Differences in Muscle Quantity and Quality by HIV Serostatus and Sex.

OBJECTIVE: People with HIV (PWH) experience greater declines in both muscle function and muscle mass with aging. Whether changes in muscle quality and quantity with aging differ between men and women with HIV and the implications on muscle function are not established. DESIGN: In coordinated substudies of the Multicenter AIDS Cohort Study and Women's Interagency HIV Study, participants completed physical function and falls assessments; total trunk/thigh density, inversely related to fatty infiltration, and area were quantified from computed tomography (CT) scans. METHODS: Generalized linear models were used to explore variables affecting density/area, and associations between area/density and physical function and falls. RESULTS: CT scans were available on 387 men (198 PWH) and 184 women (118 PWH). HIV serostatus was associated with greater lateralis, paraspinal, and hamstring area, but lower psoas area and density. Older age and female sex were associated with smaller trunk muscle area and lower density. Both lower muscle area and muscle density were associated with several measures of impaired physical function. The odds of falling were lower with greater hamstring density, but not associated with other measurers of muscle area or density. CONCLUSIONS: In summary, older adults with HIV appear to have smaller and less dense (fattier) psoas, a key component in truncal stability and hip flexion that could have implications on physical function. The longitudinal associations of muscle area and density with physical function require careful investigation, with a particular focus on characteristics and interventions that can preserve muscle area, density, and function over time.

The relationship between diabetes and depressive symptoms in men with or at risk of HIV infection.

OBJECTIVES: The aim of the study was to compare the prevalence of comorbid diabetes and depressive symptoms in men living with HIV (MLWH) with that in men without HIV infection and to determine associations between glycaemic control and depressive symptoms. METHODS: Participants included 920 MLWH and 840 men without HIV infection from the Multicenter AIDS Cohort Study (MACS) with available data regarding glycaemic status [categorized as normal for fasting blood glucose (FBG) < 100 mg/dL, prediabetes for FBG 100-125 mg/dL, and diabetes, defined by self-report, diabetes medication use or FBG ≥ 126 mg/dL on at least two consecutive visits, with diabetes classified as controlled if Hemoglobin A1c (HbA1C) < 7.5% and uncontrolled if HbA1C ≥ 7.5%]. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) score, with CES-D ≥ 16 scores classified as elevated depressive symptoms. A modified Poisson regression model with robust variance was used and adjusted for covariates including HIV serostatus. RESULTS: Compared to men without HIV infection, MLWH had a higher mean CES-D score, but a similar prevalence of diabetes (11.3% versus 12.8%, respectively; P = 0.33). The concomitant prevalence of diabetes and elevated depressive symptoms did not differ by HIV serostatus (P = 0.215). In an adjusted analysis, men with uncontrolled diabetes had a greater prevalence of depressive symptoms compared to men with normoglycaemia (prevalence ratio = 1.43; 95% confidence interval 1.11, 1.84). The association between glycaemic status and depressive symptoms did not differ by HIV serostatus (P = 0.22 for interaction). CONCLUSIONS: Both controlled and uncontrolled diabetes were independently associated with a greater prevalence of depressive symptoms, regardless of HIV serostatus. These results highlight the importance of identifying depression in people with diabetes.

Associations between subcutaneous fat density and systemic inflammation differ by HIV serostatus and are independent of fat quantity.

OBJECTIVES: Adipose tissue (AT) density measurement may provide information about AT quality among people living with HIV. We assessed AT density and evaluated relationships between AT density and immunometabolic biomarker concentrations in men with HIV. DESIGN: Cross-sectional analysis of men enrolled in the Multicenter AIDS Cohort Study. METHODS: Abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density (Hounsfield units, HU; less negative = more dense) were quantified from computed tomography (CT) scans. Multivariate linear regression models described relationships between abdominal AT density and circulating biomarker concentrations. RESULTS: HIV+ men had denser SAT (-95 vs -98 HU HIV-, P < 0.001), whereas VAT density was equivalent by HIV serostatus men (382 HIV-, 462 HIV+). Historical thymidine analog nucleoside reverse transcriptase inhibitor (tNRTI) use was associated with denser SAT but not VAT. In adjusted models, a 1 s.d. greater SAT or VAT density was associated with higher levels of adiponectin, leptin, HOMA-IR and triglyceride:HDL cholesterol ratio and lower hs-CRP concentrations in HIV- men. Conversely, in HIV+ men, each s.d. greater SAT density was not associated with metabolic parameter improvements and was significantly (P < 0.05) associated with higher systemic inflammation. Trends toward higher inflammatory biomarker concentrations per 1 s.d. greater VAT density were also observed among HIV+ men. CONCLUSIONS: Among men living with HIV, greater SAT density was associated with greater systemic inflammation independent of SAT area. AT density measurement provides additional insight into AT density beyond measurement of AT quantity alone, and may have implications for metabolic disease risk.

