within muscle, rather than an improvement in high-quality, dense skeletal muscle. Indeed, when intermuscular fat was excluded, increases in muscle area were no longer seen. Furthermore, both the overall muscle and lean muscle density decreased with 96 weeks of ART, with no difference seen between ART arms. Although the study did not include an untreated HIV control group, our results suggest that ART initiation and return to health is associated with greater fat within the trunk skeletal muscles.
First, one may question whether changes in muscle density have clinical relevance, particularly when analyzing trunk muscles rather than muscle groups in the thigh. Of the muscles included on the single-slice CT scan, the rectus is a trunk flexor, spinalis are trunk extensors, the psoas is the strongest of the hip flexors, and the oblique both rotate and flex the trunk. In combination, these core trunk muscles are particularly important in everyday activities, contribute to balance, and provide compensatory support in fall prevention [23,24]. With the caveat that much of the existing data of CT-based muscle density is derived from older adults in the Health Aging, and Body Composition study (aged 70-80 years), several analyses support the clinical relevance of CT-measured muscle fat area and density of trunk muscles in association with physical function and falls [7-12,24,25]. Furthermore, one study from Health Aging, and Body Composition study found that trunk muscle attenuation explained more of the variance in physical function than thigh muscle attenuation or area [9].
The change in skeletal muscle density (range -0.87 to -2.4 HU, Fig. 2) observed in our cohort is of a similar magnitude as that observed between comparison groups of interest or with interventions: psoas muscle density differed by 4-8% or 2-5 HU between HIV-infected individuals with or without lipodystrophy [17]. In an intervention of metformin (n = 14) versus metformin with exercise (n = 10) in HIV-infected participants, metformin alone was associated with a decline of 1 HU, versus an increase of 2 HU in the combined group [18]. In a separate intervention of healthy postmenopausal women, exercise with or without hormone replacement therapy resulted in small (1.2-1.5 HU) improvements in most thigh muscle compartments compared to control, and the change in posterior thigh muscles correlated with an improvement in running speed [26]. Last, greater trunk muscle density was associated with improvements in a Short Performance Battery test (β-coefficient range 0.50-1 HU) or measures of postural sway (β-coefficient range 0.30-6.8 HU) [27]. These studies suggest that the observed changes in muscle density with ART initiation may be clinically relevant.
The factors associated with changes in muscle fat identify at-risk populations for targeted interventions, or suggest potential mechanisms for fatty muscle infiltration. Key findings across multiple muscle groups in our study were the strong associations between increased fatty muscle infiltration (decreased Hounsfield units) among women, and decreased fatty muscle infiltration (increased Hounsfield units) among black participants following 96 weeks of ART. In prior cross-sectional studies, HIV-infected women had significantly greater intermuscular adipose tissue measured by MRI compared with HIV-infected men from two separate cohorts [28,29]; no data on differences in intramuscular adipose tissue change were reported. Furthermore, sex differences on ART-associated changes in skeletal muscle mass are infrequently described and conflicting: in a subset of participants from randomized ART initiation study, AIDS Clinical Trials Group A5224 s, no sex differences in lean body mass changes were found [30]. An observational study found a 2.0 kg annual increase in lean body mass among women versus annual decreased lean mass (-0.32 kg) among men, but did not reach statistical significance [31]; in another study by the same cohort, ART use was associated with greater appendicular lean mass among men but not women [32]. Although few associations between muscle mass and physical function have been evaluated in HIV, poorer physical function among HIV-uninfected women could be explained by differences in body composition measures including both muscle density and fat mass [33].
Muscle fat and muscle area differences by race have also been previously described, but not consistent with our results. Indeed, black race among both men and women tends to be associated with lower muscle density [7,34], without racial differences in the association between muscle density or area and physical function [34]. Data on race differences in muscle density with interventions are limited. The observed differences by race and sex may be explained by confounding factors not included in this exploratory analysis, including physical activity, nutrition, or concomitant medications.
Several limitations should be noted. First, physical function or strength assessments were not obtained, thus the direct clinical impact of muscle area and density on physical function cannot be established. We could not control for differences in exercise between subgroups. Additionally, CT scans of the thigh would have complemented the findings in the trunk muscles but were not obtained. The study population included few women and was mostly less than 50 years old, thus the study results may not be generalizable to other populations. Furthermore, the age differences in muscle mass and density may have been more pronounced with a wider age variety of participants. Finally, there were a large numbers of analyses performed without adjustment, but the magnitude and consistency of the findings across muscle groups reduce the possibility of a chance finding.
