Low Skeletal Muscle Mass in Virally Suppressed HIV Patients
In this preliminary study, we document a high prevalence of presarcopenia in community-dwelling participants with durably suppressed HIV infection and CD4 cell reconstitution. The gender-specific cutoff points for low skeletal muscle mass were based on levels associated with physical disability risk and not merely the central range of a young reference group. The odds of identifying presarcopenia were 10.7-fold greater in males compared to females in spite of the absence of clinically significant differences between male and female duration of known HIV infection.
Our finding of an association with male gender is consistent with a cohort study demonstrating lower skeletal muscle mass in midlife HIV-infected males, but not females, compared to HIV sero-negative controls. Investigators had previously proposed that the greater adipose tissue depot inherent in female gender may attenuate skeletal muscle mass loss in AIDS wasting disease, and this may be so for age-related loss as well. In the general population, females demonstrate skeletal muscle mass stability until later age than males. Our data on skeletal muscle mass in predominantly midlife participants is consistent with predisposition in males for earlier manifestation of presarcopenia. This suggests that an opportunity may exist in this population for secondary intervention. However, this requires further confirmation in longitudinal studies.
The prevalence of presarcopenia documented in this predominantly midlife group was similar to that found in community-dwelling older persons (<70 years) without known HIV infection. However, a longitudinal investigation of skeletal muscle mass loss in a community-dwelling cohort of HIV-infected participants and sero-negative controls did not find greater velocity of skeletal muscle mass loss in persons of either gender with HIV infection.
None of the participants reported current or recent IVDU or was receiving methadone maintenance therapy. However, the association of presarcopenia risk with IVDU transmission category may be a durable effect of IVDU on skeletal muscle mass maintenance and/or accrual. The increased odds for presarcopenia documented in participants reporting current recreational psychoactive substance use further suggests a negative effect of substance use (regardless of pharmacologic class or route of administration) on skeletal muscle. This is an area for further investigation.
Higher BMI, MUAC, and large skeletal frame were negatively associated with presarcopenia in our data set. This was consistent with the parallel increase in skeletal muscle mass with height and body weight seen in all 80 participants as a group. We evaluated for skeletal frame size (height-to-wrist circumference ratio), which is rarely appreciated in clinical care or research and may be more informative than height alone in risk assessment. Greater weight and larger bones requiring more force production for movement may attenuate age-related skeletal muscle loss. Use of SMI to normalize skeletal muscle for height thereby eliminating bias for greater stature is a strong point in the EWGSOP criteria. Accordingly, our prevalence rates were compared to those of investigations in which skeletal muscle was also normalized for height.
Increased odds for presarcopenia in association with MSM transmission category and current receipt of lipid-lowering medication trended toward statistical significance. This is consistent with the literature documenting lower likelihood of overweight in MSM but higher likelihood of metabolic risk factors for chronic disease. A greater percentage of patients receiving NNRTI- compared to PI-based ART demonstrated presarcopenia and the increased odds trended toward statistical significance. This finding is not consistent with a cohort study in HIV-infected men that documented an association of efavirenz with skeletal muscle gain (or attenuation of loss). Sample size limited our investigation of this trend, and this will likely be an area of future research.
Low skeletal muscle mass is central to the definition of sarcopenia. Our finding of a 90.4% negative predictive value for participants demonstrating MUAC within or above the 25th percentile suggests use of this parameter effectively identifies those patients least likely to demonstrate skeletal muscle deficit. These data (MUAC) may decrease unnecessary testing. However, the poor positive predictive value, with limited specificity and sensitivity, indicates additional need for evaluation by bioelectrical impedance analysis or dual energy X-ray absorptiometry for the diagnosis of presarcopenia or sarcopenia. In addition, low limb muscle mass has been associated with low bone mineral density in HIV-infected males, and males in the general population. Patients with a MUAC below the 25th percentile under evaluation for presarcopenia/sarcopenia may also be candidates for evaluation of bone mineral density.
