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Older MACS Men - Abdominal obesity, sarcopenia, and osteoporosis are associated with frailty in men living with and without HIV
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"frailty was associated with HIV infection as well as with central adiposity, sarcopenia, and femoral neck osteoporosis."
Frailty in HIV+ MACS Men 50-69 Years Old - "Among the men with HIV, 35% were nonfrail, 49% were prefrail, and 16% were frail." ......"We found robust associations between frailty with central adiposity and sarcopenia. To the best of our knowledge, the association between frailty and VAT area in adult men with HIV has not been previously reported."....."The interplay between frailty, muscle mass, and bone density is well recognized, and our findings in the overall cohort were consistent with those previously published among populations without HIV"
o "In a cohort of well characterized men with and without HIV, we found that sarcopenia and central adiposity (either VAT or waist circumference) were strongly associated with frailty
o The highest waist circumference tertile was associated with increased odds of both prefrailty [aOR = 2.23 (95% CI 1.25, 3.98)] and frailty [aOR = 4.18 (95% CI 1.47-11.9)] in the entire cohort, and with frailty among the group of men with HIV [aOR = 7.28 (95% CI 1.6-33.21)].
o Sarcopenia was associated with an increased odds of frailty in both the entire cohort [aOR = 2.68 (95% CI 1.11-6.45)] and men with HIV [aOR = 4.08 (95% CI 1.01-16.41)]
o Frailty but not prefrailty was strongly related to femoral neck osteoporosis in the entire cohort [aOR = 13.6 (95% CI 2.51-73.57], a]. When restricted to only those with HIV infection, the point estimate was large, but the confidence interval was quite wide [aOR = 7.96 (95% CI 0.47-133.99), b], likely because of the low numbers with osteoporosis.
o Underlying mechanisms that link central adiposity, sarcopenia, and frailty are likely due, in part, to chronic levels of underlying inflammation and immune activation. Adipose tissue, and in particular VAT, is a metabolically active tissue that contributes to heightened inflammation and immune activation . In addition to adipokines, many markers of inflammation are associated with VAT, including serum levels of interleukin (IL)-6, tumor necrosis factor alpha, and C-reactive protein . Inflammation has also been implicated as a major causative factor in the development of sarcopenia . Though no HIV-specific causality for frailty has been established among adults with HIV, an enhanced underlying inflammatory state associated with central adiposity and sarcopenia ('sarcopenic obesity') may contribute. For example, elevated IL-6 has been associated with both VAT and sarcopenia in adults with HIV , and elevated IL-6 has also been associated with frailty in adults with HIV . However, frailty is a dynamic process and frailty itself likely contributes to increased VAT and sarcopenia through many potential mechanisms including reduced physical activity.
o In summary, in this study of nearly 400 older men with and without HIV, frailty was associated with HIV infection as well as with central adiposity, sarcopenia, and femoral neck osteoporosis. The association of frailty with central adiposity, and the strong correlation between a simple clinical measure of central adiposity (waist circumference) and CT-based VAT assessment, provide additional clinical rationale supporting the annual assessment of waist circumference for both metabolic risk and for identifying frailty risk. Lastly, the high degree of overlap in central adiposity, sarcopenia, and femoral osteoporosis supports the probable existence of a common mechanistic pathway for these conditions; interventions with beneficial effects on all three outcomes may have the greatest potential to prevent, delay, or improve frailty. Longitudinal studies can further ascertain the potential causal role of these body composition changes in the pathway to frailty, and to evaluate the risks and benefits of interventions such as cardiovascular and resistance exercise, hormone-based therapies, or dietary interventions on frailty that may be mediated through changes in body composition."
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Abdominal obesity, sarcopenia, and osteoporosis are associated with frailty in men living with and without HIV
AIDS June 19 2018 - Hawkins, Kellie, L.a,b; Zhang, Longc; Ng, Derek, K.c; Althoff, Keri, N.c; Palella, Frank, J., Jr.d; Kingsley, Lawrence, A.e; Jacobson, Lisa, P.c; Margolick, Joseph, B.c; Lake, Jordan, E.f; Brown, Todd, T.g; Erlandson, Kristine, M.a
Objective: The relationships between frailty and body composition in older adults with HIV infection are poorly understood. We sought to describe associations between frailty and measures of body composition among adult men with HIV and without HIV.
Design/Methods: Men with and without HIV (age 50-69 years) in the Multicenter AIDS Cohort Study (MACS) Bone Strength Substudy were included if evaluated for frailty (by Fried phenotype) and body composition [BMI, waist circumference, abdominal visceral (VAT) and subcutaneous (SAT) adipose tissue, sarcopenia, and osteopenia/osteoporosis]. All participants with HIV infection were on antiretroviral therapy. Multivariate multinomial logistic regression models were used to determine associations of frailty with body composition.
