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 NCT0301260.

Pilot Evaluation of an Enzymatic Assay for Rapid Measurement of Antiretroviral Drug Concentrations

“…(17) TFV has higher and more variable concentrations in urine and can be detected up to 14 days after TDF ingestion. (18,19) TFV measurement is susceptible to the "white coat" effect where one is unable to distinguish recent pill ingestion from patterns of long term adherence. Intracellular TFV-DP has a longer half-life as it accumulates in red blood cells (RBCs) and peripheral blood mononuclear cells, and can provide a window into cumulative adherence over 1-2 months.…”

Perspectives on the utility and interest in a point-of-care urine tenofovir test for adherence to HIV pre-exposure prophylaxis and antiretroviral therapy: an exploratory qualitative assessment among U.S. clients and providers

“…In addition, subjective methods used to measure ART and PrEP adherence, such as self-reported adherence, are prone to social desirability bias; while commonly used objective measures, such as pill counts and pharmacy refill records, are often inaccurate and unreliable [14][15][16]. Objective metrics are available to measure adherence through pharmacokinetic analysis of concentrations of tenofovir (TFV), a drug formulation found in oral PrEP regimens and most ART regimens, which is detectable in whole blood, plasma, dried blood spots, cerebrospinal fluid, mucosal fluid, oral tissue, urine, and hair [12,[17][18][19][20][21][22][23][24][25][26][27][28][29][30]. However, widespread implementation of these metrics is limited by its expense, turnaround time, and need for specialized personnel [23,25].…”

Adherence to Antiretroviral Therapy and Pre-exposure Prophylaxis: TARGETing the Ideal Measure

“…In conclusion, Drain and colleagues [11] present novel data on the potential utility of urinary TFV concentrations as a pharmacologic measure of recent adherence to TDF/ emtricitabine. Based on the TARGET results, TFV would be most helpful to determine the absence of recent dosing within the preceding week, and could be included in the armamentarium of available tools to identify patients with significant adherence gaps, in particular once it becomes available as a point-of-care test.…”

“…In the current issue of Clinical Infectious Diseases, Drain and colleagues [11] provide a step towards achieving this goal by presenting the results of the tenofovir adherence to rapidly guide and evaluate PrEP and human immunodeficiency virus (HIV) therapy (TARGET) study, which aimed to assess the pharmacokinetics of tenofovir (TFV) in urine in 28 Thai healthy adults randomized to 3 different adherence patterns of oral tenofovir disoproxil fumarate (TDF)/emtricitabine [11,12]. In TARGET, participants took either daily dosing (Group 1: perfect adherence), 4 doses per week (Group 2: moderate adherence), or 2 doses per week (Group 3: low adherence) for a period of 6 weeks, during which drug intake was confirmed via directly observed therapy, followed by a 4-week washout period.…”

“…Additionally, the short half-life and lack of accumulation of TFV in plasma and urine indicate that steady-state concentrations achieved after repeated dosing are similar to those achieved after a single dose. Therefore, as Drain and colleagues [11] recognize in their manuscript, this adherence measure can be influenced by recent dosing not reflective of a true adherence pattern (the so-called white coat adherence [19]), leading to the misclassification of someone as being highly adherent when she/he may have been nonadherent preceding that white coat dosing. Consequently, a detectable TFV concentration in urine would be indicative of recent dosing.…”