Effects of Emtricitabine/Tenofovir on Bone Mineral Density in HIV-Negative Persons in a Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Background: Daily preexposure prophylaxis (PrEP) with oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) decreases the risk of human immunodeficiency virus (HIV) acquisition. Initiation of TDF decreases bone mineral density (BMD) in HIV-infected people. We report the effect of FTC/TDF on BMD in HIV-seronegative men who have sex with men and in transgender women.

Methods: Dual-energy X-ray absorptiometry was performed at baseline and 24-week intervals in a substudy of iPrEx, a randomized, double-blind, placebo-controlled trial of FTC/TDF PrEP. Plasma and intracellular tenofovir concentrations were measured in participants randomized to FTC/TDF.

Results: In 498 participants (247 FTC/TDF, 251 placebo), BMD in those randomized to FTC/TDF decreased modestly but statistically significantly by 24 weeks in the spine (net difference, -0.91% [95% confidence interval {CI}, -1.44% to -.38%]; P = .001) and hip (-0.61% [95% CI, -.96% to -.27%], P = .001). Changes within each subsequent 24-week interval were not statistically significant. Changes in BMD by week 24 correlated inversely with intracellular tenofovir diphosphate (TFV-DP), which was detected in 53% of those randomized to FTC/TDF. Net BMD loss by week 24 in participants with TFV-DP levels indicative of consistent dosing averaged -1.42% ± 29% and -0.85% ± 19% in the spine and hip, respectively (P < .001 vs placebo). Spine BMD tended to rebound following discontinuation of FTC/TDF. There were no differences in fractures (P = .62) or incidence of low BMD.

Conclusions: In HIV-uninfected persons, FTC/TDF PrEP was associated with small but statistically significant decreases in BMD by week 24 that inversely correlated with TFV-DP, with more stable BMD thereafter.

Clinical trials registration: NCT00458393.

Keywords: DXA; PrEP; bone; emtricitabine; tenofovir.

© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Changes from baseline in bone mineral density (BMD) during randomized treatment. Intent-to-treat results are presented as mean ± standard error percentage changes from baseline in BMD in the lumbar spine (A1) and total hip (A2) and net treatment differences (B1 and B2), calculated as percentage of change in the emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) group minus percentage of change in the placebo group, with error bars representing the 95% confidence interval. See “Results” section for data at each time-point.

Figure 2.

Association of changes in bone mineral density (BMD) at week 24 with intracellular tenofovir diphosphate (TFV-DP) levels measured at week 24. Among participants randomized to emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) who had detectable TFV-DP levels, there was a significant inverse association across the full range of TFV-DP concentrations measured in both the spine and hip (A and B, respectively; P = .01 in both) using cubic spline to model the mean change in BMD by TFV-DP level. The figures display the 95% confidence interval and mean values for participants randomized to placebo (black symbols: spine, 0.34% ± 0.19%; hip, 0.30% ± 0.12%) and those randomized to FTC/TDF with TFV-DP below the limit of quantitation (BLQ; blue symbols: spine, −0.03% ± 0.30%; hip, −0.08% ± 0.19%).

Figure 3.

Changes from baseline in bone mineral density (BMD) through week 72 during randomized treatment, based on detection of drug in plasma at each time-point. In plasma, tenofovir (TFV) or emtricitabine (FTC) was detected in 57%, 48%, and 53% of those randomized to FTC/tenofovir disoproxil fumarate (TDF) at weeks 24, 48, and 72, respectively. Decreases in BMD in the spine (A) and hip (B) were statistically significant vs placebo in the groups with detectable drug levels at each time-point (for drug detection vs placebo: ***P < .001; **P < .01; *P < .05).