Dose proportionality and half-life of tenofovir in hair samples from those with differing adherence to TDF or TAF-based regimens monitored by directly observed therapy

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Dose proportionality and half-life of tenofovir in hair samples from those with differing adherence to TDF or TAF-based regimens monitored by directly observed therapy

David Nerguizian¹, Mary Morrow¹, Samantha MaWhinney¹, Monica Gandhi², Hideaki Okochi² and Peter Anderson¹

¹University of Colorado; ²University of California

Background: Objective adherence metrics to antiretroviral therapy have been proven useful in interpreting clinical trial results. Hair tenofovir (TFV) concentrations are indicative of average adherence over approximately 1 month. The pharmacokinetics of TFV in hair have not been fully elucidated for TDF and TAF therapy following directly observed therapy (DOT) in people without HIV infection. The DOT-DBS and TAF-DBS studies, which used DOT to determine TFV-DP concentration benchmarks associated with variable adherence regimens, collected hair at regular intervals. This analysis aimed to assess concentrations, dose proportionality, comparability and the apparent half-life of TFV in hair from TDF and TAF.

Methods: Hair samples were collected from adults without HIV in the DOT-DBS and TAF-DBS studies receiving either TDF 300 mg/FTC 200 mg or TAF 25 mg/FTC 200 mg, respectively, at 33%, 67% or 100% of daily doses. Participants were randomized to one adherence group for 12 weeks followed by a 12-week washout and then randomized to a different adherence group and followed for 12 additional weeks (36 weeks total). Approximately 100–200 hair strands were cut from the occipital portion of the scalp every 3 weeks. TFV concentrations were determined by a previously validated LC-MS/MS assay—reported as ng TFV/mg hair—and week 12 and 36 concentrations were summarized by treatment (TDF or TAF) and adherence group (33%, 67% or 100%). Dose proportionality was assessed using the power model. Ln TFV, concentrations were modelled linearly vs. Ln dose. Proportionality was assumed if the slope's 90% confidence interval (CI) was within 0.80 and 1.25. The apparent half-lives from TAF and TDF were determined assuming exponential decay during the 12-week washout phase.

Results: Seventy samples were collected from 38 DOT-DBS participants (50% male; 7% Black, 55% White, 26% Hispanic) and 68 samples were collected from 35 TAF-DBS participants (51% male; 14% Black, 69% White, 17% Hispanic). Mean (%CV) TFV concentrations from TDF treatment were 0.0165 ng/mg (40.9%), 0.0454 (182%) and 0.0395 ng/mg (36.5%), while from TAF treatment they were 0.0142 ng/mg (30.9%), 0.0275 (28.5%) and 0.0409 ng/mg (42.1%) in the 33%, 67% and 100% adherence groups, respectively. Concentrations of TFV from TDF were less than dose proportional (slope 90% CI: 0.62, 0.96), and proportionality was still not achieved after removing one 67% dosing outlier (90% CI: 0.62, 0.94). TFV from TAF was dose proportional (slope 90% CI: 0.8, 1.04). The TFV half-life (IQR) was estimated to be 30 days (26, 35) from TAF and 25 days (23, 28) from TDF.

Conclusions: Hair TFV concentrations were of similar magnitude between TDF and TAF treatment despite much lower plasma TFV exposures arising from TAF, previously reported in people living with HIV. These findings may suggest unique TAF pharmacology in hair follicles, which may contain cathepsin A or CES1 causing local TFV release. Hair TFV concentrations from TDF were not dose proportional but were dose proportional from TAF. The apparent washout half-lives of TFV depend on hair growth rate. These findings inform using hair TFV to assess adherence to TDF and TAF PrEP regimens.