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Adherence gradient strongly tied to sofosbuvir
triphosphate level in HCV/HIV group
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19th International Workshop on Clinical Pharmacology of Antiviral Therapy
Mark Mascolini
Increasingly stronger adherence to anti-HCV antivirals ledipasvir/sofosbuvir (LDV/SOF) translated into higher blood and cellular concentrations of 007-TP, the active SOF triphosphate, in an HCV/HIV group of drug injectors with electronically measured adherence [1]. Researchers from the University of Colorado, Aurora, suggested that 007-TP may offer a useful measure of adherence and cumulative drug dosing.
Data on the pharmacology of 007-TP are limited, and no research has explored the interplay between SOF adherence and 007-TP exposure. To address these issues, University of Colorado investigators assessed the impact of LDV/SOF adherence on 007-TP concentrations in dried blood spots and peripheral blood mononuclear cells (PBMCs).
The Colorado team randomized HCV/HIV-infected people taking LDV/SOF once daily for 12 weeks to one of two adherence protocols: (1) directly observed therapy (DOT) using a video-streaming smartphone or (2) wirelessly observed therapy (WOT) using a Wisepill device. They measured 007-TP concentrations at weeks 2, 4, 6, 8, 10, and 12. Researchers assessed the association between DOT- and WOT-measured adherence and 007-TP exposure with mixed models accounting for repeated measures and inter- and intraindividual variability. They modeled percent adherence as a continuous variable and in gradients: 50-75%, and >75%.
Of the 39 participants, 85% were men, 73% nonblack, and 21% cirrhotic. Median age stood at 51 years, weight at 71 kg, and baseline estimated glomerular filtration rate (eGFR) at 84 mL/min. Median (interquartile range, IQR) 007-TP levels measured 616 fmol/punch (IQR 447 to 783) in dried blood spots and 1820 fmol/million cells (IQR 1212 to 2596) in PBMCs. Approximate half-life of 007-TP was 104 h in blood spots and 26 h in PBMCs.
Median adherence measured 94% (IQR 86% to 100%) and ranged widely from 7% to 100%. For every 10% increase in adherence, dried blood spot 007-TP concentration rose 7% (95% confidence interval [CI] 3.8% to 10%), a highly significant change (P < 0.0001). In PBMCs every 10% increase in adherence meant a 23% increase (95% CI 15% to 31%) in 007-TP level (P < 0.0001).
In a multivariate model percent adherence proved the most significant predictor of 007-TP concentration after adjustment for other variables. In dried blood spots geometric mean 007-TP rose significantly as adherence improved (P = 0.002):
>50-75%: 547 (95% CI 349 to 859)
>75%: 622 (95% CI 397 to 976)
The same proved true for geometric mean 007-TP in PBMCs (P < 0.0001):
>50-75%: 867 (95% CI 333 to 2254)
>75%: 1853 (95% CI 739 to 4646)
The University of Colorado investigators concluded that "gradients of percent adherence to LDV/SOF measured using electronic monitoring were strongly associated with 007-TP concentrations in dried blood spots and PBMCs."
Reference
1. Jimmerson L, Marrow M, MaWhinney S, et al. Intracellular 007-TP concentrations are associated with gradients of adherence to ledipasvir/sofosbuvir. 19th International Workshop on Clinical Pharmacology of Antiviral Therapy. May 22-24, 2018. Baltimore. Abstract 2.
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