Results: A total of 399 men, including 199 men with HIV and 200 men without HIV, both with median age 60 years, constituted our study population. Frailty prevalence was 16% (men with HIV) vs. 8% (men without HIV).
HIV serostatus was associated with a 2.43 times higher odds of frailty (P = 0.01).
Higher waist circumference, VAT, sarcopenia, and femoral neck osteoporosis were associated with increased odds of frailty (aOR 4.18, 4.45, 4.15, and 13.6, respectively, and all P < 0.05); BMI and SAT were not. None of these measures presented a differential association with frailty by HIV serostatus (all P > 0.20).
Conclusion: Higher abdominal obesity and sarcopenia were associated with frailty among men with and without HIV. Assessment of these body composition parameters may help detect frailty in the clinical setting.
Background
Frailty is a clinical entity that is easy to recognize but difficult to define. It represents a vulnerability to adverse health outcomes and is the result of factors contributing to poor health and natural aging. Similarities between frailty and HIV infection have been observed since early in the HIV epidemic . Prior to the use of effective antiretroviral therapy (ART), men with HIV in the Multicenter AIDS Cohort Study (MACS) were nine times more likely to have a frailty-related phenotype than men without HIV (13.9 vs. 1.5% prevalence) . Despite ART-induced viral suppression, adults with HIV infection continue to have higher rates of frailty than matched HIV-uninfected populations . Furthermore, even in the presence of HIV viral suppression, chronic comorbid illnesses (neurocognitive impairment, depression, co-infection with other viruses) and lifestyle factors common in people with HIV infection (e.g. smoking) are strongly associated with and likely contribute to the development of frailty .
Since the advent of effective ART, the life expectancy of people with HIV has been extended dramatically . However, the combination of aging, ART toxicities, and lifestyle, among other factors, has contributed to an increasing prevalence of obesity, declining skeletal muscle mass, and a high prevalence of osteopenia or osteoporosis in aging adults with HIV infection . A recent AIDS Clinical Trials Group (ACTG) long-term study that followed persons up to 7 years post-ART initiation found that, compared with people without HIV, those with HIV gained more trunk fat and lost more lean mass and more bone mineral density (BMD) at the lumbar spine . Another study reported that obese adults with HIV had a higher trunk-to-appendicular fat ratio (1.58 vs. 1.32; P = 0.05) and greater visceral fat mass (1.97 vs. 1.60 kg, P = 0.04) compared with HIV-uninfected with comparable BMI .
Associations between frailty and greater BMI, lower muscle mass, and BMD have been described among adults without HIV, and may contribute to pathogenesis or clinical manifestations of frailty . Among people living with HIV, frailty has been associated with higher BMI, greater total fat mass, and trunk fat . In other studies, frailty has been associated with low lean mass, low BMD , higher waist-to-hip ratio but not waist circumference (WC) , and obesity . Whether the relationship between body composition and frailty differs in persons with HIV, among whom lipodystrophy, wasting, and osteoporosis are common, is not known.
We sought to determine associations between frailty and a diverse panel of measures of body composition that each capture and summarize different aspects of body composition among adult men with HIV and a comparison group of demographically similar men without HIV. These included summarized measures of overall adiposity (BMI), a clinical measure of abdominal obesity (WC), specific regions of adiposity [subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT)], presence of 'sarcopenia' based upon lean mass-derived appendicular skeletal muscle index (ASMI), and lastly bone density by the presence of osteoporosis or osteopenia in the lumbar spine and femoral neck. We hypothesized that greater VAT and lower lean mass would be associated with frailty.
Results
Of 399 men included in the study, 199 were men with HIV and 200 were men without HIV. As shown in , the groups were similar by age, education-attained, physical activity level, alcohol, and tobacco use. Men with HIV were significantly less likely to be white and were more likely to have an injection drug use history. Men with HIV had greater proportions of depressive symptoms, viral hepatitis, diabetes, kidney disease, and hypertension compared with men without HIV, although not all of the differences were statistically significant. Among men with HIV, median CD4+ cell count was 641 cells/μl and median cumulative exposed time on ART was 12.5 years.
Among the men with HIV, 35% were nonfrail, 49% were prefrail, and 16% were frail. Among the men without HIV, 43% were nonfrail, 49% were prefrail, and 8.0% were frail (). As shown in , median measures of overall adiposity, abdominal adiposity, lean mass/sarcopenia, and bone density were similar between men with and without HIV. Measures of specific regions of adiposity were significantly different: VAT was higher among men with HIV and SAT was higher in men without HIV (P < 0.05). As shown in , of participants that had all three measurements, 39% were sarcopenic, 49% had high VAT (>130 cm2), 13% had osteopenia/osteoporosis, and 11% with both sarcopenia and high VAT. The percentage of men with sarcopenia was 41% (76/185) among men with HIV vs. 36% (67/186; P = 0.32) among men without HIV; VAT elevation was present in 56% (104/185) vs. 41% (76/186; P = 0.004) and osteopenia/osteoporosis among 16% (30/185) vs. 9% (17/186) (P = 0.003), respectively.
