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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Immunity and Disease Prevention Research » Research » Publications at this Location » Publication #331463

Research Project: Assessing the Impact of Diet on Inflammation in Healthy and Obese Adults in a Cross-Sectional Phenotyping Study and a Longitudinal Intervention Trial

Location: Immunity and Disease Prevention Research

Title: Decline in bone mass with tenofovir disoproxil fumarate/emtricitabine is associated with hormonal changes in the absence of renal impairment when used by HIV uninfected adolescent boys and young men for HIV pre-exposure

Author
item Havens, Peter - Medical College Of Wisconsin
item Stephensen, Charles
item Van Loan, Marta
item Schuster, Gertrud - University Of California
item Woodhouse, Leslie
item Flynn, Patricia - St Jude Children’s Research Hospital
item Gordon, Catherine - University Of Cincinnati
item Pan, Cynthia - Medical College Of Wisconsin
item Rutledge, Brandy - Westat Inc
item Liu, Nancy - Westat Inc
item Wilson, Craig - University Of Alabama
item Hazra, Rohan - Bethesda Health Research
item Hosek, Sybil - John H Stroger, Jr Hospital Of Cook County
item Anderson, Peter - University Of Colorado
item Seifert, Sharon - University Of Colorado
item Kapogiannis, Bill - Bethesda Health Research
item Mulligan, Kathleen - University Of San Francisco

Submitted to: Clinical Infectious Diseases
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/24/2016
Publication Date: 12/24/2016
Citation: Havens, P.L., Stephensen, C.B., Van Loan, M.D., Schuster, G., Woodhouse, L.R., Flynn, P.M., Gordon, C.M., Pan, C.G., Rutledge, B., Liu, N., Wilson, C.M., Hazra, R., Hosek, S.G., Anderson, P.L., Seifert, S.M., Kapogiannis, B.G., Mulligan, K. 2016. Decline in bone mass with tenofovir disoproxil fumarate/emtricitabine is associated with hormonal changes in the absence of renal impairment when used by HIV uninfected adolescent boys and young men for HIV pre-exposure. Clinical Infectious Diseases. 64/317-325.

Interpretive Summary: The antiretroviral drug tenofovir disoproxil fumarate (TDF) is used to treat HIV infection. Recently studies have shown that when TDF is taken by HIV-negative individuals it can prevent infection as well. However, this drug has adverse effects on bone health, decreasing bone mineral density. In the present study, we aimed to define the relative importance of renal and endocrine changes when HIV-negative men at risk of infection started taking TDF in a controlled intervention trial. We measured changes in blood and urine markers of the nutritional (vitamin D), endocrine (parathyroid hormone [PTH] and fibroblast growth factor 23 [FGF23]), and kidney function pathways (serum creatinine and renal tubular reabsorption of phosphate [TRP]) affecting bone health. We explored the relationship of these variables to changes in bone mineral density (BMD) using TDF levels in red blood cells to categorize participants into high and low drug exposure groups. The study involved 101 men 15 to 22 years of age monitored for 48 weeks. Half (52%) were African American. Those with high TDF levels had increased PTH and decreased FGF23 by study week 4, with no differences in serum creatinine or phosphate or TRP. At 48 weeks, those with high TDF levels had significantly lower hip bone mineral density (by 3.3%) than did those with low TDF levels. Among the nutritional, endocrine and kidney function variables, only FGF23 showed a significant association with this loss in bone mineral density. These results suggest that this endocrine pathway (FGF23-PTH), which regulates calcium and phosphate absorption and excretion, is negatively affected by TDF use and is a likely cause of loss of bone mineral density in these study volunteers. Interventions to prevent or minimize this effect should be explored.

Technical Abstract: Background. We aimed to define the relative importance of renal and endocrine changes in tenofovir disoproxil fumarate (TDF)-related bone toxicity. Methods. In a study of daily TDF/emtricitabine (FTC) pre-exposure prophylaxis (PrEP) in HIV uninfected young men who have sex with men, we measured changes from baseline in blood and urine markers of the parathyroid hormone (PTH)-vitamin D-fibroblast growth factor 23 (FGF23) axis; serum creatinine; and renal tubular reabsorption of phosphate (TRP). We explored the relationship of those variables to changes in bone mineral density (BMD). Tenofovir-diphosphate (TFV-DP) in red blood cells was used to categorize participants into high and low drug exposure groups (HiExp and LoExp, respectively). Results. The sample included 101 participants, mean (SD) age 19.6 (1.8), range 15 to 22 years; 52 (51.5%) were African American. Compared to LoExp, participants with HiExp showed an increase in PTH from baseline and decline in FGF23 by study week 4, with no differences in serum creatinine or phosphate or TRP. At 48 weeks, the median (IQR) percent decline in total hip BMD was greater in those with HiExp compared to LoExp (-1.59 (2.77) vs +1.54 (3.34)%, respectively; p=0.001), and in the HiExp group, correlated with week 4 TFV-DP (inversely; r = -0.60, p=0.002) and FGF23 (directly; r = 0.42; p = 0.039), but not with other variables. Conclusions. These findings support the short-term renal safety of TDF/FTC PrEP in HIV-seronegative young men, and suggest that endocrine disruption (PTH-FGF23) is a primary contributor to TDF-associated BMD decline in this age group.