Bone Mineral Density Changes among HIV-Uninfected Young Adults in a Randomised Trial of Pre-Exposure Prophylaxis with Tenofovir-Emtricitabine or Placebo in Botswana

<div><p>Background</p><p>Tenofovir-emtricitabine (TDF-FTC) pre-exposure prophylaxis (PrEP) has been found to be effective for prevention of HIV infection in several clinical trials. Two studies of TDF PrEP among men who have sex with men showed slight bone mineral density (BMD) loss. We investigated the effect of TDF and the interaction of TDF and hormonal contraception on BMD among HIV-uninfected African men and women.</p><p>Method</p><p>We evaluated the effects on BMD of using daily oral TDF-FTC compared to placebo among heterosexual men and women aged 18–29 years enrolled in the Botswana TDF2 PrEP study. Participants had BMD measurements at baseline and thereafter at 6-month intervals with dual-energy X-ray absorptiometry (DXA) scans at the hip, spine, and forearm.</p><p>Results</p><p>A total of 220 participants (108 TDF-FTC, 112 placebo) had baseline DXA BMD measurements at three anatomic sites. Fifteen (6.8%) participants had low baseline BMD (z-score of <−2.0 at any anatomic site), including 3/114 women (2.6%) and 12/106 men (11.3%) (p = 0.02). Low baseline BMD was associated with being underweight (p = 0.02), having high blood urea nitrogen (p = 0.02) or high alkaline phosphatase (p = 0.03), and low creatinine clearance (p = 0.04). BMD losses of >3.0% at any anatomic site at any time after baseline were significantly greater for the TDF-FTC treatment group [34/68 (50.0%) TDF-FTC vs. 26/79 (32.9%) placebo; p = 0.04]. There was a small but significant difference in the mean percent change in BMD from baseline for TDF-FTC versus placebo at all three sites at month 30 [forearm −0.84% (p = 0.01), spine −1.62% (p = 0.0002), hip −1.51% (p = 0.003)].</p><p>Conclusion</p><p>Use of TDF-FTC was associated with a small but statistically significant decrease in BMD at the forearm, hip and lumbar spine. A high percentage (6.8%) of healthy Batswana young adults had abnormal baseline BMD Further evaluation is needed of the longer-term use of TDF in HIV-uninfected persons.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT00448669?term=NCT00448669&rank=1" target="_blank">NCT00448669</a></p></div

The comparison of calculated population biochemical reference values for participants screened (N = 1786; Females = 770 and Males = 1016) for the TDF2 Botswana study with DAIDS and BOTUSA site established ranges.

<p>The comparison of calculated population biochemical reference values for participants screened (N = 1786; Females = 770 and Males = 1016) for the TDF2 Botswana study with DAIDS and BOTUSA site established ranges.</p

Baseline characteristics of TDF2 DXA sub study participants who had at least one DXA bone mineral density scan at forearm, spine and hip: Botswana, 2007–2010.

a<p>These are the 74 participants that only had a baseline DXA scan.</p>b<p>These are the 147 participants that had at least one follow-up DXA scan (Longitudinal cohort).</p

Comparison of the calculated Botswana TDF2 screened cohort reference intervals with the reference intervals used in Botswana and other African countries.

<p>*Botswana Ministry of health Patient management system Roche Integra derived values.</p><p>**Botswana Ministry of health reference values using the Beckman coulter AU680 analyzer.</p

The TDF2 Botswana PrEp lab reference values Consort diagram.

<p>The TDF2 Botswana PrEp lab reference values Consort diagram.</p

The calculated population biochemical reference values for participants screened (N = 1786; Females = 770 and Males = 1016) for the TDF2 Botswana study.

<p>Note:</p><p>*P-value is for the Wilcoxon rank-sum test for Females versus Males.</p

Mean percent bone mineral density (BMD) change (with 95% confidence intervals) from baseline to subsequent months by treatment group (TDF-FTC versus placebo).

<p>Mean percent bone mineral density (BMD) change (with 95% confidence intervals) from baseline to subsequent months by treatment group (TDF-FTC versus placebo).</p

Kaplan-Meier estimates of time (28 day months) from date HIV was detected using nucleic acid amplification until the mid-point date between the last non-reactive and first reactive oral fluid HIV test.

<p>(A) By study drug group: tenofovir or placebo. (B) Controlling for study drug group, by HIV subtype: CRF01_AE or other subtypes.</p

HIV test results of participants in the Bangkok Tenofovir Study, 2005–2012.

<p>OraQuick, OraQuick Rapid HIV-1/2 Antibody Test; EIA, enzyme immune assay; NAAT, nucleic-acid amplification test. ^aTwo participants with reactive OraQuick tests during follow-up were later found to have been HIV-infected before enrollment. ^bPlasma collected at 3-monthly visits from participants with a non-reactive OraQuick test result was tested for HIV using EIA.</p