Switching to Tenofovir Alafenamide in Elvitegravir-Based Regimens: Pharmacokinetics and Antiviral Activity in Cerebrospinal Fluid

Abstract

Background: Tenofovir alafenamide fumarate (TAF) co-formulated with elvitegravir (EVG; E), cobicistat (C), and emtricitabine (F), a recommended antiretroviral regimen, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF) as well as neurocognitive (NC) performance change in participants switching from E/C/F/tenofovir disoproxil fumarate (TDF) to E/C/F/TAF.

Methods: This was a 24-week, single-arm, open-label study in treatment-experienced adults living with human immunodeficiency virus (HIV). Nine participants switched from E/C/F/TDF (150/150/200/300 mg once daily) to E/C/F/TAF (150/150/200/10 mg once daily) at week 12. CSF and total plasma concentrations of EVG, TDF, TAF, tenofovir (TFV), and HIV RNA levels were measured at baseline and week 24. NC performance was estimated by the Montreal Cognitive Assessment.

Results: EVG concentrations in CSF and the CSF:plasma ratio remained stable (P = .203) over time. Following the switch, TFV concentrations in CSF and plasma declined (P = .004), although the TFV CSF:plasma ratio increased (P = .004). At week 24, median TAF plasma concentration was 11.05 ng/mL (range, 2.84-147.1 ng/mL) 2 hours postdose but was below assay sensitivity 6 hours after dosing. TAF was below assay sensitivity in all CSF specimens. HIV RNA was ≤40 copies/mL in all CSF and plasma specimens. Three participants (33%) had NC impairment at baseline and 2 (22%) remained impaired at week 24.

Conclusions: Switch to E/C/F/TAF was associated with reductions in TFV concentrations in CSF but stable EVG concentrations that exceeded the 50% inhibitory concentration for wild-type HIV, suggesting that EVG achieves therapeutic concentrations in the central nervous system. No virologic failure or significant NC changes were detected following the switch.

Clinical trials registration: NCT02251236.

Keywords: HIV; cerebrospinal fluid; elvitegravir; tenofovir alafenamide.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Distribution of tenofovir alafenamide fumarate (TAF) into plasma and cerebrospinal fluid: comparison with tenofovir disoproxil fumarate (TDF). TAF and TDF are prodrugs of tenofovir. TAF has been developed to produce the comparable potency as TDF combined with an improved safety profile. TAF has longer plasma half-life and greater plasma stability (~90 minutes) than TDF (~0.4 minute) [14, 15]. Abbreviations: GI, gastrointestinal; HIV, human immunodeficiency virus; TFV, tenofovir.

Figure 2.

A, Elvitegravir concentrations in plasma and cerebrospinal fluid (CSF). B, Tenofovir concentrations in plasma and CSF. Abbreviation: IC50, half maximal inhibitory concentration.

Figure 3.

Changes in tenofovir (TFV) concentrations. A, TFV concentrations in plasma. B, TFV concentrations in cerebrospinal fluid (CSF). C, TFV CSF-to-plasma concentration ratio.