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Associations of Muscle Density and Area With Coronary Artery Plaque and Physical Function.
Erlandson, KM, Umbleja, T, Lu, MT, Taron, J, Ribaudo, HJ, Overton, ET, Presti, RM, Haas, DW, Sax, PE, Yin, MT, et al
Journal of acquired immune deficiency syndromes (1999). 2023;(2):174-184
Abstract
OBJECTIVE Skeletal muscle quality and mass are important for maintaining physical function during advancing age. We leveraged baseline data from Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) to evaluate whether paraspinal muscle density and muscle area are associated with cardiac or physical function outcomes in people with HIV (PWH). METHODS REPRIEVE is a double-blind randomized trial evaluating the effect of pitavastatin for primary prevention of major adverse cardiovascular events in PWH. This cross-sectional analysis focuses on participants who underwent coronary computed tomography at baseline. Lower thoracic paraspinal muscle density (Hounsfield units [HU]) and area (cm 2 ) were assessed on noncontrast computed tomography. RESULTS Of 805 PWH, 708 had paraspinal muscle measurements. The median age was 51 years and 17% were natal female patients. The median muscle density was 41 HU (male) and 30 HU (female); area 13.2 cm 2 /m (male) and 9.9 cm 2 /m (female). In adjusted analyses, greater density (less fat) was associated with a lower prevalence of any coronary artery plaque, coronary artery calcium score >0, and high plaque burden ( P = 0.06); area was not associated with plaque measures. Among 139 patients with physical function measures, greater area (but not density) was associated with better performance on a short physical performance battery and grip strength. CONCLUSIONS Among PWH, greater paraspinal muscle density was associated with a lower prevalence of coronary artery disease while greater area was associated with better physical performance. Whether changes in density or area are associated with changes in CAD or physical performance will be evaluated through longitudinal analyses in REPRIEVE.
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What about tocilizumab? A retrospective study from a NYC Hospital during the COVID-19 outbreak.
Mehta, M, Purpura, LJ, McConville, TH, Neidell, MJ, Anderson, MR, Bernstein, EJ, Dietz, DE, Laracy, J, Gunaratne, SH, Miller, EH, et al
PloS one. 2021;(4):e0249349
Abstract
BACKGROUND Tocilizumab, an interleukin-6 receptor blocker, has been used in the inflammatory phase of COVID-19, but its impact independent of corticosteroids remains unclear in patients with severe disease. METHODS In this retrospective analysis of patients with COVID-19 admitted between March 2 and April 14, 2020 to a large academic medical center in New York City, we describe outcomes associated with tocilizumab 400 mg (without methylprednisolone) compared to a propensity-matched control. The primary endpoints were change in a 7-point ordinal scale of oxygenation and ventilator free survival, both at days 14 and 28. Secondary endpoints include incidence of bacterial superinfections and gastrointestinal perforation. Primary outcomes were evaluated using t-test. RESULTS We identified 33 patients who received tocilizumab and matched 74 controls based on demographics and health measures upon admission. After adjusting for illness severity and baseline ordinal scale, we failed to find evidence of an improvement in hypoxemia based on an ordinal scale at hospital day 14 in the tocilizumab group (OR 2.2; 95% CI, 0.7-6.5; p = 0.157) or day 28 (OR 1.1; 95% CI, 0.4-3.6; p = 0.82). There also was no evidence of an improvement in ventilator-free survival at day 14 (OR 0.8; 95% CI, 0.18-3.5; p = 0.75) or day 28 (OR 1.1; 95% CI, 0.1-1.8; p = 0.23). There was no increase in secondary bacterial infection rates in the tocilizumab group compared to controls (OR 0.37; 95% CI, 0.09-1.53; p = 0.168). CONCLUSIONS There was no evidence to support an improvement in hypoxemia or ventilator-free survival with use of tocilizumab 400 mg in the absence of corticosteroids. No increase in secondary bacterial infections was observed in the group receiving tocilizumab.
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Effect of vitamin D3 and calcium carbonate supplementation on muscle strength in postmenopausal women living with HIV.