Associations between frailty and HIV
HIV infection was associated with a 2.43-fold (95% CI 1.23-4.79) increase in the odds of frailty, but was not significantly associated with increased risk of prefrailty (aOR = 1.19, 95% CI 0.78-1.82), in adjusted analyses (reviewed in the footnote of ).
Associations between frailty and adiposity in multivariate analyses
In adjusted models, there were no significant associations between BMI and prefrailty or frailty among the entire cohort or the group of men with HIV (all P >0.05, ). The highest waist circumference tertile was associated with increased odds of both prefrailty [aOR = 2.23 (95% CI 1.25, 3.98)] and frailty [aOR = 4.18 (95% CI 1.47-11.9)] in the entire cohort, and with frailty among the group of men with HIV [aOR = 7.28 (95% CI 1.6-33.21)]. In the entire cohort, the highest tertile of VAT was associated with a 4.45-fold greater odds of frailty [95% CI 1.41-14.04] in relation to the middle and lower tertile of VAT, . A similar odds of frailty with increased VAT was observed in the group of men with HIV but did not meet significance [aOR = 3.71 (95% CI 0.71-19.24)]. The highest tertile of SAT was associated with prefrailty [aOR = 1.85 (95% CI 1.05-3.27)] but not frailty in the entire cohort [aOR = 1.54 (95% CI 0.54-4.42)]; SAT was not associated with frailty [aOR = 4.92 (95% CI 0.89-27.37)] or prefrailty [aOR = 2.26 (95% CI 0.8-6.36)] among men with HIV. As shown in , there was a positive correlation between waist circumference and VAT in both the entire cohort (r = 0.62, P < 0.0001) and the men with HIV (r = 0.56, P < 0.0001).
Associations between frailty and sarcopenia in multivariate analyses
Sarcopenia was associated with an increased odds of frailty in both the entire cohort [aOR = 2.68 (95% CI 1.11-6.45)] and men with HIV [aOR = 4.08 (95% CI 1.01-16.41)], . There was no interaction between VAT and sarcopenia [aOR = 0.79 (95% CI 0.07-8.79)].
Associations between frailty and bone density
Frailty but not prefrailty was strongly related to femoral neck osteoporosis in the entire cohort [aOR = 13.6 (95% CI 2.51-73.57], a]. When restricted to only those with HIV infection, the point estimate was large, but the confidence interval was quite wide [aOR = 7.96 (95% CI 0.47-133.99), b], likely because of the low numbers with osteoporosis. Lumbar spine BMD was not associated with prefrailty or frailty in either the entire cohort or the group of men with HIV (full multivariate results are shown in Supplementary Table 1, http://links.lww.com/QAD/B267).
Effect of HIV serostatus and viral suppression
In separate models, the effect of HIV serostatus on the relationship between body composition and frailty or prefrailty was evaluated: no body composition measures demonstrated a differential association with either prefrail or frailty by HIV serostatus (see Supplementary Table 1, http://links.lww.com/QAD/B267; all P values for interaction >0.20). In a sensitivity analysis restricted to HIV-infected men with HIV-1 RNA less than 50 copies/ml, the direction and magnitude of effects of body composition on frailty remained consistent compared with results estimated among the group of men with HIV.
Discussion
In a cohort of well characterized men with and without HIV, we found that sarcopenia and central adiposity (either VAT or waist circumference) were strongly associated with frailty. In contrast, BMI and SAT were not associated with frailty. Although HIV was associated with increased frailty, the effect of these body composition measurements on frailty did not differ by HIV serostatus . In contrast to prior studies linking frailty to low CD4+ cell count and a history of AIDS , we did not find an association between frailty and HIV-specific factors, likely reflective of low rates of clinical AIDS and high CD4+ T-cell counts.
We found robust associations between frailty with central adiposity and sarcopenia. To the best of our knowledge, the association between frailty and VAT area in adult men with HIV has not been previously reported. One small prior study of people with HIV found that greater trunk fat but not lean mass was associated with frailty , in contrast to the strong association we found between sarcopenia and frailty among both men with and without HIV. In a previously reported case-control study of middle-aged, adults with HIV, we similarly found that low-functioning adults had greater sarcopenia (by ASMI) than high-functioning controls . Also similar to this previously published study, we found no association between BMI and frailty, perhaps because of the relatively small range of BMIs observed in our cohort or the restricted upper range of BMI . The lack of an identifiable association between frailty and BMI is likely multifactorial. First, the relationship between BMI and frailty may be not be linear; many prior studies of both people living with and without HIV, have identified both low and high BMI as risk factors for development of frailty . Second, BMI is not an accurate assessment of adiposity : Low BMI is likely a marker of loss in muscle mass or fat, and is often seen in conjunction with comorbidities common in frailty (e.g. chronic obstructive pulmonary disease, chronic kidney disease). A higher BMI could be a marker of increased lean mass or increased adipose tissue, with the latter associated with increased levels of inflammation and the presence of comorbid diseases that impede function (arthritis, coronary artery disease, diabetes mellitus) . Thus, separate measures of fat and lean mass describe the components of body composition associated with frailty more accurately than the 'composite' measure of BMI.
