Association of Fat With Physical Function
Six low-function (20%) and 6 high-function (13%) subjects were obese based on BMI, and 4 low-function (13%) but no high-function subjects were underweight. BMI was not significantly different between low-function (geometric mean 25.5 kg/m2, 95% CI: 24.0 to 27.1 kg/m2) and high-function groups (24.2 kg/m2, 95% CI: 22.4 to 26.0 kg/m2, P = 0.25). Relative body fat was slightly higher among low-function (28.2% ± 1.6%) than high-function persons (25.0% ± 1.4%), but this was not significant after adjusting for CD4, current protease inhibitor use, or any use of zidovudine, didanosine, or stavudine (P = 0.14). Fat mass, fat index, fat distribution, and the fat mass ratio were not associated with greater odds of being low function (Table 3). In general and as expected, women had higher median percentage of body fat than men (33% vs 23%). When considering all subjects and adjusting for functional status, age, gender, and time since HIV diagnosis, demographics, smoking or alcohol use, or class of ART were not significantly associated with increased odds of higher relative body fat (all P ≥ 0.11).
Association of Muscle With Physical Function
Total lean body mass, appendicular lean mass, and ASMI were lower (all P < 0.05) among low-function subjects compared with high-function controls (Table 3). Using ASMI cut points,26 27 (35%) of all subjects met criteria for low muscle mass and 15 (50%) of the low-function subjects were classified as sarcopenic. We found a greater odds of low muscle mass among subjects with low function (OR: 2.5, 95% CI: 1.0 to 6.1, P = 0.04). When considering all subjects and adjusting for functional status, age, gender, and time since HIV diagnosis, lower BMI (OR: 1.7, 95% CI: 1.2 to 2.2, P < 0.001), but not demographics, smoking or alcohol use, or ART class, were associated with increased odds of low muscle mass (all P ≥ 0.11). Serum albumin (OR: 0.8, 95% CI: 0.2 to 2.6, P = 0.68), hemoglobin (OR: 0.96, 95% CI: 0.7 to 1.3, P = 0.81), and testosterone (OR: 1.0, 95% CI: 0.9 to 1.1, P = 0.95) were not associated with an increased odds of low muscle mass.
Association of Bone With Physical Function
Overall, 11 subjects (14%) had osteoporosis at the lumbar spine and 3 subjects (4%) had osteoporosis at the hip. Osteopenia or osteoporosis was more common among low-function subjects: 20 low-function group (67%) had osteopenia or osteoporosis at the lumbar spine compared with 18 (38%) in the high-function group (P = 0.02); 19 low-function persons (68%) had osteopenia or osteoporosis at the hip compared with 16 (33%) in the high-function group (P = 0.01). Low BMD and T scores at both the hip and lumbar spine were associated with greater odds of being low function. The predictive values of low BMD and T score at the lumbar spine and total hip were robust to adjustments for BMI, nadir CD4+ T-cell count, current tenofovir use, and smoking status (Table 3). By the FRAX tool, each 1% increase in the 10-year probability of a major osteoporotic fracture of a hip fracture was associated with a nonsignificant 1.2 (95% CI: 0.9 to 1.5, P = 0.11) and 1.9 (95% CI: 0.9 to 4.4, P = 0.25) greater odds, respectively, of low function. When considering factors related to osteopenia/osteoporosis among all subjects and adjusting for functional status, age, gender, and time since HIV diagnosis, white race (OR: 6.0, 95% CI: 1.4 to 26.0, P = 0.02) was associated with greater odds of osteopenia or osteoporosis. A trend toward greater odds of osteopenia or osteoporosis was seen with incrementally higher age (OR: 1.1, 95% CI: 0.99 to 1.3, P = 0.08). An incremental decrease in BMI was associated with an increased odds of osteopenia or osteoporosis (OR: 1.3, 95% CI: 1.1 to 1.5, P = 0.002). No significant associations were detected with ethnicity, tobacco or alcohol use, or class of ART (all P ≥ 0.25).
Association of Hormonal Alteration With Physical Function
Lower IGF-1 and IGFBP-3 were associated with significantly greater odds of being low function (Table 3). Among all subjects and adjusting for functional status, age, gender, and duration of HIV diagnosis, hepatitis B or C was associated with greater odds of having low IGF-1 or IGFBP-3 (OR: 3.5, 95% CI: 1.2 to 10.2, P = 0.03; OR: 6.6, 95% CI: 2.0 to 22.0, P = 0.002) and alcohol use was associated with greater odds of low IGFBP-3 (OR: 15.7, 95% CI: 2.8 to 88.5, P = 0.002).
Nine (30%) low-function and 13 (27%) high-function subjects were found to have vitamin D deficiency; 13 (43%) low-function and 12 (25%) high-function subjects had vitamin D insufficiency. Serum 25-OH vitamin D was not a significant predictor of functional group (Table 3; P = 0.11). Among all subjects and adjusting for functional status, age, gender, and duration of HIV diagnosis, no significant associations were seen with demographic characteristics, ART class, or BMI (all P ≥ 0.24).
