Abstract
Background: Incomplete adherence to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) reduces effectiveness. Adherence biomeasures (i.e. drug concentrations in biological specimen) are more accurate than self-report. TDF/FTC’s intracellular active metabolites (tenofovir-diphosphate; TFVdp and FTC-triphosphate; FTCtp) can be quantified in different types of blood samples to estimate adherence. To optimize adherence estimation, we investigated approaches to measure TFVdp and FTCtp in four blood matrices. Methods: Twelve HIV-negative, healthy volunteers were enrolled in a single center, open-label, 3-phase, directly observed therapy study. LC-MS/MS methods quantified TFVdp/FTCtp in dried blood spots, volumetrically accurate microsampling, upper layer packed cells and peripheral blood mononuclear cells (PBMCs). Non-compartmental analysis estimated half-lives and accumulation ratios. Correlations characterized relationships between clinical variables and exposure. Regression models were fit to determine concentrations associated with <4 and ≥4 doses/week; correct classification percentages were determined. Results: Terminal half-life estimates of 3-4 vs 15-22 days distinguished between moderate-term (FTCtp in all samples; TFVdp in PBMCs) versus long-term (TFVdp in red blood cell-containing matrices) measures. Model-derived thresholds accurately categorized <4 and ≥4 doses/week when including both metabolites for 14- and 28-day dosing periods (81-91% and 82-85%, respectively). Within each classification and regression trees analyses containing both moderate- and long-term measures, dried blood spots exhibited highest accuracy to predict stable (74-94%) and changing (42-47%) adherence patterns. Conclusion: We demonstrate higher accuracy of moderate-term biomeasures to classify adherence over a 14-day period compared to long-term biomeasures to classify adherence over a 28-day period. Combined moderate- and long-term biomeasures predicted stable and changing adherence patterns, with dried blood spots exhibiting highest accuracy.
Published Version
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