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Title:   Author  item
                                            HAVENS, PETER - Medical College Of Wisconsinitem
                                            KISER, JENNIFER - University Of Coloradoitem
                                            Stephensen, Charlesitem
                                            HAZRA, ROHAN - National Institutes Of Health (NIH)item
                                            FLYNN, PATRICIA - St Jude Children’s Research Hospitalitem
                                            WILSON, CRAIG - University Of Alabamaitem
                                            RUTLEDGE, BRANDY - Westat Incitem
                                            BETHEL, JAMES - Westat Incitem
                                            PAN, CYNTHIA - Medical College Of Wisconsinitem
                                            Woodhouse, Leslieitem
                                            Van Loan, Martaitem
                                            LIU, NANCY - Westat Incitem
                                            LUJAN-ZILBERMANN, JORGE - University Of South Floridaitem
                                            BAKER, ALYNE - Tulane Universityitem
                                            KAPOGIANNIS, BILL - National Institutes Of Health (NIH)item
                                            GORDON, CATHERINE - Rhode Island Hospitalitem
                                            MULLIGAN, KATHLEEN - University Of California
  Submitted to: Antimicrobial Agents and Chemotherapy
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 8/24/2013
                                    Publication  Date: 11/1/2013
                                    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


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