Measurement of MUAC can be performed by most clinicians, requiring minimal patient disrobing, no special equipment (apart from an inelastic tape measure), or complex mathematical operations for use of the result. It is less susceptible to distortion by fluid retention than lower extremity circumferences and is largely independent of height. However, it may not be an appropriate parameter in those with lymphedema, anasarca, or extreme obesity.
The 4 participants with sarcopenia demonstrated low handgrip strength in addition to low skeletal muscle mass and were older than participants with presarcopenia or normal SMI. In longitudinal studies, lower midlife handgrip strength and greater rate of strength decline over time were predictive of future physical disability. We believe this underscores the need for clinical evaluation of muscle strength, in addition to muscle mass, in the care of midlife and older HIV-infected patients.
Our study was limited by sample size and its cross-sectional design. We identified associations but could not infer temporal relationships or causation. In addition, our study was not powered to detect associations with specific cART regimens. Denervation has been linked to age-related skeletal muscle change and investigation of whether a history of exposure to potentially neurotoxic antiretrovirals (ie, the thymidine analogs or didanosine) is associated with presarcopenia in patients with HIV infection is an area for future work. There was only 1 female in the presarcopenia group and this prevented use of gender as a covariate in logistic regression models. Participants were privately insured or receiving Medicare with supplemental private insurance and had a median 2 years postsecondary education. This suggests that they may have achieved better quality of life with fewer health damaging exposures, such as food insecurity and/or unstable housing, than many HIV-infected patients in the United States, where HIV infection is strongly associated with urban poverty. Evaluation for skeletal muscle deficit in persons with access to antiretroviral medications whose ability to act in their own interest is nevertheless constrained is an area for future investigation.
In conclusion, in the present study of HIV-infected persons 45 years or older with durably suppressed HIV infection, we found highly prevalent presarcopenia in midlife in association with male gender. Male gender, IVDU transmission category, or current recreational psychoactive substance use markedly increased odds for the identification of presarcopenia in participants. Our data set suggests that MUAC percentile may improve patient selection for evaluation of skeletal muscle mass and function in clinical care. Longitudinal investigations are needed to determine the impact of low midlife skeletal muscle mass on disability rates in aging HIV-infected persons in care and appropriate preventive interventions.
Discussion
In this preliminary study, we document a high prevalence of presarcopenia in community-dwelling participants with durably suppressed HIV infection and CD4 cell reconstitution. The gender-specific cutoff points for low skeletal muscle mass were based on levels associated with physical disability risk and not merely the central range of a young reference group. The odds of identifying presarcopenia were 10.7-fold greater in males compared to females in spite of the absence of clinically significant differences between male and female duration of known HIV infection.
Our finding of an association with male gender is consistent with a cohort study demonstrating lower skeletal muscle mass in midlife HIV-infected males, but not females, compared to HIV sero-negative controls. Investigators had previously proposed that the greater adipose tissue depot inherent in female gender may attenuate skeletal muscle mass loss in AIDS wasting disease, and this may be so for age-related loss as well. In the general population, females demonstrate skeletal muscle mass stability until later age than males. Our data on skeletal muscle mass in predominantly midlife participants is consistent with predisposition in males for earlier manifestation of presarcopenia. This suggests that an opportunity may exist in this population for secondary intervention. However, this requires further confirmation in longitudinal studies.
The prevalence of presarcopenia documented in this predominantly midlife group was similar to that found in community-dwelling older persons (<70 years) without known HIV infection. However, a longitudinal investigation of skeletal muscle mass loss in a community-dwelling cohort of HIV-infected participants and sero-negative controls did not find greater velocity of skeletal muscle mass loss in persons of either gender with HIV infection.
None of the participants reported current or recent IVDU or was receiving methadone maintenance therapy. However, the association of presarcopenia risk with IVDU transmission category may be a durable effect of IVDU on skeletal muscle mass maintenance and/or accrual. The increased odds for presarcopenia documented in participants reporting current recreational psychoactive substance use further suggests a negative effect of substance use (regardless of pharmacologic class or route of administration) on skeletal muscle. This is an area for further investigation.
