confUrine Tenofovir Concentrations Correlate with Plasma and Relates to TDF Adherence: A Randomized Directly-observed Pharmacokinetic Trial (TARGET Study)

BACKGROUND: Direct measurement of tenofovir (TFV) in urine could be an objective measure to monitor adherence to pre-exposure prophylaxis (PrEP) or TFV-based antiretroviral therapy (ART). We describe urine TFV concentrations in adults with controlled levels of adherence to advance development and enable interpretation of point-of-care urine assays. METHODS: We conducted a three-arm randomized, open-label, pharmacokinetic study of tenofovir disoproxil fumarate (TDF) 300mg/emtricitabine (FTC) 200mg among HIV-uninfected adults. Participants were randomized to receive controlled TDF/FTC dosing as: (1) 'perfect' adherence (daily), (2) 'moderate' adherence (four doses/week), or (3) 'low' adherence (two doses/week). We obtained trough spot urine and plasma samples during a six-week directly-observed therapy period and a four-week washout period. TFV concentrations were compared between adherence arms using one-way analysis of variance. RESULTS: Among 28 participants, mean age was 33 years and 16 (57%) were male. Correlation between TFV plasma and urine concentrations was strong (rho=0.78; p<0.0001). Median [IQR] steady-state trough TFV concentrations (ng/mL) for perfect, moderate, and low TDF adherence in plasma were 41 [26-52], 16 [14-19], 4 [3-5]; and in urine were 6,480 [3,940-14,300], 3,405 [2,210-5,020], and 448 [228-675]. Trough TFV concentrations at steady state were significantly different between the three adherence arms for plasma (p<0.0001) and urine (p=0.0002). 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 three randomized adherence groups. CONCLUSIONS: Urine TFV concentrations can inform interpretation of novel point-of-care urine-based TFV assays to assess recent TDF adherence.