Yin, MT, Bucovsky, M, Williams, J, Brunjes, D, RoyChoudhury, A, Colon, I, Ferris, DC, Olender, S, Schulze, PC, Sharma, A, et al
Antiviral therapy. 2020;(8):411-418
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BACKGROUND Both falls and fractures are increased in older persons living with HIV (PLWH). Low serum total 25-hydroxyvitamin D (25-OHD) levels have been associated with falls, fractures and poor muscle strength. We hypothesized that vitamin D (VitD) supplementation would improve muscle strength in postmenopausal PLWH. METHODS In a 12-month prospective, randomized, double-blind, study of 69 African American and Hispanic postmenopausal PLWH on antiretroviral therapy with 25-OHD ≥10 ng/ml and ≤32 ng/ml, we investigated the effects of daily low (1,000 IU; n=31) and moderate (3,000 IU; n=38) cholecalciferol doses on lean mass and strength. Change in lean body mass was assessed by dual-energy X-ray absorptiometry (DXA), and isometric and isokinetic muscle strength in the dominant lower extremity was assessed using the Biodex System 4 Pro. RESULTS Mean age was 56 ±5 years, median CD4+ T-cell count 722 cells/mm3 and 74% had HIV RNA≤50 copies/ml. Serum 25-OHD did not differ at baseline, but was higher in the moderate than low VitD group at 6 and 12 months. In both groups, there were significant increases in lower extremity isokinetic torque, work and power at 12 months, with no change in lean mass. CONCLUSIONS VitD supplementation was associated with a modest increase in lower extremity strength in postmenopausal PLWH, without a concomitant increase in muscle mass. Magnitude of increase in strength were similar with 3,000 IU and 1,000 IU daily. Future larger studies will be required to determine the optimal dose of VitD to improve muscle strength and to determine whether supplementation reduces the risk of falls and fractures in PLWH.
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A Randomized Placebo-Controlled Trial of Low- Versus Moderate-Dose Vitamin D3 Supplementation on Bone Mineral Density in Postmenopausal Women With HIV.
Yin, MT, RoyChoudhury, A, Bucovsky, M, Colon, I, Ferris, DC, Olender, S, Agarwal, S, Sharma, A, Zeana, C, Zingman, B, et al
Journal of acquired immune deficiency syndromes (1999). 2019;80(3):342-349
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Prevalence of fracture is 2 to 3-fold higher in women with HIV over age 50 than in the general population. The aim of this study was to compare the effects of two doses of vitamin D3 repletion (3000 IU Vs 1000 IU) on bone turnover and change in bone mass and microarchitecture in postmenopausal women with HIV. The study is a randomised placebo-controlled study which recruited women with HIV aged between 40 and 70 years. The participants were randomised to 3000 vs 1000 IU vitamin D3 daily together with 500mg calcium carbonate twice daily. Results indicate that moderate dose vitamin D3 (3000 IU) supplementation in minority postmenopausal women with HIV on established antiretroviral therapy (treatment for HIV) did not appear to have a greater impact on bone mineral density or bone turnover than low dose vitamin D3 supplementation (1000 IU). Authors conclude that further studies are required to determine whether vitamin D3 supplementation is beneficial in this patient population, and if so, what dose provides the maximum benefit in terms of musculoskeletal health in persons aging with HIV.
Abstract
BACKGROUND Prevalence of osteoporosis and fracture is increased among older people with HIV. We compared the effects of low (1000 IU) vs moderate (3000 IU) vitamin D3 (VitD) supplementation on areal bone mineral density (aBMD) and volumetric bone mineral density (vBMD) in African American and Hispanic postmenopausal women with HIV on antiretroviral therapy. METHODS We performed a 12-month prospective, randomized, double-blind, placebo-controlled study with primary outcomes of change in aBMD by dual-energy X-ray absorptiometry (DXA) and secondary outcomes of change in vBMD by quantitative computed tomography and bone turnover markers. An intent-to-treat analysis was performed on 85 randomized subjects (43 low and 42 moderate) for primary DXA outcomes, and complete case analysis was performed for secondary outcomes. RESULTS Mean age was 56 ± 5 years, median CD4 count was 722 cells/mm, and 74% had HIV RNA ≤ 50 copies/mL. Serum 25-OHD was higher in the moderate than low VitD group at 6 months (33.1 ± 10.3 vs 27.8 ± 8.1 ng/mL, P = 0.03) and 12 months, but parathyroid hormone levels remained similar. Percent change in aBMD, vBMD, and bone turnover markers did not differ between low and moderate VitD groups before or after adjustment for baseline aBMD. CONCLUSIONS VitD supplementation at 3000 IU daily increased mean total 25-OHD levels in postmenopausal women with HIV, but we did not find evidence of an effect on BMD beyond those observed with 1000 IU daily. Future studies are necessary to determine whether VitD supplementation is beneficial in this patient population, and if so, what dose is optimal for skeletal health.
