Assessing PrEP Adherence/Exposure Using Hair Samples
Assessing PrEP Adherence/Exposure Using Hair Samples
Objective 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.
Design 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.
Methods 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).
Results 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).
Conclusions 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.
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. 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 and World Health Organization citing broad indications. Optimal strategies for PrEP administration are under intense investigation.
Although PrEP was effective in reducing HIV acquisition in some trials, 2 large trials in sexually active African women (FEM-PrEP and VOICE) were unable to demonstrate efficacy of daily TDF/FTC in reducing HIV acquisition. Rates of study product use in major PrEP trials as assessed by self-report or product return counts have been high (88%–95%), but direct measures of drug exposure indicate lower rates of actual use. Of paramount importance to the effective rollout of PrEP in both resource-rich and resource-limited settings is the incorporation of novel, accurate, and feasible ways to estimate adherence.
Although adherence is described as the "behavioral bridge from efficacy to effectiveness" in PrEP, each method to quantitate drug-taking has limitations. Self-report can be limited by recall bias, poor recollection, or a desire to please the provider ("social desirability bias"). Although pill counts and medication event monitoring systems (MEMS) can improve the accuracy of adherence monitoring, neither measure can record actual drug consumption nor quantify pharmacokinetic parameters.
Pharmacologic measures of exposure, most often involving the measurement of antiretrovirals in a matrix such as plasma, peripheral blood mononuclear cells (PBMCs), dried blood spots, or hair, reflect both adherence and pharmacokinetics. 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) and may be susceptible to "white coat effects," where adherence improves transiently before visits. Drug levels in PBMCs have also proven useful in the interpretation of PrEP trial results, providing information on exposure over longer periods (7–14 days), although procedures to process, isolate, and count PBMCs can be costly and technically challenging. Drug levels in dried blood spots can reflect both recent and cumulative exposure and were recently used in a large cohort of PrEP users; although easier to collect and process than PBMCs, dried blood spots require standardization against hemoglobin concentrations and sample volume for interpretation. Hair collection is noninvasive and does not require phlebotomy, and hair levels of ARVs reflect uptake from the systemic circulation over weeks to months, representing a long-term measure of exposure. Moreover, hair concentrations of tenofovir (TFV) are strongly and linearly related to dose.
Intermittent PrEP may facilitate adherence, reduce costs, and has demonstrated efficacy in simian models and, in a recent trial, in men who have sex with men (MSM) although this strategy is not yet clinically approved. Studies investigating intermittent PrEP in humans have demonstrated tolerability, safety, and now efficacy, but adherence to intermittent PrEP, and measuring it accurately, can pose challenges. Comparing pharmacokinetic measures with more "traditional" measures of drug exposure (eg, self-report or MEMS) could provide insight into the utility of these measures across different PrEP dosing patterns and guide the selection of these measures in PrEP studies/settings. Multiple biologic samples for exposure monitoring (plasma, PBMCs, and hair) were collected in 2 phase II trials investigating daily or intermittent PrEP in HIV-negative serodiscordant couples in Uganda and MSM in Kenya. We report here an analysis comparing hair levels of FTC and TFV with self-report of pill-taking, MEMS-caps openings, and plasma and PBMC drug concentrations in these 2 trials.
Abstract and Introduction
Abstract
Objective 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.
Design 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.
Methods 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).
Results 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).
Conclusions 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.
Introduction
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. 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 and World Health Organization citing broad indications. Optimal strategies for PrEP administration are under intense investigation.
Although PrEP was effective in reducing HIV acquisition in some trials, 2 large trials in sexually active African women (FEM-PrEP and VOICE) were unable to demonstrate efficacy of daily TDF/FTC in reducing HIV acquisition. Rates of study product use in major PrEP trials as assessed by self-report or product return counts have been high (88%–95%), but direct measures of drug exposure indicate lower rates of actual use. Of paramount importance to the effective rollout of PrEP in both resource-rich and resource-limited settings is the incorporation of novel, accurate, and feasible ways to estimate adherence.
Although adherence is described as the "behavioral bridge from efficacy to effectiveness" in PrEP, each method to quantitate drug-taking has limitations. Self-report can be limited by recall bias, poor recollection, or a desire to please the provider ("social desirability bias"). Although pill counts and medication event monitoring systems (MEMS) can improve the accuracy of adherence monitoring, neither measure can record actual drug consumption nor quantify pharmacokinetic parameters.
Pharmacologic measures of exposure, most often involving the measurement of antiretrovirals in a matrix such as plasma, peripheral blood mononuclear cells (PBMCs), dried blood spots, or hair, reflect both adherence and pharmacokinetics. 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) and may be susceptible to "white coat effects," where adherence improves transiently before visits. Drug levels in PBMCs have also proven useful in the interpretation of PrEP trial results, providing information on exposure over longer periods (7–14 days), although procedures to process, isolate, and count PBMCs can be costly and technically challenging. Drug levels in dried blood spots can reflect both recent and cumulative exposure and were recently used in a large cohort of PrEP users; although easier to collect and process than PBMCs, dried blood spots require standardization against hemoglobin concentrations and sample volume for interpretation. Hair collection is noninvasive and does not require phlebotomy, and hair levels of ARVs reflect uptake from the systemic circulation over weeks to months, representing a long-term measure of exposure. Moreover, hair concentrations of tenofovir (TFV) are strongly and linearly related to dose.
Intermittent PrEP may facilitate adherence, reduce costs, and has demonstrated efficacy in simian models and, in a recent trial, in men who have sex with men (MSM) although this strategy is not yet clinically approved. Studies investigating intermittent PrEP in humans have demonstrated tolerability, safety, and now efficacy, but adherence to intermittent PrEP, and measuring it accurately, can pose challenges. Comparing pharmacokinetic measures with more "traditional" measures of drug exposure (eg, self-report or MEMS) could provide insight into the utility of these measures across different PrEP dosing patterns and guide the selection of these measures in PrEP studies/settings. Multiple biologic samples for exposure monitoring (plasma, PBMCs, and hair) were collected in 2 phase II trials investigating daily or intermittent PrEP in HIV-negative serodiscordant couples in Uganda and MSM in Kenya. We report here an analysis comparing hair levels of FTC and TFV with self-report of pill-taking, MEMS-caps openings, and plasma and PBMC drug concentrations in these 2 trials.