In summary, initiation of ART among HIV-infected persons was associated with an increase in truncal skeletal muscle area, which is likely a reflection of increased fat within the muscle rather than an increase in high-quality skeletal muscle. We were unable to detect differences in skeletal muscle fat by ART type in the current cohort; rather, changes in skeletal muscle fat were more closely associated with race and sex. Future studies should seek to understand reasons for race or sex differences, such as differences in physical activity, diet, hormonal changes, or genetic factors. Increased fatty muscle has been associated with weakness, falls, and a decline in physical activity among older adults; similar clinical significance should be established among HIV-infected middle-aged and older adults. Last, interventions such as diet and exercise should be investigated as potential therapies to limit fat accumulation within skeletal muscle and prevent long-term functional and metabolic complications."
Objective: A greater burden of physical function impairment occurs in HIV-infected adults; the impact of antiretroviral therapy (ART) initiation on muscle density (less dense = more fat), a measure of muscle quality, is unknown.
Design: AIDS Clinical Trials Group Study A5260s, a cardiometabolic substudy of A5257, randomized HIV-infected, ART-naive adults to ritonavir-boosted atazanavir, darunavir, or raltegravir with tenofovir/emtricitabine backbone. Single-slice abdominal computed tomography scans from baseline and week 96 were reanalyzed for total and lean muscle area and density.
Methods: Two-sample t-tests described the differences between baseline and week 96 variables. Linear regression analysis was used to explore the role of a priori identified variables and potential confounders.
Results: Participants (n = 235) were mostly men (90%); 31% were Black non-Hispanic; 21% were Hispanic. Over 96 weeks, small but significant increases were seen in oblique/transverse abdominal, rectus, and psoas muscle total area (range 0.21-0.83 cm2; P < 0.05) but not the lean muscle component (all P ≥ 0.33). Significant decreases in overall density, consistent with increases in fat, were seen in all muscle groups (range -0.87 to -2.4 HU; P < 0.01); for the lean muscle component, only decreases in oblique/transverse abdominal and rectus reached statistical significance (P < 0.05). In multivariable analyses, Black race was associated with increased muscle density and female sex with decreased density; treatment arm was not associated with changes in mass or density.
Conclusion: The ART-associated increase in muscle area, regardless of regimen, is likely a reflection of increased fat within the muscle. The consequences of fatty infiltration of muscle on subsequent muscle function require further investigation.
Introduction
Owing to the success of antiretroviral therapy (ART), more than half of the individuals diagnosed with HIV in the United States are age 50 or older, and an estimated 70% in European countries will be over age 50 by 2030 [1]. Prior studies have shown that HIV-infected older adults are at an increased risk for frailty and physical function impairment compared with HIV-uninfected adults of similar age [2-5]. Physical function is determined, in part, by the quality and quantity of skeletal muscle. In healthy, HIV-uninfected adults, both muscle quality and quantity decline beginning in the fourth or fifth decade of life. With age, the decline in skeletal muscle quality is characterized by an accumulation of fat both around and within the muscle bundle. The increase in skeletal muscle fat can be measured noninvasively by lower density [Hounsfield units (HU)] on computed tomography (CT) scan or by MRI [6], and is strongly correlated with lipid content by skeletal muscle biopsy [7]. Importantly, greater skeletal muscle fat in the thigh or the postural support muscles measured by CT scan are consistently strong predictors of worse physical function, and often stronger predictors of physical function than measures of skeletal muscle mass [8-12].
Changes in body fat with ART initiation are well described, and large gains (up to 30% in the first 2 years) in visceral adiposity occur even with contemporary ART [13-15]. Few studies have described the changes in skeletal muscle fat that occur with HIV infection; to the best of our knowledge, no studies have described changes in skeletal muscle fat with ART initiation. Compared with HIV-uninfected men, HIV-infected men had lower density (greater fatty infiltration) of the mid-thigh muscle bundle and lower muscle quality with age, even after multivariable adjustment including visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) [16]. Among younger HIV-infected persons with body fat changes (previously referred to as lipodystrophy), decreased psoas muscle density was more strongly associated with insulin resistance than BMI, SAT, lean body mass, or ART [17]. Exercise interventions among HIV-infected populations have led to significant improvement in muscle fat attenuation, providing evidence of the reversibility of these findings [18,19].
The goal of this analysis was to determine the changes in skeletal muscle area and density that occur with initiation of ART among ART-naive, HIV-infected adults, and explore variables associated with these changes. As VAT and total body weight increase with ART, we hypothesized that ART initiation would similarly be associated with an increase in muscle fat, a possible mechanism for physical function impairment.
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