Normal laboratory reference intervals among healthy adults screened for a HIV pre-exposure prophylaxis clinical trial in Botswana.

Accurate clinical laboratory reference values derived from a local or regional population base are required to correctly interpret laboratory results. In Botswana, most reference intervals used to date are not standardized across clinical laboratories and are based on values derived from populations in the United States or Western Europe.We measured 14 hematologic and biochemical parameters of healthy young adults screened for participation in the Botswana HIV Pre-exposure Prophylaxis Study using tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) (TDF2 Study). Reference intervals were calculated using standard methods, stratified by gender, and compared with the site-derived reference values used for the TDF2 study (BOTUSA ranges), the Division of AIDS (DAIDS) Grading Table for Adverse Events, the Botswana public health laboratories, and other regional references.Out of 2533 screened participants, 1786 met eligibility criteria for participation in study and were included in the analysis. Our reference values were comparable to those of the Botswana public health system except for amylase, blood urea nitrogen (BUN), phosphate, total and direct bilirubin. Compared to our reference values, BOTUSA reference ranges would have classified participants as out of range for some analytes, with amylase (50.8%) and creatinine (32.0%) producing the highest out of range values. Applying the DAIDS toxicity grading system to the values would have resulted in 45 and 18 participants as having severe or life threatening values for amylase and hemoglobin, respectively.Our reference values illustrate the differences in hematological and biochemical analyte ranges between African and Western populations. Thus, the use of western-derived reference laboratory values to screen a group of Batswana adults resulted in many healthy people being classified as having out-of-range blood analytes. The need to establish accurate local or regional reference values is apparent and we hope our results can be used to that end in Botswana

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

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

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

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