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Vitamin D does not modulate immune-mediated bone loss during ART initiation.
Yin, MT, Chan, ES, Brown, TT, Kinslow, J, Martinson, J, Landay, A, Melbourne, KM, Ribaudo, HJ, Overton, ET, ,
Antiviral therapy. 2019;(5):355-362
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BACKGROUND Vitamin D (VitD) and calcium (Ca) supplementation attenuates antiretroviral therapy (ART)-associated bone loss, but it is unclear whether this effect is mediated through immunomodulation. METHODS In this exploratory analysis of A5280, a 48-week, randomized, double-blind, placebo-controlled study of VitD/Ca supplementation with ART initiation, we characterized lymphocyte phenotypes and receptor activator of nuclear factor kappa-B ligand (RANKL) expression by median fluorescence intensity (MFI) at baseline and 48 weeks. Changes were evaluated within and between treatment groups by Wilcoxon signed rank and rank sum tests, respectively. Spearman correlations estimated relationships between cellular phenotypes and bone mineral density (BMD). RESULTS Of 165 participants enrolled, 138 had samples for cellular phenotypes (64 VitD/Ca, 74 placebo). Markers of CD4, CD8 activation (CD38+HLA-DR+) declined (all P<0.001), but did not differ between arms. There was no decline in either %T-cells (CD4 and CD8) expressing RANKL or expression of RANKL by MFI. CD4 and CD8 activation markers were not correlated with BMD at baseline (r<0.15 and P>0.09 for all), but greater declines in CD4 activation correlated with greater declines in hip and spine BMD in both arms (0.25 ≤r ≤0.37, all P<0.05). A greater decline in CD8 activation was correlated with greater declines in both hip and spine BMD in the placebo arm only (hip r=0.31, P=0.009; spine r=0.25, P=0.035). CONCLUSIONS Reductions in T-cell activation are characteristic of ART initiation, but only correlated modestly with bone loss. VitD/Ca supplementation does not appear to mitigate bone loss through modulation of immune activation or expression of RANKL. TRIAL REGISTRATION NUMBER NCT01403051.
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Continued Interest and Controversy: Vitamin D in HIV.
Hsieh, E, Yin, MT
Current HIV/AIDS reports. 2018;(3):199-211
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PURPOSE OF REVIEW Vitamin D (VitD) deficiency is highly prevalent among HIV-infected individuals. Given the overlapping risk for several chronic disease and immunomodulatory outcomes from both long-standing HIV and VitD deficiency, there is great interest in clarifying the clinical role of VitD for this population. RECENT FINDINGS Recent studies have expanded our knowledge regarding the epidemiology and mechanisms of VitD deficiency-associated outcomes in the setting of HIV. Clinical trials focusing on VitD supplementation have demonstrated a positive impact on bone mineral density in subgroups of HIV-infected individuals initiating ART or on suppressive ART regimens; however, significant heterogeneity exists between studies and data are less consistent with other clinical outcomes. Further research is needed to clarify uncertainly in several domains, including identifying patients at greatest risk for poor outcomes from VitD deficiency, standardizing definitions and measurement techniques, and better quantifying the benefits and risks of VitD supplementation across different demographic strata for skeletal and extra-skeletal outcomes.
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Racial differences in calculated bioavailable vitamin D with vitamin D/calcium supplementation.
