Emtricitabine-Triphosphate in Dried Blood Spots as a Marker of Recent Dosing

Abstract

New objective measures of antiretroviral adherence are needed. We determined if emtricitabine triphosphate (FTC-TP) in dried blood spots (DBS) can be used as a marker of recent dosing with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC). The half-life of FTC-TP was estimated in DBS samples obtained from an intensive pharmacokinetic (PK) study of coformulated TDF-FTC in HIV-negative and HIV-infected participants. The concordance of quantifiable FTC-TP in DBS with tenofovir (TFV)/FTC in plasma was evaluated by utilizing paired plasma-DBS samples from participants enrolled in 2 large preexposure prophylaxis (PrEP) open-label trials. The time to FTC-TP nondetectability after TDF-FTC dosing was evaluated utilizing DBS from HIV-negative participants enrolled in a directly observed therapy study of variable adherence to TDF-FTC. The mean (95% confidence interval [CI]) terminal half-life of FTC-TP in the PK study was 35 (23 to 47) h. A total of 143/163 (88%) samples obtained 0 to 48 h post-TDF-FTC dose had quantifiable FTC-TP in DBS, compared with 2/93 (2%) and 0/87 (0%) obtained >48 and >96 h postdose. In 746 paired plasma-DBS samples from 445 participants enrolled in PrEP trials, when both TFV/FTC in plasma were below the limit of quantification, FTC-TP was as well in 98.9% of the samples, and when either TFV or FTC in plasma was quantifiable, FTC-TP was as well in 90.5% of the samples. The half-life of FTC-TP in DBS is short relative to that of TFV-diphosphate (TFV-DP), making it a surrogate for TFV-FTC detection in plasma. FTC-TP can be quantified in DBS simultaneously with TFV-DP, which quantifies cumulative adherence to TDF-FTC. (The clinical trials discussed in this article have been registered at ClinicalTrials.gov under identifiers NCT01040091, NCT02022657, NCT00458393, NCT01772823, and NCT02012621.).

FIG 1

Mean (95% CI) accumulation phase (a) and terminal phase (b) half-lives (t_1/2) of FTC-TP in DBS in HIV-negative and HIV-infected participants enrolled in Cell-PrEP (each symbol represent a different participant). In the accumulation phase (a), the circles indicate HIV-negative individuals and the triangles indicate HIV-infected individuals. Solid line represents the fitted FTC-TP concentration.

FIG 2

Proportions of samples with quantifiable FTC-TP in 746 DBS samples obtained from 445 PrEP participants enrolled in iPrEx-OLE and ATN 110 according to the dosing category (determined by TFV-DP in DBS). The dashed red square represents individuals with evidence of preappointment dosing. <2 doses per week, TFV-DP BLQ to <350 fmol/punch; 2 or 3 doses per week, TFV-DP 350 to 699 fmol/punch; ≥4 doses per week, TFV-DP ≥700 fmol/punch.