Abstract
Background: HIV pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine is effective when taken daily. Previously, we developed a urine assay capable of detecting the prodrug tenofovir (TFV) in patients taking tenofovir disoproxil fumarate (TDF)-based PrEP. However, tenofovir alafenamide (TAF) has replaced TDF due to its different safety profile for HIV treatment and was recently approved as PrEP. Given the need to ensure the aforementioned assay remains available for the purpose of objective adherence monitoring, it is critical to ensure its accuracy for detecting TFV in patients taking TAF.Methods: Blood and urine samples were collected from 3 cohorts of patients: (1) 10 participants living with HIV (PLWH) with suppressed virus on a TAF-based regimen, (2) 10 HIV-participants administered 1 dose of TAF/FTC followed by urine and plasma sampling for 7 days starting 1–3 h post-dose, and (3) 10 HIV-participants administered 7 doses of TAF/FTC followed by urine and plasma sampling for 10 days starting 1–3 h after the last dose. Samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with high sensitivity and specificity for TFV. HIV-samples were compared to a historical cohort administered one dose of TDF/FTC.Results: PLWH were 90% male, 40% African American, and 10% Hispanic (mean age = 57 y; SD 8.88 y). HIV-participants were 55% male and 70% Caucasian (mean age = 31.6 y; SD 7.70 y). Samples from PLWH demonstrated TFV concentrations 2 logs higher in urine than plasma (1,000 ng/mL vs ±10 ng/mL) at the time of collection. Urine samples following a single dose of TAF in HIV-participants yielded TFV concentrations ranging from 100 to 1,000 ng/mL 1–3 h post-dose and remained >100 ng/mL for 6 days in 8 of 10 participants. Urine samples collected after 7 consecutive doses of TAF yielded TFV concentrations >1,000 ng/mL 1–3 h after dosing discontinuation, with TFV concentrations >1,00 ng/mL 7 days post discontinuation in 8 of 10 participants. Urine TFV concentrations following TAF administration were comparable to those from a historical cohort administered TDF/FTC. Plasma TFV concentrations were low(±10 ng/mL) in both HIV-cohorts at all time points.Conclusions: TFV persists in urine at detectable concentrations in participants taking TAF/FTC for at least 7 days despite largely undetectable plasma concentrations, with urine TFV concentrations comparable to patients taking TDF/FTC. This study demonstrates the ability of a urine TFV assay to measure recent TAF adherence.
Highlights
In patients taking tenofovir disoproxil fumarate (TDF)-based regimens, it has been demonstrated that TFV concentrations can be reliably measured in urine, that urine TFV concentrations correlate well with plasma concentrations, and TFV detection in urine reflects medication usage over a window of 1 to at least 7 days after oral FTC/TDF ingestion (Koenig et al, 2017)
In a 24-week study of 10 HIV-negative subjects receiving daily FTC/TDF for Pre-exposure prophylaxis (PrEP), urine TFV concentration >1,000 ng/mL was highly predictive of presence of TFV in plasma (>10 ng/mL) (PPV 0.95, 95%CI, 0.82–0.99; NPV 0.79, 95%CI, 0.49–0.95), suggesting that the urine assay could clearly identify patients who had not taken medication within the previous 48 h as their urine TFV concentrations were 10 to >100 ng/mL; Koenig et al, 2017)
Urine TFV assessment fills a gap left by plasma, dried blood spot (DBS), and hair assessments by providing information about medication adherence over at least a 7 day period: single plasma concentrations only reflect a small window of exposure (2–3 days; Clevenbergh et al, 2002; Nettles et al, 2006; CastilloMancilla et al, 2013), and hair analysis and DBS reflect average drug exposures over 1–3 months (Garrett et al, 2019; Hare et al, 2019)
Summary
Pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) is highly effective in preventing HIV when taken daily (Garcia-Lerma et al, 2010; Grant et al, 2010; Myers and Mayer, 2011; Prejean et al, 2011; Baeten et al, 2012; Thigpen et al, 2012; Choopanya et al, 2013; Centers for disease control and prevention, 2014; Van Laarhoven et al, 2017), but patient self-report and pill counts are unreliable methods for monitoring adherence (Mimiaga et al, 2009; Poynten et al, 2010). Given the need to ensure the aforementioned assay remains available for the purpose of objective adherence monitoring, it is critical to ensure its accuracy for detecting TFV in patients taking TAF
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