Underlying mechanisms that link central adiposity, sarcopenia, and frailty are likely due, in part, to chronic levels of underlying inflammation and immune activation. Adipose tissue, and in particular VAT, is a metabolically active tissue that contributes to heightened inflammation and immune activation . In addition to adipokines, many markers of inflammation are associated with VAT, including serum levels of interleukin (IL)-6, tumor necrosis factor alpha, and C-reactive protein . Inflammation has also been implicated as a major causative factor in the development of sarcopenia . Though no HIV-specific causality for frailty has been established among adults with HIV, an enhanced underlying inflammatory state associated with central adiposity and sarcopenia ('sarcopenic obesity') may contribute. For example, elevated IL-6 has been associated with both VAT and sarcopenia in adults with HIV , and elevated IL-6 has also been associated with frailty in adults with HIV . However, frailty is a dynamic process and frailty itself likely contributes to increased VAT and sarcopenia through many potential mechanisms including reduced physical activity.
The interplay between frailty, muscle mass, and bone density is well recognized, and our findings in the overall cohort were consistent with those previously published among populations without HIV , even in the absence of statistical significance. The prevalence of osteopenia and osteoporosis was lower than that seen in prior studies of HIV cohorts, which may have decreased power to attain statistical significance. Additionally, other HIV-specific factors likely to contribute to low BMD including CD4+ cell nadir and long-term use of TDF; adjustment for these factors may have explained a greater proportion of low BMD than frailty.
Lastly, we assessed associations between waist circumference and VAT. Waist circumference is a validated surrogate for VAT in HIV-uninfected persons . Recently published clinical guidelines on obesity and lipodystrophy in adults with HIV recommend measurement of annual waist circumference , based on growing evidence that central adiposity, particularly VAT, is associated with adverse health outcomes. We found a strong, positive correlation between waist circumference and VAT in both the entire cohort (r = 0.62, P < 0.0001) and the men with HIV (r = 0.56, P< 0.0001). Our findings corroborate a prior study that showed self-reported waist gain and waist circumference correlated with DXA-derived and CT-derived measures of abdominal fat, including VAT, among adults with HIV . Furthermore, the strong association between waist circumference and frailty emphasizes the clinical importance of waist circumference measurement, and suggests that waist circumference may be an easy, clinically accessible marker for adults with HIV at increased risk for frailty.
The strengths of this study include the control group of men without but at risk for HIV, similar demographically to the group of men with HIV who were studied. Body composition measurements from DXA and CT scans allowed for more thorough and precise comparisons than BMI or DXA alone. Further, all men with HIV were prescribed ART and the vast majority of the participants were virologically suppressed. This study had several limitations: the cross-section design restricted our ability to establish temporality between the independent and dependent variables. The results may not be applicable to more racially diverse population or to women, especially with respect to hormonal changes associated with aging and differences in body composition. The exclusion of participants with a BMI of greater than 35 kg/m2 may have introduced a bias that precluded finding an association between BMI and frailty, although this represents less than 2% of the MACS. Lastly, more contemporary definitions of sarcopenia as described by the The European Working Group on Sarcopenia in Older People and the International Working Group on Sarcopenia, focus on both loss of muscle mass and function (gait speed or grip strength). As these measures of function are also components the outcome of frailty, we did not use these definitions.
In summary, in this study of nearly 400 older men with and without HIV, frailty was associated with HIV infection as well as with central adiposity, sarcopenia, and femoral neck osteoporosis. The association of frailty with central adiposity, and the strong correlation between a simple clinical measure of central adiposity (waist circumference) and CT-based VAT assessment, provide additional clinical rationale supporting the annual assessment of waist circumference for both metabolic risk and for identifying frailty risk. Lastly, the high degree of overlap in central adiposity, sarcopenia, and femoral osteoporosis supports the probable existence of a common mechanistic pathway for these conditions; interventions with beneficial effects on all three outcomes may have the greatest potential to prevent, delay, or improve frailty. Longitudinal studies can further ascertain the potential causal role of these body composition changes in the pathway to frailty, and to evaluate the risks and benefits of interventions such as cardiovascular and resistance exercise, hormone-based therapies, or dietary interventions on frailty that may be mediated through changes in body composition.
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