Vitamin D₃ Supplementation in Batswana Children and Adults with HIV: A Pilot Double Blind Randomized Controlled Trial

<div><p>Objectives</p><p>Since vitamin D insufficiency is common worldwide in people with HIV, we explored safety and efficacy of high dose cholecalciferol (D₃) in Botswana, and evaluated potential modifiers of serum 25 hydroxy vitamin D change (Δ25D).</p><p>Design</p><p>Prospective randomized double-blind 12-week pilot trial of subjects ages 5.0–50.9 years.</p><p>Methods</p><p>Sixty subjects randomized within five age groups to either 4000 or 7000IU per day of D₃ and evaluated for vitamin D, parathyroid hormone, HIV, safety and growth status. Efficacy was defined as serum 25 hydroxy vitamin D (25D) ≥32ng/mL, and safety as no simultaneous elevation of serum calcium and 25D. Also assessed were HIV plasma viral RNA viral load (VL), CD4%, anti-retroviral therapy (ART) regime, and height-adjusted (HAZ), weight-adjusted (WAZ) and Body Mass Index (BMIZ) Z scores.</p><p>Results</p><p>Subjects were 50% male, age (mean±SD) 19.5±11.8 years, CD4% 31.8±10.4, with baseline VL log₁₀ range of <1.4 to 3.8 and VL detectable (>1.4) in 22%. From baseline to 12 weeks, 25D increased from 36±9ng/ml to 56±18ng/ml (p<0.0001) and 68% and 90% had 25D ≥32ng/ml, respectively (p = 0.02). Δ25D was similar by dose. No subjects had simultaneously increased serum calcium and 25D. WAZ and BMIZ improved by 12 weeks (p<0.04). HAZ and CD4% increased and VL decreased in the 7000IU/d group (p<0.04). Younger (5–13y) and older (30–50y) subjects had greater Δ25D than those 14–29y (26±17 and 28±12 vs. 11±11ng/ml, respectively, p≤0.001). Δ25D was higher with efavirenz or nevirapine compared to protease inhibitor based treatment (22±12, 27±17, vs. 13±10, respectively, p≤0.03).</p><p>Conclusions</p><p>In a pilot study in Botswana, 12-week high dose D₃ supplementation was safe and improved vitamin D, growth and HIV status; age and ART regimen were significant effect modifiers.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT02189902" target="_blank">NCT02189902</a></p></div

Clinical and laboratory values for subjects over time by D₃ dose group.

<p>*Significantly different from baseline within the dose group at p<0.05 (LME model adjusted for age, sex and baseline value)</p><p>**p≤0.01</p><p>***p<0.001</p><p>^a n = 49, Bioavailable 25(OH)D and DBP at baseline (24 at 4000 and 25 at 7000IU/d D₃) and n = 51 12 weeks visit (26 at 4000 and 25 at 7000IU/d D₃)</p><p>^b n = 56, CD4 baseline and 12 weeks visit (27 at 4000 and 29 at 7000IU/d D₃)</p><p>^c n = 41, RNA viral load analysis baseline and 12-week visit (20 at 4000 and 21 at 7000IU/d vit D₃)—as these 41 subjects had VL run at the same laboratory both times—baseline and 12 weeks</p><p>^d n = 40 subjects <20y with calculated Z scores for body size variables (20 in 4000 and 20 in 7000IU/d group). HIV, human immunodeficiency virus; BMI, body mass index</p><p>CD4, cluster of differentiation; PTH, parathyroid hormone; DBP, vitamin D binding protein.</p><p>Clinical and laboratory values for subjects over time by D₃ dose group.</p

Characteristics of Subjects at Baseline by D₃ Dose Group.

<p>*Dose groups significantly different p<0.05</p><p>^a n = 59, one subject had unknown HIV acquisition</p><p>^b n = 40 for subjects <20y with calculated Z scores for body size variables (20 in 4000 and 20 in 7000IU/d group) n = 20 for subject ≥20y (10 in 4000 and 10 in 7000IU/d group)</p><p>^c n = 54 subjects with date of diagnosis for HIV (28 in 4000 and 26 in 7000IU/d group)</p><p>^d n = 59 subjects with date of initiation of ART treatment (30 in 4000 and 29 in 7000IU/d group)</p><p>^e n = 56 subjects with HIV CDC classification data and CD4 counts from medical record review (27 in 4000 and 29 in 7000IU/d group)</p><p>^f n = 59 with CD4% baseline (29 in 4000 and 30 in 7000IU/d group)</p><p>^g n = 53 RNA viral load at baseline (26 in 4000 and 27 in 7000IU/d group)</p><p>^h Tenofovir was used only in combination with NNRTI-based regimens.</p><p>HIV, human immunodeficiency virus; BMI, body mass index; CDC, Center for Disease Control; Clinical categories: N = asymptomatic, A = mildly symptomatic, B = moderately symptomatic, and C = severely symptomatic with AIDS defining illness; CD4 cluster of differentiation; PI, protease inhibitor-based anti-retroviral treatment (ART); NNRTI, non-nucleoside reverse transcriptase-based ART.</p><p>Characteristics of Subjects at Baseline by D₃ Dose Group.</p

Serum 25D Before and After High Dose D₃ Supplementation.

<p><b>A</b>. By Dose group (4000 IU/d or 7000IU/d). * Change in 25D significantly different from baseline at both 6 and 12 weeks, p<0.01. <b>B</b>. By age group. ¥ Change in 25D significantly less in subjects ages 14–29 y than those ages 4–13 y and 30–50 y age groups, p<0.004. <b>C</b>. By anti-retroviral therapy (ART) regime. ¥ Change in 25D significantly greater in Efavirenz and Nevirapine groups than in PI (protease inhibitor) or tenofovir groups, p<0.03</p

Novel and previously identified BMI and WHR_adjBMI loci at <i>P</i> < 5×10⁻⁸ in African ancestry discovery and replication samples, and European ancestry replication samples.

<p>Novel and previously identified BMI and WHR_adjBMI loci at <i>P</i> < 5×10⁻⁸ in African ancestry discovery and replication samples, and European ancestry replication samples.</p

Additional novel BMI and WHR_adjBMI loci at <i>P</i> < 5×10⁻⁸ in sex-stratified analyses of African ancestry discovery and replication samples.

<p>Additional novel BMI and WHR_adjBMI loci at <i>P</i> < 5×10⁻⁸ in sex-stratified analyses of African ancestry discovery and replication samples.</p