Urine Tenofovir Concentrations Correlate With Plasma and Relate to Tenofovir Disoproxil Fumarate Adherence: A Randomized, Directly Observed Pharmacokinetic Trial (TARGET Study)

Abstract

Background: Direct measurement of tenofovir (TFV) in urine could be an objective measure to monitor adherence to preexposure prophylaxis (PrEP) or TFV-based antiretroviral therapy (ART).

Methods: We conducted a 3-arm randomized, pharmacokinetic study of tenofovir disoproxil fumarate (TDF) 300 mg/emtricitabine (FTC) 200 mg among adults living with human immunodeficiency virus. Participants were randomized to receive controlled TDF/FTC dosing as (1) "perfect" adherence (daily); (2) "moderate" adherence (4 doses/week); or (3) "low" adherence (2 doses/week). We obtained trough spot urine and plasma samples during a 6-week directly observed therapy period and a 4-week washout period. TFV concentrations were compared between adherence arms using 1-way analysis of variance.

Results: Among 28 participants, the median age was 33 years and 16 (57%) were male. Correlation between TFV plasma and urine concentrations was strong (ρ = 0.78; P < .0001). Median (interquartile range) steady-state trough TFV concentrations (ng/mL) for perfect, moderate, and low TDF adherence were 41 (26-52), 16 (14-19), and 4 (3-5) in plasma; and 6480 (3940-14 300), 3405 (2210-5020), and 448 (228-675) in urine. Trough TFV concentrations at steady state were significantly different between the 3 adherence arms for plasma (P < .0001) and urine (P = .0002). Following drug cessation, TFV concentrations persisted longer in urine than plasma samples. Washout urine TFV concentrations and time to undetectable concentrations did not differ between the 3 randomized adherence groups.

Conclusions: Urine TFV concentrations can inform interpretation of novel point-of-care urine-based TFV assays to assess recent TDF adherence.

Clinical trials registration: NCT03012607

Trial registration: ClinicalTrials.gov NCT03012607 NCT03012607 NCT00301260.

Keywords: HIV; antiretroviral treatment; directly observed therapy; preexposure prophylaxis; tenofovir.

Figure 1.

Consolidated Standards of Reporting Trials diagram of recruitment, randomization, follow-up, and analysis for the Tenofovir Adherence to Rapidly Guide and Evaluate Preexposure Prophylaxis and Human Immunodeficiency Virus Therapy study. Abbreviation: HBsAg, hepatitis B surface antigen.

Figure 2.

Correlation of quantifiable spot urine and plasma tenofovir concentrations (ng/mL) (n = 199). A locally estimated scatterplot smoothing curve fit to quantified tenofovir concentrations and 95% confidence interval within the shaded area.

Figure 3.

Trough tenofovir concentrations in plasma and spot urine by randomized adherence arm (“low” = 2 doses/week, sampled 96 hours after dosing; “moderate” = 4 doses/week, 48 hours after dosing; “perfect” = 7 doses/week, 24 hours after dosing) at steady state. The thick center line in each box plot indicates the median, top of the box marks the 75th percentile, bottom of the box marks the 25th percentile, and whiskers mark upper and lower bounds excluding outliers. Outliers are defined as values 1.5 times the interquartile range above the upper quartile or below the lower quartile. Six plasma tenofovir concentrations that were detectable but below the lower limit of quantification (3.0 ng/mL) in the low adherence group were assigned a value of 1.5 ng/mL.

Figure 4.

Proportion of plasma and urine samples with tenofovir (TFV) levels above the limit of quantification (A), and median TFV concentration in urine (B), for liquid chromatography–tandem mass spectrometry during the drug washout period. A, Plasma is indicated with a solid line and urine with a dotted line. Threshold of detection was <3 ng/mL for plasma and <50 ng/mL for urine. Sample size of 7, 7, and 8 in the perfect, moderate, and low adherence arms, respectively, on day 6. B, Interquartile range is represented by a vertical bar for each day and each adherence arm. Sample size of 7, 7, and 8 in the perfect, moderate, and low adherence arms, respectively, on day 6. Single imputation was performed for samples with detectable TFV concentrations but below the lower limit of quantification (50 ng/mL) using 25 ng/mL.