Studies of daily emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for HIV preexposure 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, crossover 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 (25 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 1,605 (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 1,250 fmol/punch, which were estimated 25th percentiles for 2, 4, and 7 doses/week. 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% confidence intervals [CIs], 6.5, 27.4%) lower TFV-DP than females. The thresholds of 350, 700, and 1,250 fmol/punch were achieved by 75% of men taking ≥1.2, 3.2, and 6 doses/week and 75% of women taking ≥0.6, 2.0, and 5.3 doses/week, 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. (This study has been registered at ClinicalTrials.gov under identifier NCT02022657.).

O ral preexposure prophylaxis (PrEP) using coformulated tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) has proven effective in preventing HIV infection in high-risk individuals (1-7). Unfortunately, PrEP efficacy has not been consistent across all studies, mostly due to variations in drug adherence (8)(9)(10). Multiple studies have demonstrated that sustained drug adherence and exposure are the main factors that determine success in PrEP (1, 5). However, despite its importance, no gold standard measure of antiretroviral adherence is currently available in routine clinical practice, and adequately quantifying adherence continues to be a challenge.Plasma and intracellular tenofovir (TFV) and TFV-diphosphate (TFV-DP) levels have been shown to be powerful markers of adherence to PrEP (1, 5, 11). In particular, TFV-DP in red blood cells (RBCs), measured using dried blood spots (DBS), was found to be a strong marker of cumulative adherence to TDF-FTC and highly predictive of PrEP efficacy in men who have sex with men (MSM) (5,7,12). This is due to the uniquely long intracellular half-life (17 days) of TFV-DP in RBCs (and DBS), which leads to high accumulation with optimal adherence, so that adherence gradients can be estimated. This is informative about cumulative TDF dosing (adherence) over an extended period (6). However, because of its long half-life, TFV-DP in DBS is unable to discriminate between patterns of recent versus remote dosing and cannot adequately detect variations in very recent dosing. Similar to TFV, FTC (the other component of the currently approved PrEP regimen) is also phosphorylated and trapped inside RBCs as FTC-triphosphate (FTC-TP) (13), with the advantage that it can be simultaneously quantified in DBS, along with TFV-DP. Although the pharmacokinetics of TFV-DP in DBS have been defined (6), our current knowledge about the disposition of FTC-TP in this matrix is limited. In addition, it remains unknown whether FTC-TP in DBS can provide adherence information complementary to that provided by TFV-DP.In this study, we aimed to characterize the pharmacokinetics of FTC-TP in DBS and to evaluate its utility as a marker of recent dosing with TDF-FTC.

Background The secondary lymphoid tissues (LTs), lymph nodes (LNs) and gut-associated lymphoid tissue (GALT) are considered reservoirs for HIV. Antiretrovirals (ARVs) have lower penetration into LT. In vitro models predictive of ARV LT penetration have not been established. Objectives To develop an in vitro model of LT bioavailability using human lymphoid endothelial cells (HLECs) and investigate its predictability with in vivo pharmacokinetic (PK) studies in mice. Methods ARV bioavailability in HLECs was evaluated at the maximum plasma concentration (Cmax) observed in HIV-infected patients. ARVs were: abacavir, atazanavir, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, maraviroc, raltegravir, rilpivirine, ritonavir, tenofovir disoproxil fumarate and the PK booster cobicistat. The LT PK of representative drugs showing high (efavirenz), intermediate (dolutegravir) and low (emtricitabine) HLEC bioavailability was investigated in BALB/c mice given 50/10/30 mg/kg efavirenz/dolutegravir/emtricitabine orally, daily for 3 days. The concordance of in vitro and in vivo ARV bioavailability was examined. Results ARVs showed high (>67th percentile; rilpivirine, efavirenz, elvitegravir and cobicistat), intermediate (67th–33rd percentile; ritonavir, tenofovir disoproxil fumarate, dolutegravir and maraviroc) and low (<33rd percentile; atazanavir, darunavir, raltegravir, emtricitabine and abacavir) HLEC bioavailability. The hierarchy of efavirenz, dolutegravir and emtricitabine bioavailability in LN, gut and brain tissues of mice was: efavirenz>dolutegravir>emtricitabine. Conclusions ARVs displayed distinct HLEC penetration patterns. PK studies of representative ARVs in LT of mice were concordant with HLEC bioavailability. These findings support further development of this approach and its translational predictability in humans.

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