Relationship between Grip Strength and Nonalcoholic Fatty Liver Disease in Men Living with HIV Referred to a Metabolic Clinic.

This study aimed to assess the relationship between grip strength (GS) and nonalcoholic fatty liver (NAFLD) in treated HIV-infected men. We included 169 HIV-infected men. GS was assessed using a hand-grip dynamometer. NALFD was defined by liver-spleen attenuation ratio <1.1 on computed tomography. Mean (SD) age was 57 (6) years and BMI 24.5 (2.9) kg/m2. NAFLD was diagnosed in 33% of men; sarcopenia was present in 28%. Mean (SD) hand grip strength in the dominant hand was 37.5 (7.6) kg. In multivariate logistic regression, intermediate and low GS were associated with higher risk of NAFLD (OR 3.05; CI 1.27-7.61, p=0.01; OR 2.47; CI 1.01-6.19, p=0.05, respectively). GS has an inverse association with NAFLD prevalence in HIV-infected men. Specific mechanisms through which muscle weakness and NAFLD are related require further exploration but are not accounted for merely by the burden of comorbid illness, HIV disease stage, or ART exposure.

The Growth Hormone Releasing Hormone Analogue, Tesamorelin, Decreases Muscle Fat and Increases Muscle Area in Adults with HIV.

BACKGROUND: Tesamorelin, a growth hormone-releasing hormone analogue, decreases visceral adipose tissue in people living with HIV, however, the effects on skeletal muscle fat and area are unknown. OBJECTIVES: The goals of this exploratory secondary analysis were to determine the effects of tesamorelin on muscle quality (density) and quantity (area). DESIGN: Secondary, exploratory analysis of two previously completed randomized (2:1), clinical trials. SETTING: U.S. and Canadian sites. PARTICIPANTS: People living with HIV and with abdominal obesity. Tesamorelin participants were restricted to responders (visceral adipose tissue decrease ≥8%). INTERVENTION: Tesamorelin or placebo. MEASUREMENTS: Computed tomography scans (at L4-L5) were used to quantify total and lean density (Hounsfield Units, HU) and area (centimeters2) of four trunk muscle groups using a semi-automatic segmentation image analysis program. Differences between muscle area and density before and after 26 weeks of tesamorelin or placebo treatment were compared and linear regression models were adjusted for baseline and treatment arm. RESULTS: Tesamorelin responders (n=193) and placebo (n=148) participants with available images were similar at baseline; most were Caucasian (83%) and male (87%). In models adjusted for baseline differences and treatment arm, tesamorelin was associated with significantly greater increases in density of four truncal muscle groups (coefficient 1.56-4.86 Hounsfield units; all p<0.005), and the lean anterolateral/abdominal and rectus muscles (1.39 and 1.78 Hounsfield units; both p<0.005) compared to placebo. Significant increases were also seen in total area of the rectus and psoas muscles (0.44 and 0.46 centimeters2; p<0.005), and in the lean muscle area of all four truncal muscle groups (0.64-1.08 centimeters2; p<0.005). CONCLUSIONS: Among those with clinically significant decrease in visceral adipose tissue on treatment, tesamorelin was effective in increasing skeletal muscle area and density. Long term effectiveness of tesamorelin among people with and without HIV, and the impact of these changes in daily life should be further studied.

To T or not to T: Differences in Testosterone Use and Discontinuation by HIV Serostatus among Men who Have Sex with Men.

OBJECTIVES: The aim of the study was to characterize contemporary patterns and correlates of testosterone therapy (TTh) use and discontinuation by HIV serostatus among men in the Multicenter AIDS Cohort Study (MACS). METHODS: Self-reported testosterone use data were collected semiannually from 2400 (1286 HIV-infected and 1114 HIV-uninfected) men who have sex with men. Multivariable Poisson regression was used to estimate prevalence ratios for TTh use and predictors of TTh discontinuation (2012-2015). RESULTS: Use was higher among HIV-infected compared with HIV-uninfected men in all age strata, with an age-adjusted prevalence of 17% vs. 5%, respectively (adjusted prevalence ratio 3.7; P < 0.001). Correlates of use in the multivariable model were similar by HIV serostatus: white race, the Los Angeles (LA) site, more than one recent sexual partner, non-smoking status, and higher American Heart Association/American College of Cardiology (AHA/ACC) cardiovascular disease (CVD) risk score category (approximately 70% of testosterone users were in the high-risk category). Compared with HIV-uninfected men, HIV-infected men more frequently reported building muscle mass as a motivation for testosterone use. The TTh discontinuation rate was 20.9/100 person-years [95% confidence interval (CI) 17.3, 25.0/100 person-years]. Relative to HIV-uninfected men, HIV-infected men were half as likely to discontinue (adjusted incidence rate ratio 0.4; P < 0.001). Discontinuation was 40% higher in the period after the US Food and Drug Administration (FDA) safety communication for testosterone in 2014, independent of co-factors (P = 0.06). CONCLUSIONS: Given the high prevalence of both TTh use and CVD risk among HIV-infected men, the benefits and risks of TTh should be examined in future studies of aging HIV-infected men and monitored routinely in clinical practice.

