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United States Department of Agriculture

Agricultural Research Service

Research Project: Dietary Modulation of Immune Function and Oxidative Stress

Location: Immunity and Disease Prevention Research Unit

Title: Higher plasma vitamin D binding protein and lower free calcitriol with tenofovir treatment: Cause of a functional vitamin D deficiency?

Authors
item Havens, Peter -
item Kiser, Jennifer -
item Stephensen, Charles
item Hazra, Rohan -
item Flynn, Patricia -
item Wilson, Craig -
item Rutledge, Brandy -
item Bethel, James -
item Pan, Cynthia -
item Woodhouse, Leslie
item Van Loan, Marta
item Liu, Nancy -
item Lujan-Zilbermann, Jorge -
item Baker, Alyne -
item Kapogiannis, Bill -
item Gordon, Catherine -
item Mulligan, Kathleen -

Submitted to: Antimicrobial Agents and Chemotherapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 24, 2013
Publication Date: November 1, 2013
Citation: Havens, P.L., Kiser, J.J., Stephensen, C.B., Hazra, R., Flynn, P.M., Wilson, C.M., Rutledge, B., Bethel, J., Pan, C.G., Woodhouse, L.R., Van Loan, M.D., Liu, N., Lujan-Zilbermann, J., Baker, A., Kapogiannis, B.G., Gordon, C., Mulligan, K. 2013. Higher plasma vitamin D binding protein and lower free calcitriol with tenofovir treatment: Cause of a functional vitamin D deficiency. Antimicrobial Agents and Chemotherapy. 57:619-28.

Interpretive Summary: People with inflammatory conditions, including HIV infection, may be at risk for loss of bone mineral density due to effects on calcium and phosphate absorption and metabolism. In HIV infection, anti-HIV drug treatments may also affect bone mineral density by independent pathways. One such drug is Tenofovir disoproxil fumarate (TDF). It causes bone, endocrine and renal changes, by mechanisms that may include alterations of vitamin D-mediated regulation of calcium balance, and hence bone density. Using baseline data from a multicenter study in HIV-infected youth on stable treatment including (N=118) or not including TDF (N=85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23), and bone turnover markers. Pharmacokinetic-pharmacodynamic associations with plasma TFV and intracellular TDF were also explored. The study concluded that higher plasma TDF concentrations were associated with lower free 1,25-dihydroxy vitamin D concentrations (the active metabolite of vitamin D), suggesting a functional vitamin D deficiency which appeared to cause an increase in parathyroid hormone levels in subjects with normal vitamin D status (for healthy adults). In addition, TDF-associated changes in fibroblast growth factor-23 levels might explain differences seen in phosphate handling. These data suggest that TDF treatment alters two different pathways that could affect bone mineral density.

Technical Abstract: Background: Tenofovir disoproxil fumarate (TDF) causes bone, endocrine and renal changes, by unknown mechanism(s). There are limited data on tenofovir (TFV) pharmacokinetics and these effects. Methods: Using baseline data from a multicenter study in HIV-infected youth on stable treatment with cART containing TDF (N=118) or not containing TDF (noTDF; N=85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium- parathyroid hormone (PTH) balance, phosphate metabolism (tubular reabsorption of phosphate (TRP) and fibroblast growth factor 23 (FGF23) , and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma TFV and intracellular tenofovir diphosphate (TFV-DP) concentrations among those on TDF were explored. Results: Mean age was 20.9 (S.D. 2.0) years; 63% were male; and 52% were African American. Compared to the noTDF group, those in the TDF group showed lower mean estimated glomerular filtration rate, lower TRP, higher PTH, and higher 1,25-OH(2) vitamin D (1,25-OHD). The highest quintile of plasma TFV concentrations was associated with higher vitamin D binding protein (VDBP), lower free 1,25-OHD, higher 25-OH vitamin D and higher serum calcium. The highest quintile of intracellular TFV-DP concentration was associated with lower FGF23. Conclusion: Higher plasma TFV concentrations were associated with higher VDBP and lower free 1,25-OHD, suggesting a functional vitamin D deficiency resulting in increased PTH. Finding lower FGF-23 with higher intracellular TFV-DP suggests a different mechanism might explain TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: TFV with PTH and altered calcium balance, and TFV-DP with hypophosphatemia and FGF23 regulation. The clinical trials registration number for this study is NCT00490412, available online at http://clinicaltrials.gov/ct2/show/NCT00490412

Last Modified: 10/25/2014
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