Higher BMI, MUAC, and large skeletal frame were negatively associated with presarcopenia in our data set. This was consistent with the parallel increase in skeletal muscle mass with height and body weight seen in all 80 participants as a group. We evaluated for skeletal frame size (height-to-wrist circumference ratio), which is rarely appreciated in clinical care or research and may be more informative than height alone in risk assessment. Greater weight and larger bones requiring more force production for movement may attenuate age-related skeletal muscle loss. Use of SMI to normalize skeletal muscle for height thereby eliminating bias for greater stature is a strong point in the EWGSOP criteria. Accordingly, our prevalence rates were compared to those of investigations in which skeletal muscle was also normalized for height.
Increased odds for presarcopenia in association with MSM transmission category and current receipt of lipid-lowering medication trended toward statistical significance. This is consistent with the literature documenting lower likelihood of overweight in MSM but higher likelihood of metabolic risk factors for chronic disease. A greater percentage of patients receiving NNRTI- compared to PI-based ART demonstrated presarcopenia and the increased odds trended toward statistical significance. This finding is not consistent with a cohort study in HIV-infected men that documented an association of efavirenz with skeletal muscle gain (or attenuation of loss). Sample size limited our investigation of this trend, and this will likely be an area of future research.
Low skeletal muscle mass is central to the definition of sarcopenia. Our finding of a 90.4% negative predictive value for participants demonstrating MUAC within or above the 25th percentile suggests use of this parameter effectively identifies those patients least likely to demonstrate skeletal muscle deficit. These data (MUAC) may decrease unnecessary testing. However, the poor positive predictive value, with limited specificity and sensitivity, indicates additional need for evaluation by bioelectrical impedance analysis or dual energy X-ray absorptiometry for the diagnosis of presarcopenia or sarcopenia. In addition, low limb muscle mass has been associated with low bone mineral density in HIV-infected males, and males in the general population. Patients with a MUAC below the 25th percentile under evaluation for presarcopenia/sarcopenia may also be candidates for evaluation of bone mineral density.
Measurement of MUAC can be performed by most clinicians, requiring minimal patient disrobing, no special equipment (apart from an inelastic tape measure), or complex mathematical operations for use of the result. It is less susceptible to distortion by fluid retention than lower extremity circumferences and is largely independent of height. However, it may not be an appropriate parameter in those with lymphedema, anasarca, or extreme obesity.
The 4 participants with sarcopenia demonstrated low handgrip strength in addition to low skeletal muscle mass and were older than participants with presarcopenia or normal SMI. In longitudinal studies, lower midlife handgrip strength and greater rate of strength decline over time were predictive of future physical disability. We believe this underscores the need for clinical evaluation of muscle strength, in addition to muscle mass, in the care of midlife and older HIV-infected patients.
Our study was limited by sample size and its cross-sectional design. We identified associations but could not infer temporal relationships or causation. In addition, our study was not powered to detect associations with specific cART regimens. Denervation has been linked to age-related skeletal muscle change and investigation of whether a history of exposure to potentially neurotoxic antiretrovirals (ie, the thymidine analogs or didanosine) is associated with presarcopenia in patients with HIV infection is an area for future work. There was only 1 female in the presarcopenia group and this prevented use of gender as a covariate in logistic regression models. Participants were privately insured or receiving Medicare with supplemental private insurance and had a median 2 years postsecondary education. This suggests that they may have achieved better quality of life with fewer health damaging exposures, such as food insecurity and/or unstable housing, than many HIV-infected patients in the United States, where HIV infection is strongly associated with urban poverty. Evaluation for skeletal muscle deficit in persons with access to antiretroviral medications whose ability to act in their own interest is nevertheless constrained is an area for future investigation.
In conclusion, in the present study of HIV-infected persons 45 years or older with durably suppressed HIV infection, we found highly prevalent presarcopenia in midlife in association with male gender. Male gender, IVDU transmission category, or current recreational psychoactive substance use markedly increased odds for the identification of presarcopenia in participants. Our data set suggests that MUAC percentile may improve patient selection for evaluation of skeletal muscle mass and function in clinical care. Longitudinal investigations are needed to determine the impact of low midlife skeletal muscle mass on disability rates in aging HIV-infected persons in care and appropriate preventive interventions.
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