Brief Report: Recovery of Bone Mineral Density After Discontinuation of Tenofovir-Based HIV Pre-exposure Prophylaxis

Abstract

Background: Oral tenofovir disoproxil fumarate (TDF) for HIV prevention and treatment is associated with decreases in bone mineral density (BMD). Previous reports suggest that these changes may be reversible after discontinuation of TDF.

Setting: A metabolic substudy of 498 participants in a randomized, placebo-controlled HIV prevention trial of oral coformulated TDF with emtricitabine (TDF/FTC, Truvada) for HIV pre-exposure prophylaxis (PrEP) enrolling a global sample of men who have sex with men and trans women.

Methods: Participants underwent dual X-ray absorptiometry to quantify bone mineral density (BMD) in the hip and spine during PrEP and at 2 visits after stopping (median of 23 and 79 weeks post-PrEP, respectively). Results are stratified by pharmacologic measure of TDF/FTC adherence.

Results: There was no significant difference in change in hip/spine BMD at any time point between placebo and those with low adherence. Adherent participants had a mean (standard error) BMD change at TDF/FTC discontinuation of -1.02% (0.24) in the hip and -1.84% (0.36) in the spine. After stop, annualized BMD increases of 1.13% per year (0.27) in hip and 1.81% per year (0.36) in spine BMD were observed in adherent participants compared with 0.19% (0.16) and 0.74% (0.21) in the placebo group, respectively (P = 0.003, both comparisons). On average, BMD returned to baseline levels by 1 year after PrEP stop. Recovery was consistent across age, baseline BMD z-score, and treatment duration.

Conclusions: Mean BMD returns to baseline levels within 12-18 months after TDF-based PrEP discontinuation in both hip and spine with consistency across participant subgroups.

Clinical trials registration: clinicaltrials.gov NCT00458393.

Conflict of interest statement

Conflicts of interest: The iPrEx studies were sponsored by the US National Institutes of Health with co-funding from the Bill and Melinda Gates Foundation; study medication was donated by Gilead Sciences, which also supported travel expenses for non-US investigators to attend study meetings. RMG and DVG have received fees from and RMG has received a research grant from ViiV, a manufacturer of an investigational compound being investigated for use as PrEP. PLA receives study drug and contract work from Gilead Sciences. All other authors have no conflicts to declare.

Figures

Figure 1

Percentage Change in Total Hip Bone Mineral Density (BMD) from Baseline Value by Randomized Treatment and Stratified by Level of Intracellular Tenofovir Diphosphate (TFV-DP) in fmol per Million Viable Cells at Week 24 of Randomized Trial. Bars Indicate One Standard Error. X-axis (Panels a–h): Time Since iPrEx Randomization Y-axis (Panels a–h): Percent Change in Total Hip BMD Panel Headings

1. All Participants – Available Scans

2. All Participants – Results of Multiple Imputation

3. Participants Aged < 25 years at iPrEx Entry

4. Participants Aged ≥ 25 years at iPrEx Entry

5. Baseline Hip Z-score < −1 at iPrEx Entry

6. Baseline Hip Z-score ≥ 1 at iPrEx Entry

7. Duration Randomized Treatment ≥ 1 Year

8. Duration Randomized Treatment < 1 Year

Black Line: Randomized to Placebo Red Line: Randomized to TDF/FTC with TFV-DP ≥ 16 at week 24 Blue Line: Randomized TDF/FTC with TFV-DP

Figure 2

Percentage Change in L1–L4 Spine Bone Mineral Density (BMD) from Baseline Value by Randomized Treatment and Stratified by Level of Intracellular Tenofovir Diphosphate (TFV-DP) in fmol per Million Viable Cells at Week 24 of Randomized Trial. Bars Indicate One Standard Error. X-axis (Panels a–h): Time Since iPrEx Randomization Y-axis (Panels a–h): Percent Change in L1–L4 Spine BMD Panel Headings

1. All Participants – Available Scans

2. All Participants – Results of Multiple Imputation

3. Participants Aged < 25 years at iPrEx Entry

4. Participants Aged ≥ 25 years at iPrEx Entry

5. Baseline Spine Z-score < −1 at iPrEx Entry

6. Baseline Spine Z-score ≥ 1 at iPrEx Entry

7. Duration Randomized Treatment ≥ 1 Year

8. Duration Randomized Treatment < 1 Year

Black Line: Randomized to Placebo Red Line: Randomized to TDF/FTC with TFV-DP ≥ 16 at week 24 Blue Line: Randomized TDF/FTC with TFV-DP