Urine Assay for Tenofovir to Monitor Adherence in Real Time to Tenofovir Disoproxil Fumarate/Emtricitabine as Preexposure Prophylaxis

HC Koenig; K Mounzer; GW Daughtridge; CE Sloan; L Lalley-Chareczko; GS Moorthy; SC Conyngham; AF Zuppa; LJ Montaner; P Tebas

Disclosures

HIV Medicine. 2017;18(6):412-418. 

In This Article

Abstract and Introduction

Abstract

Objectives Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is approved for pre-exposure prophylaxis (PrEP) against HIV infection. Adherence is critical for the success of PrEP, but current adherence measurements are inadequate for real-time adherence monitoring. We developed and validated a urine assay to measure tenofovir (TFV) to objectively monitor adherence to PrEP.

Methods We developed a urine assay using high-performance liquid chromatography coupled to tandem mass spectrometry with high sensitivity/specificity for TFV that allowed us to determine TFV concentrations in log10 categories between 0 and 10 000 ng/mL. We validated the assay in three cohorts: (1) HIV-positive subjects with undetectable viral loads on a TDF/FTC-based regimen, (2) healthy HIV-negative subjects who received a single dose of TDF/FTC, and (3) HIV-negative subjects receiving daily TDF/FTC as PrEP for 24 weeks.

Results The urine assay detected TFV with greater sensitivity than plasma-based measures and with a window of measurements within 7 days of the last TDF/FTC dose. Based on the urine log-linear clearance after the last dose and its concordance with all detectable plasma levels, a urine TFV concentration > 1000 ng/mL was identified as highly predictive of the presence of TFV in plasma at > 10 ng/mL. The urine assay was able to distinguish high and low adherence patterns within the last 48 h (> 1000 ng/mL versus 10–1000 ng/mL), as well as nonadherence (< 10 ng/mL) extended over at least 1 week prior to measurement.

Conclusions We provide proof of concept that a semiquantitative urine assay measuring levels of TFV could be further developed into a point-of-care test and be a useful tool to monitor adherence to PrEP.

Introduction

Pre-exposure prophylaxis (PrEP) has the potential for tremendous public health benefit through decreasing the still high incidence of new HIV infections. Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) used as PrEP is at least 90% effective in preventing HIV infection when taken daily,[1,2] and up to 99% effective when subjects are taking seven daily doses per week.[3] PrEP is recommended in the USA by the Centers for Disease Control and Prevention,[4] and by the World Health Organization globally,[5] as a powerful tool for millions of individuals at substantial risk for HIV infection. Adherence to PrEP is critical for its success, but unfortunately we do not have adequate methods to monitor adherence in real time. Self-report and pill counts are unreliable methods for monitoring adherence,[6,7] particularly in populations at high risk of acquiring HIV infection, such as young men of colour who have sex with men (yMSMc).[8]

How to accurately monitor and identify suboptimal adherence to PrEP, and develop strategic interventions to maintain adherence levels necessary for effectiveness, is a key gap in implementing this otherwise highly effective prevention therapy.[6,7] Therapeutic drug monitoring has been useful for assessment of adherence in other fields, specifically adherence to psychiatric medications, treatment for substance abuse disorders, and treatment for improved blood pressure control in patients with resistant hypertension.[9–12] Furthermore, behavioural changes are maximized when feedback is made available close to the behaviour that needs modification.[13,14]

With regard to TDF/FTC, previously published means of measuring medication levels in patients receiving PrEP [dried blood spot (DBS) or hair analysis] require sample collection procedures that may not be acceptable to patients outside of clinical trials,[15,16] are associated with delays in reporting that prevent implementation of timely effective interventions, and provide information that does not reflect recent PrEP use. Plasma tenofovir (TFV) concentrations have been measured in clinical trials but can only provide information about adherence in the last 24–36 h.[17] DBS has been used for adherence monitoring and typically provides an average adherence over the preceding 3 months,[18–20] although preliminary data suggest that FTC measurement in DBS can be a marker of recent dosing.[21] A 3-month window would be useful in the HIV treatment setting, but may be less relevant during PrEP administration where temporal adherence with regard to exposure may be more critical.

Alternative adherence strategies have been proposed, including intermittent PrEP (IPERGAY) timed around exposure periods[22] and prevention-effective adherence where PrEP is used only during periods of risk exposure to maximize prevention effectiveness and minimize unnecessary risk of medication toxicity and cost at times of decreased risk.[23,24] In addition, self-reported adherence to PrEP has correlated more closely with drug levels in open-label studies such as the PROUD study, where all 52 subjects who reported taking PrEP had detectable TFV levels in plasma.[3,25] Thus, for the clinician evaluating PrEP use in patients, the key question is to identify real-time lapses in adherence that would leave the user at a higher risk for infection during periods of risk.

Finally, any test intended to be used for repeated monitoring in adolescents and young adults, who have the fastest rising incidence rates for HIV infection, would have to be highly acceptable to this population; youth and young adults have been shown to prefer non-blood draw or needle-requiring assays in HIV testing (50.5% chose rapid oral swab, 30.3% chose traditional venipuncture and 19.2% chose rapid fingerstick blood test),[26] although preferences may differ when monitoring adherence to PrEP. A urine-based test would address many of these concerns.

The goal of this study was to develop and validate a urine assay to measure the concentration of TFV (the active metabolite of the prodrug TDF) in order to objectively monitor adherence to PrEP in a clinical setting.

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