Vitamin D3 supplementation increases fibroblast growth factor-23 in HIV-infected youths treated with tenofovir disoproxil fumarate

Abstract

Background: Tenofovir (TDF) is associated with phosphaturia and elevated 1,25 dihydroxy vitamin D (1,25-OH(2)D). Fibroblast growth factor 23 (FGF23) causes phosphaturia and increases in response to elevated 1,25-OH(2)D. Vitamin D-binding protein (VDBP) binds to 1,25-OH(2)D, decreasing its biological activity, and is elevated in individuals with higher plasma tenofovir concentrations. We compared FGF23 and VDBP before and after vitamin D3 (VITD) supplementation in youths treated with combination antiretroviral therapy (cART) containing or not containing TDF.

Methods: A randomized controlled trial in HIV-positive youths aged 18-25 years enrolled participants based on cART treatment with TDF (TDF; n=118) or without TDF (no-TDF; n=85), and randomized within those groups to VITD (50,000 IU every 4 weeks) or placebo (PL). We measured FGF23 and VDBP and calculated free 1,25-OH(2)D at baseline and week 12, and compared changes by TDF treatment and VITD randomized group.

Results: At baseline, serum FGF23 concentration showed a quadratic relationship with 1,25-OH(2)D most pronounced in the TDF group. At week 12, total and free 1,25-OH(2)D increased in the VITD but not PL groups, independent of TDF use. FGF23 increased in the TDF group receiving VITD, but there was no FGF23 change in the no-TDF group receiving VITD or the PL groups. The adjusted mean change in FGF23 from baseline to week 12 was 7.7 pg/ml in the TDF/VITD group, compared with -1.7 (no-TDF/VITD, P=0.010), -1.3 (TDF/PL, P=0.006) and 1.1 (no-TDF/PL, P=0.035).

Conclusions: These results suggest that TDF-containing cART may alter the FGF23 response to vitamin D supplementation in HIV-infected youths. Clinical trials number: NCT00490412.

Conflict of interest statement

None of the authors has a significant conflict of interest to report.

Figures

Figure 1. Baseline FGF23 shows a quadratic relationship with baseline total 1,25-OH(2)D, more pronounced in the TDF than the no-TDF group

a. No tenofovir disoproxil fumarate in cART (No-TDF Group): Regression Equation: 57.716 + [(−0.2583) * Baseline 1,25-OH(2)D(pmol/L)] + [(0.0009) * Baseline 1,25-OH(2)D (pmol/L) * Baseline 1,25-OH(2)D (pmol/L)] P value = 0.053 Critical point = 143.50 pmol/L b. Tenofovir disoproxil fumarate in cART (TDF Group): Regression Equation: 57.547 + [(−0.2733) * Baseline 1,25-OH(2)D (pmol/L)] + [(0.0010) * Baseline 1,25-OH(2)D (pmol/L)] * Baseline 1,25-OH(2)D (pmol/L) P value = 0.004 Critical point = 136.65 pmol/L The nonparametric Loess smoothed curve confirms the presence of a quadratic relationship.

Figure 2. Serum FGF23 concentration at baseline, and change in FGF23 from baseline to week 12, by baseline vitamin D status and tenofovir disoproxil fumarate use

Panel A. Median Fibroblast Growth Factor 23 (FGF23) serum concentrations at baseline for all study participants, by presence of tenofovir disoproxil fumarate (TDF; black bars) or absence (no-TDF; grey bars) in combination antiretroviral (cART) regimen; and by baseline vitamin D nutritional status of serum 25-OHD =20 ng/mL. P values for comparison between TDF and no-TDF groups. Panel B. Median FGF23 change from baseline to week 12 for those participants randomized to receive vitamin D supplementation. P values are for statistical significance of the change from baseline to week 12, Wilcoxon signed rank test. There were no statistically significant changes in the no-TDF group randomized to vitamin D, or in either group (TDF or no-TDF) randomized to placebo. It is the interaction of TDF and vitamin D supplementation that is associated with increased FGF23 (see text).