A Novel Algorithm to Improve PrEP Adherence Monitoring Using Dried Blood Spots

Abstract

Tenofovir diphosphate (TFVdp; an active metabolite of oral HIV pre‐exposure prophylaxis (PrEP)) is measured in dried blood spots (DBS) to estimate adherence. However, TFVdp's long half‐life in whole blood may lead to misclassification following a recent change in adherence. PrEP's other metabolite, emtricitabine triphosphate (FTCtp), has a shorter half‐life in whole blood but adherence thresholds are undefined. We characterized DBS TFVdp and FTCtp concentrations across many dosing scenarios. Population pharmacokinetic models were fit to TFVdp and FTCtp DBS concentrations from a directly observed therapy study (NCT03218592). Concentrations were simulated for 90 days of daily dosing followed by 90 days of 1 to 7 doses/week and for event‐driven PrEP (edPrEP) scenarios. Thresholds of 1,000 and 200 fmol/punch, for TFVdp and FTCtp, respectively, were reflective of taking 4 doses/week (a minimum target for effective PrEP in men). TFVdp was < 1,000 fmol/punch for 17 days after initiating daily PrEP and > 1,000 fmol/punch for 62 days after decreasing to 3 doses/week. Respectively, FTCtp was < 200 fmol/punch for 4 days and > 200 fmol/punch for 6 days. Accuracy of edPrEP adherence classification depended on duration between last sex act and DBS sampling for both measures with misclassification ranging from 9–100%. These data demonstrate adherence misclassification by DBS TFVdp for 2 months following a decline in adherence, elucidating the need for FTCtp to estimate recent adherence. We provide proof of principle that individualized interpretation is needed to support edPrEP adherence monitoring. Our collective approach facilitates clinicians' ability to interpret DBS results and administer patient‐centric interventions.

Medication adherence framework: A population‐based pharmacokinetic approach and its application in antimalarial treatment assessments

“…They also investigated the sensitivity of the adherence predictions if patients missed the last dose or the two last doses 10 . A recent study used a population‐based PK approach to assess the adherence of a long half‐life drug, tenofovir diphosphate 35 . However, additional investigations of the predictive ability are needed before the methods can be utilized in a clinical setting.…”

“… 10 A recent study used a population‐based PK approach to assess the adherence of a long half‐life drug, tenofovir diphosphate. 35 However, additional investigations of the predictive ability are needed before the methods can be utilized in a clinical setting. We expanded these approaches to wider conditions, such as various model structures, different half‐lives, between‐patient variability, and bioanalytical assay limitations.…”

Prepare Romania: study protocol for a randomized controlled trial of an intervention to promote pre-exposure prophylaxis adherence and persistence among gay, bisexual, and other men who have sex with men

“…To collect the primary outcome, DBS sample collection occurs at each follow-up visit, allowing for analysis of binary (≥ 1000 fmol vs. < 1000 fmol/punch TFVdp) and continuous (fmol TFVdp) operationalizations of the adherence outcome. PrEP adherence of ≥ 4 doses per week, equivalent to ≥ 1000 fmol TFVdp, has been shown to be protective against HIV transmission [ 43 ]. The binary outcome will serve as the primary outcome.…”

Patterns of daily oral HIV PrEP adherence among people who inject drugs in Ukraine: an analysis of biomarkers

“…We used the TFVdp threshold of ≥700 fmol/punch to indicate ≥4 doses/week on average over the past 2−3 months [9]. The interpretation of TFVdp/FTCtp level combinations in DBS was based on pharmacokinetic modelling [15] and population pharmacokinetic studies [12, 13].…”

“…Recent advances in the development of biomarkers, including unique pharmacokinetic profiles of PrEP metabolites tenofovir diphosphate (TFVdp) and emtricitabine triphosphate (FTCtp), allow objective and more accurate measurements of adherence [11][12][13][14] compared to traditional measures. A combination of the two metabolites reduces misclassification compared to each metabolite alone [15]. After the Bangkok Tenofovir Study, only three studies analysed PrEP adherence among PWID using biomarkers [16][17][18].…”