Abstract
The efficacy of pre-exposure prophylaxis (PrEP) in HIV will diminish with poor adherence; pharmacologic measures of drug exposure have proven critical to PrEP trial interpretation. We assessed drug exposure in hair against other pharmacologic and more routinely used measures to assess pill-taking. Participants were randomized to placebo, daily PrEP, or intermittent PrEP to evaluate safety and tolerability of daily versus intermittent tenofovir/emtricitabine (TFV/FTC) in 2 phase II PrEP clinical trials conducted in Africa. Different measures of drug exposure, including self-report, medication event monitoring system (MEMS)-caps openings, and TFV/FTC levels in hair and other biomatrices were compared. At weeks 8 and 16, self-reported pill-taking, MEMS-caps openings, and TFV/FTC levels in hair, plasma, and peripheral blood mononuclear cells (PBMCs) were measured. Regression models evaluated predictors of TFV/FTC concentrations in the 3 biomatrices; correlation coefficients between pharmacologic and nonpharmacologic measures were calculated. Both trials were registered on ClinicalTrials.gov (NCT00931346/NCT00971230). Hair collection was highly feasible and acceptable (100% in week 8; 96% in week 16). In multivariate analysis, strong associations were seen between pharmacologic measures and MEMS-caps openings (all P < 0.001); self-report was only weakly associated with pharmacologic measures. TFV/FTC hair concentrations were significantly correlated with levels in plasma and PBMCs (correlation coefficients, 0.41-0.86, all P < 0.001). Measuring TFV/FTC exposure in small hair samples in African PrEP trials was feasible and acceptable. Hair levels correlated strongly with PBMC, plasma concentrations, and MEMS-caps openings. As in other PrEP trials, self-report was the weakest measure of exposure. Further study of hair TFV/FTC levels in PrEP trials and demonstration projects to assess adherence/exposure is warranted.
Highlights
The efficacy of pre-exposure prophylaxis (PrEP) in which at-risk HIV-uninfected individuals take antiretrovirals to prevent HIV acquisition has been demonstrated in several recent trials.[1,2,3,4,8,9] Based on these results, a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) taken daily as PrEP was approved by the US Food and Drug Administration for high-risk individuals in 2012 with recently updated guidelines from the Centers of Diseases Control[5] and World Health Organization[6] citing broad indications
Strong associations were seen between pharmacologic measures and monitoring systems (MEMS)-caps openings; self-report was only weakly associated with pharmacologic measures
TFV/FTC hair concentrations were significantly correlated with levels in plasma and peripheral blood mononuclear cells (PBMCs)
Summary
The efficacy of pre-exposure prophylaxis (PrEP) in which at-risk HIV-uninfected individuals take antiretrovirals to prevent HIV acquisition has been demonstrated in several recent trials.[1,2,3,4,8,9] Based on these results, a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) taken daily as PrEP was approved by the US Food and Drug Administration for high-risk individuals in 2012 with recently updated guidelines from the Centers of Diseases Control[5] and World Health Organization[6] citing broad indications. Measurement of antiretroviral (ARV) levels in single plasma samples has been frequently used to monitor exposure in PrEP trials, but represent a small window of exposure (2–7 days)[23,24,25] and may be susceptible to “white coat effects,” where adherence improves transiently before visits.[26,27] Drug levels in PBMCs have proven useful in the interpretation of PrEP trial results,[1,28] providing information on exposure over longer periods (7–14 days), procedures to process, isolate, and count PBMCs can be costly and technically challenging. Hair concentrations of tenofovir (TFV) are strongly and linearly related to dose.[34]
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