A novel REverSe Transcriptase Chain Termination (RESTRICT) assay for near-patient, objective monitoring of long-term PrEP adherence

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ABSTRACT Oral pre-exposure prophylaxis (PrEP), composed of tenofovir disoproxil fumarate and emtricitabine, is effective for preventing HIV acquisition, but PrEP efficacy is highly dependent on drug adherence. In several trials and implementation studies, PrEP clients have difficulties maintaining adequate adherence and persistence, and monitoring their PrEP use is challenging. PrEP providers have relied on self-reported adherence, which is often inaccurate and unreliable. The lack of an objective PrEP adherence monitoring tool has led to inefficient counseling and poor supportive care. To address these issues, we completed a randomized pharmacokinetic study to determine drug levels during controlled directly-observed PrEP. Longer-term metabolites, such as tenofovir-diphosphate (TFV-DP) (~17-day half-life), provide a more accurate picture of long-term PrEP adherence. We recently developed a novel enzymatic assay that semi-quantitatively measures the concentration of TFV-DP by measuring inhibition of reverse transcriptase, which is the cellular target of oral PrEP drugs. In this proposal, our primary objectives are optimizing the REverSe TRanscrIptase Chain Termination (RESTRICT) assay to measure drug concentrations of PrEP clients, to establish validation for CLIA criteria when implemented in a near-patient clinical lab, and to evaluate the feasibility and acceptability of using the RESTRICT assay for drug level measurement among PrEP clients and providers. We will test our central hypotheses with three specific aims: (1) to calibrate and optimize the RESTRICT assay for measuring long-term TFV-DP drug concentrations, compared to gold-standard liquid chromatography tandem mass spectrometry (LC-MS/MS) measurement; (2) to validate the RESTRICT assay for meeting established CLIA criteria to enable clinical reporting of an objective near-patient measure for monitoring long-term TFV-DP drug concentrations; (3) to evaluate the feasibility and acceptability of near-patient TFV-DP testing among PrEP clients and providers at a major PrEP clinic in Seattle. Our proposed study will be the first to validate a rapid, near-patient long-term objective measure of oral PrEP adherence. This study will also provide crucial data on the feasibility and acceptability of a novel approach for improving PrEP delivery and monitoring to prevent HIV transmission. The results of this study will develop a new tool that may help improve PrEP delivery in the US and worldwide.