The roles of adiposity, sarcopenia, and osteopenia/osteoporosis in functional impairment and frailty are well described among multiple elderly cohorts.7,8,10 Little is known, however, about the relationships of these normal aging processes to physical function in HIV-infected persons who are at increased risk for premature body and bone composition changes due to HIV-1, ART, and/or chronic inflammation.2,11,13,33 In the current study, we provided the first quantitative comparison of fat, muscle, and bone in HIV-infected persons with low or high function.
The frequency of low muscle mass was particularly surprising given the relatively young age (mean: 52 years) of the cohort and similar to what is commonly reported among persons 10–25 years older than the participants in our study.34,35 The implications of this finding are concerning because low muscle mass and sarcopenia are associated with functional dependence and increased mortality among both HIV-infected and HIV-uninfected adults.12,26,36
BMD and T scores in our entire middle-aged HIV-infected population, and the low-function cohort in particular, were also similar to those of older persons without HIV infection.13,37,38 A decrease in BMD of 1 SD among older women is associated with a 37–49% increased risk of fracture.39 The difference between groups in our cohort was slightly less, but nonetheless indicates a significant increase in fracture risk among low-function persons. Functional impairment is a consistently strong predictor of increased fall risk in HIV-infected and -uninfected elderly.40–42 The combination of increased fall risk and lower BMD highlights the importance of evaluating, monitoring, and modifying risks for both falls and bone fragility to prevent fractures among persons aging with HIV.40,43 In addition, persons with impaired physical function are less likely to engage in regular physical activity, and a resultant decline in muscle mass from physical inactivity may amplify the decline in BMD with age (Fig. 1). Although low-function subjects had a slightly greater frequency of vitamin D deficiency or insufficiency compared with high-function subjects, we were unable to detect significant differences in serum vitamin D concentrations possibly due to the fact that nearly 30% of low-function subjects were receiving vitamin D replacement therapy.
Low functional status was associated with low serum IGF-1 and IGFBP-3 concentrations in our cohort. Indeed, levels of IGF-1 in our low-function group (99 ± 8 ng/mL) were comparable with those reported in healthy men 70–80 years of age (125 ± SD of 48 ng/mL)44 and frail women 70–79 years of age (104 ± SD of 2 ng/mL).45 An age-related decline in the GH/IGF-1-axis has been well described,46,47 but the unexpectedly low levels of IGF-1 in our cohort, even after adjusting for potential confounders, may represent early somatopause as a manifestation of premature aging in HIV-1 infection. Whether low IGF-1 in our physically impaired group is due to an age-related decrease in GH–releasing hormone, impaired pituitary release of GH, impaired IGF-1 production, or related to hypothalamic infiltration of HIV or side effects of ART is not known.48–51
In our cohort, BMI and measures of fat were not significantly different between low- and high-functioning groups. This finding contrasts to findings from a cohort of “frail” (defined by at least 2 deficits in physical performance test, peak oxygen uptake, activities of daily living, or instrumental activities of daily living), HIV-infected subjects in the Rochester, New York area that demonstrated higher BMI, waist circumference, fat mass, and trunk fat than HIV-infected nonfrail controls.52 The discordance between studies may reflect the lower prevalence of obesity in Colorado compared with New York. In county-specific data collected by the Centers for Disease Control, 30.3% of adults in Monroe County, New York are obese compared with less than 20% of adults in counties of the Denver metropolitan area.53 Indeed, the average BMI of our cohort was 25 kg/m2 compared with 29 kg/m2 in the Rochester cohort.52
Our study had several limitations. First, we did not include an HIV-uninfected cohort. We used trunk fat as a measure of central adiposity but did not include visceral fat. Visceral fat accumulates with ART,54 is more proinflammatory and insulin-resistant than subcutaneous fat,55 and, thus, could contribute to low lean mass and osteopenia. The relatively low BMI in our cohort may make our results less applicable to more obese patient populations in the United States. Additionally, our cohort was intentionally limited to HIV-infected persons on successful ART. This focus allowed us to study the relationship of body composition and physical function in persons aging during successful HIV-1 treatment as opposed to persons with complications of untreated HIV-1 infection. Body composition can vary considerably by age, genetics, and gender. We attempted to reduce potential confounding by these factors by matching our low- and high-function cases by age and gender. Last, we demonstrated an association between physical function, body composition, and somatotropic hormones at a single time point. This cross-sectional design precludes conclusions regarding the direction and causality of the relationship of functional capacity to body composition.
Our findings indicate that functional impairment in middle-aged adults with HIV-1 infection is associated with low muscle mass, BMD, IGF-1, and IGFBP-3. These characteristics may be a manifestation of early “somatopause” in middle-aged HIV-infected adults (pathway postulated in Fig. 1).6–9,56,57 Longitudinal studies are needed to elucidate the complex interactions among bone, muscle, fat, GH/IGF-1, and physical function in HIV-infected adults during ART. Further studies should investigate the impact of interventions to increase bone, muscle, or IGF-1 on functional capacity among persons aging with HIV infection.
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Keywords:© 2013 by Lippincott Williams & Wilkins
frailty; HIV; sarcopenia; osteoporosis; growth hormone; vitamin D