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 Preexposure Prophylaxis

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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. Clinical Trials Registration: NCT01769469

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