Yin, MT, Chan, ES, Brown, TT, Tebas, P, McComsey, GA, Melbourne, KM, Napoli, A, Hardin, WR, Ribaudo, HJ, Overton, ET, et al
AIDS (London, England). 2017;(17):2337-2344
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OBJECTIVES Some studies suggest that bioavailable 25-dihydroxyvitamin D [25-(OH)D] is more accurate than total 25-(OH)D as an assessment of vitamin D (VitD) status in black individuals. We hypothesized that increases in bioavailable 25-(OH)D would correlate better with improvement in bone outcomes among black HIV-infected adults. DESIGN This is a secondary analysis of AIDS Clinical Trials Group A5280, a randomized, double-blind study of VitD3 and calcium supplementation in HIV-infected participants initiating antiretroviral therapy. METHODS Effect of VitD/calcium on total and calculated bioavailable 25-(OH)D, parathyroid hormone, bone turnover markers, and bone mineral density in black and nonblack participants were evaluated at 48 weeks. Wilcoxon signed-rank tests and Wilcoxon rank sum tests assessed within and between-race differences. RESULTS Of 165 participants enrolled, 129 (40 black and 89 nonblack) had complete data. At baseline, black participants had lower total 25-(OH)D [median (Q1,Q3) 22.6 (15.8, 26.9) vs. 31.1 (23.1, 38.8) ng/ml, P < 0.001] but higher bioavailable 25-(OH)D [2.9 (1.5, 5.2) vs. 2.0 (1.5, 3.0) ng/ml, P = 0.022] than nonblack participants. After 48 weeks of VitD/calcium supplementation, bioavailable 25-(OH)D increased more in black than nonblack participants, but there were no between-race differences change in bone turnover markers or bone mineral density. The associations between increases in 25-(OH)D levels and change in bone outcomes appeared similar for both total and bioavailable 25-(OH)D. CONCLUSION Baseline and change in bioavailable 25-(OH)D were higher among black adults initiating antiretroviral therapy with VitD/calcium; however, associations between 25-(OH)D and bone outcomes appeared similar for total and bioavailable 25-(OH)D. The assessment of total 25-(OH)D may be sufficient for evaluation of VitD status in black HIV-infected individuals. TRIAL REGISTRATION NUMBER NCT01403051.
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Vitamin D Supplementation Does Not Affect Metabolic Changes Seen With ART Initiation.
Muhammad, J, Chan, ES, Brown, TT, Tebas, P, McComsey, GA, Melbourne, K, Hardin, R, Willig, AL, Yin, MT, Ribaudo, H, et al
Open forum infectious diseases. 2017;(4):ofx210
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BACKGROUND Insulin resistance and lipid changes are common after antiretroviral therapy (ART) initiation. Observational studies suggest that vitamin D supplementation reduces the risk of developing diabetes and improves lipid profiles. METHODS This 48-week prospective, randomized, double-blind, placebo-controlled study evaluated high-dose vitamin D3 (4000 IU daily) plus calcium supplementation (1000 mg calcium carbonate daily) in HIV-infected participants initiating ART with efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). Changes in insulin resistance (as estimated by homeostatic model assessment), fasting lipid profile, and components of the metabolic syndrome were assessed at baseline, 24 weeks, and 48 weeks. Stratified Wilcoxon rank sum tests and stratified normal score tests were used to evaluate differences between treatment arms, stratified by screening 25-OH vitamin D stratum (≤/>20 ng/mL). RESULTS A total of 165 participants enrolled: 79 in the vitamin D/calcium (Vit D/Cal) arm and 86 in the placebo arm. Only the placebo arm experienced a modest increase in insulin resistance at week 24 (P < .001). While increases in total and high-density lipoprotein cholesterol were significant in both arms at weeks 24 and 48, increases in low-density lipoprotein cholesterol at week 24 were only identified in the placebo arm (P = .011). Body mass index remained stable, whereas modest increases in waist circumference were observed in the placebo arm. Metabolic syndrome was present in 19 participants (12%) at baseline and 20 participants (14%) at week 48, without differences between arms. CONCLUSIONS Vit D/Cal supplementation over 48 weeks did not alter the lipid profile or glucose metabolism experienced with initiation of EFV/FTC/TDF in ART-naïve persons. Vitamin D supplementation is unlikely to be an effective strategy to attenuate metabolic dysregulations with ART initiation.
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Efavirenz is associated with higher bone mass in South African children with HIV.