Brief report: Circulating markers of fibrosis are associated with immune reconstitution status in HIV-infected men.

INTRODUCTION: Lymphoid tissue fibrosis may contribute to incomplete immune reconstitution on antiretroviral therapy (ART) via local CD4+ T lymphocyte (CD4) depletion. Hyaluronic acid (HA) increases with fibrotic burden. CXCL4 concentrations increase in response to pro-fibrotic stimuli, but lower CXCL4 concentrations in HIV-infected individuals may reflect successful immune evasion by HIV. We investigated relationships between circulating HA and CXCL4 concentrations and immune reconstitution on ART in HIV-infected Multicenter AIDS Cohort Study participants. METHODS: HIV-infected men on ART for >1 year with cryopreserved plasma samples and suppressed post-ART HIV-1 RNA were included. Men with post-ART CD4 <200 cells/mm3 were defined as immunologic non-responders (n = 25). Age-/race-matched men with post-ART CD4 >500 cells/mm3 served as controls (n = 49). HA and CXCL4 concentrations were measured via ELISA. RESULTS: Median pre-ART CD4 was 297 cells/mm3 for non-responders vs 386 cells/mm3 for controls. Median post-ART CD4 was 141 cells/mm3 for non-responders and 815 cells/mm3 for controls. HIV infection duration was 23 years, with median time on ART 13 years for non-responders vs 11 years for controls. Pre-ART HA and CXCL4 concentrations did not vary by eventual immune reconstitution status. Post-ART HA concentrations tended to be higher (85 vs 36 ng/mL, p = 0.07) and CXCL4 concentrations were lower (563 vs 1459 ng/mL, p = 0.01) among non-responders. Among men with paired pre-/post-ART samples, non-responders had greater HA increases and CXCL4 decreases than controls (HA: 50 vs 12 ng/mL, p = 0.04; CXCL4: -1258 vs -405 ng/mL, p = 0.01). CONCLUSIONS: Higher circulating concentrations of HA and lower concentrations of CXCL4 are associated with failure of immune reconstitution on ART.

Switch to raltegravir decreases soluble CD14 in virologically suppressed overweight women: the Women, Integrase and Fat Accumulation Trial.

OBJECTIVES: Soluble CD14 (sCD14) is a monocyte activation marker associated with increased mortality in HIV infection. We assessed 48-week changes in sCD14 and other inflammatory biomarkers in virologically suppressed, HIV-infected women switching to raltegravir (RAL) from a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI). METHODS: HIV-infected women with central adiposity and HIV-1 RNA < 50 HIV-1 RNA copies/mL continued their thymidine-sparing nucleoside reverse transcriptase inhibitor (NRTI) backbone and were randomized to switch to open-label RAL at week 0 (immediate) or 24 (delayed). In an exploratory analysis, inflammatory biomarkers were measured on stored fasting plasma. RESULTS: Of the 37 evaluable subjects, 78% were non-White; the median age was 43 years, the median body mass index (BMI) was 32 kg/m(2) and the median CD4 count was 558 cells/µL. At baseline, biomarker values were similar between groups. After 24 weeks, median sCD14 significantly declined in subjects switching to RAL [-21% (P < 0.001) vs. PI/NNRTI -5% (P = 0.49); between-group P < 0.01]. After 48 weeks, immediate-switch subjects maintained this decline and delayed-switch subjects experienced a similar decline following the switch to RAL (-10%; within-group P < 0.01). Immediate-switch subjects also experienced an initial increase in tumour necrosis factor (TNF)-α that was neither maintained after 48 weeks nor seen in delayed-switch subjects. After adjustment for multiple testing, only declines in sCD14 remained significant. CONCLUSIONS: In this randomized trial of women with central adiposity, a switch to RAL from a PI or NNRTI was associated with a statistically significant decline in sCD14. Further studies are needed to determine whether integrase inhibitors have improved monocyte activation profiles compared with PIs and/or NNRTIs, and whether measured differences between antiretroviral agents translate to demonstrable clinical benefit.