Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots following Directly Observed Therapy: the DOT-DBS Study [PublishAheadOfPrint]

Studies of daily emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for HIV pre-exposure prophylaxis (PrEP) in men who have sex with men (MSM) modeled intracellular tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) to assess adherence and corresponding PrEP outcomes. We conducted a prospective, randomized, cross-over pharmacokinetic study of TFV-DP in DBS during 33%, 67% or 100% of daily dosing, under directly observed therapy (DOT). Participants were assigned to two 12-week dosing regimens, separated by a 12-week washout. Forty-eight adults (24 women) from Denver and San Francisco were included. TFV-DP exhibited a median half-life of 17 days, reaching steady-state in 8 weeks. TFV-DP was dose-proportional with mean (SD) steady-state concentrations of 530 (159), 997 (267), and 1542 (405) fmol/punch for the 33%, 67% and 100% arms, respectively. Prior work in MSM demonstrated clinically meaningful TFV-DP thresholds of 350, 700, and 1250 fmol/punch, which were estimated 25^th percentiles for 2, 4, and 7 doses/wk. In the present study, corresponding TFV-DP was within 3% of the prior estimates and subgroups by site, race, and sex, were within 14% of prior estimates, although males had 17.6% (95%CI 6.5, 27.4%) lower TFV-DP compared with females. The thresholds of 350, 700, and 1250 fmol/punch were achieved by 75% of men taking ≥1.2, 3.1, and 6 doses/wk, and 75% of women taking ≥0.6, 2.1, and 5.3 doses/wk, indicating that lower dosing reached these thresholds for both sexes. In conclusion, TFV-DP arising from DOT was similar to previous estimates, and is useful for interpreting PrEP adherence and study outcomes.

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