Arpadi, SM, Shiau, S, Strehlau, R, Patel, F, Mbete, N, McMahon, DJ, Kaufman, JJ, Coovadia, A, Kuhn, L, Yin, MT
AIDS (London, England). 2016;(16):2459-2467
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BACKGROUND We investigate if switching from a ritonavir-boosted lopinavir (LPV/r)-based to an efavirenz-based antiretroviral therapy (ART) regimen is associated with beneficial bone development. METHODS The CHANGES Bone Study follows HIV-infected children who participated in a noninferiority randomized trial in Johannesburg, South Africa evaluating the safety and efficacy of preemptive switching to efavirenz (n = 106) compared with remaining on LPV/r (n = 113). HIV-uninfected children were also recruited. Whole-body and lumbar spine bone mineral content (BMC) were assessed by dual-energy X-ray absorptiometry at a cross-sectional visit. BMC Z-scores adjusted for sex, age, and height were generated. Physical activity and dietary intake were assessed. CD4 percentage and viral load were measured. We compared bone indices of HIV-infected with HIV-uninfected children and LPV/r with efavirenz by intent-to-treat. RESULTS The 219 HIV-infected (52% boys) and 219 HIV-uninfected (55% boys) children were 6.4 and 7.0 years of age, respectively. Mean ART duration for HIV-infected children was 5.7 years. Whole-body BMC Z-score was 0.17 lower for HIV-infected children compared with HIV-uninfected children after adjustment for physical activity, dietary vitamin D and calcium (P = 0.03). Whole-body BMC Z-score was 0.55 higher for HIV-infected children switched to efavirenz compared with those remaining on LPV/r after adjustment for physical activity, dietary vitamin D and calcium, CD4 percentage, and viral load (P < 0.0001). CONCLUSION South African HIV-infected children receiving ART have lower bone mass compared with HIV-uninfected controls. Accrued bone mass is positively associated with switching to efavirenz-based ART compared with remaining on LPV/r, providing additional rationale for limiting LPV/r exposure once viral suppression has been achieved.
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Longitudinal increase in vitamin D binding protein levels after initiation of tenofovir/lamivudine/efavirenz among individuals with HIV.
Hsieh, E, Fraenkel, L, Han, Y, Xia, W, Insogna, KL, Yin, MT, Zhu, T, Cheng, X, Li, T
AIDS (London, England). 2016;(12):1935-42
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OBJECTIVE To examine longitudinal change in vitamin D binding protein (DBP) levels during the first year after initiation of tenofovir disoproxil fumarate (TDF)/lamivudine/efavirenz and compare these findings with concurrent changes in markers of skeletal metabolism. DESIGN Secondary analysis of plasma samples collected from an ongoing multicenter clinical trial. METHODS Plasma samples collected at 0, 24, and 48 weeks after initiation of TDF + lamivudine + efavirenz from 134 adult participants enrolled in a multicenter randomized trial were analyzed. Data regarding sociodemographic and clinical characteristics were obtained as part of the parent study. Laboratory analyses included plasma DBP, intact parathyroid hormone, total 25-hydroxy vitamin D, phosphorus, the bone resorption marker collagen type 1 cross-linked C-telopeptide, and the bone formation marker total procollagen type 1 N-terminal propeptide. Repeated measures analysis of variance was used to measure changes in biomarkers over time. RESULTS Our sample included 108 men and 26 women (mean age 33.6 ± 9.6 years). Median levels of DBP increased significantly from baseline to 48 weeks [154 (91.8-257.4) versus 198.3 (119.6-351.9) μg/ml, P < 0.001]. A concurrent rise in intact parathyroid hormone levels was observed over the same period [32.3 (24.4-40.9) versus 45.2 (35.1-60.4) pg/ml, P < 0.001]; however, 25-hydroxy vitamin D and phosphorus levels remained stable. Bone resorption and formation markers rapidly increased from 0 to 24 weeks, followed by a slight decline or plateau, but remained significantly elevated at 48 weeks (P < 0.001). CONCLUSION Our study provides longitudinal data supporting a potential role for DBP in bone loss associated with TDF-based therapy. Further research to elucidate the mechanistic pathways and clinical impact of these findings is warranted.