Plasma concentration of neurofilament light chain protein decreases after switching from tenofovir disoproxil fumarate to tenofovir alafenamide fumarate

Linn Hermansson, Aylin Yilmaz, Richard W Price, Staffan Nilsson, Scott McCallister, Tariro Makadzange, Moupali Das, Henrik Zetterberg, Kaj Blennow, Magnus Gisslen, Linn Hermansson, Aylin Yilmaz, Richard W Price, Staffan Nilsson, Scott McCallister, Tariro Makadzange, Moupali Das, Henrik Zetterberg, Kaj Blennow, Magnus Gisslen

Abstract

Background: Because tenofovir alafenamide (TAF) leads to significantly lower plasma tenofovir concentrations than tenofovir disoproxil fumarate (TDF) and is a stronger substrate for P-glycoprotein (P-gp) than TDF, TAF could lead to decreased central nervous system (CNS) tenofovir exposure than TDF. We aimed to determine if switching from TDF to TAF increases the risk of neuronal injury, by quantifying plasma levels of neurofilament light protein (NfL), a sensitive marker of neuronal injury in HIV CNS infection.

Methods: Plasma NfL concentration was measured at baseline, week 24, and week 84 in stored plasma samples from 416 participants (272 switching to elvitegravir (E)/cobicistat (C)/emtricitabine (F)/TAF and 144 continuing E/C/F/TDF) enrolled in the randomized, active-controlled, multicenter, open-label, noninferiority Gilead GS-US-292-0109 trial.

Results: While plasma NfL levels in both groups were within the normal range, we found a small but significant decrease in the E/C/F/TAF arm after 84 weeks from a geometric mean of 9.3 to 8.8 pg/mL (5.4% decline, 95% CI 2.0-8.4, p = 0.002). This change was significantly different (p = 0.001) from that of the E/C/F/TDF arm, in which plasma NfL concentration changed from 9.7 pg/mL at baseline to 10.2 pg/mL at week 84 (5.8% increase, 95% CI -0.8-12.9, p = 0.085). This increase is in line with what could be expected in normal ageing. Plasma NfL concentrations significantly correlated with age. No correlation was found between plasma NfL and serum creatinine.

Conclusions: We found no biomarker evidence of CNS injury when switching from TDF to TAF. It is unclear whether the small decrease in plasma NfL found after switch to TAF is of any clinical relevance, particularly with plasma NfL levels in both arms remaining within the limits found in HIV-negative controls. These results indicate that switching from TDF to TAF appears safe with regard to neuronal injury.

Conflict of interest statement

We have the following interests: This study was funded in part by Gilead Sciences (CO-SE-292-4080). SM, TM, and MD are employees of Gilead Sciences. HZ has served at scientific advisory boards for Roche Diagnostics, Wave, Samumed and CogRx, has given lectures in symposia sponsored by Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg (all outside submitted work). KB has served as a consultant or at advisory boards for Alector, Biogen, CogRx, Lilly, MagQu, Novartis and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg, all unrelated to the work presented in this paper. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Plasma NfL changes over time.
Fig 1. Plasma NfL changes over time.
(a) Plasma NfL concentrations in participants on tenofovir alafenamide fumarate (TAF) (red, n = 272)) and tenofovir disoproxil fumarate (TDF) (blue, n = 144). Values are presented as geometric means and error bars indicate 95% confidence intervals. (b) Percent change in plasma NfL and 95% confidence intervals from baseline, to week 24 (TAF n = 271, TDF n = 142), and to week 84 (TAF n = 267, TDF n = 140). Plasma NfL was significantly higher in the TDF group and there was a significant difference between the groups in plasma NfL change from baseline to week 84.
Fig 2. Serum creatinine changes over time.
Fig 2. Serum creatinine changes over time.
(a) Serum creatinine in participants on tenofovir alafenamide fumarate (TAF) (red, n = 272) and tenofovir disoproxil fumarate (TDF) (blue, n = 142). Values are presented as geometric means and error bars indicate 95% confidence intervals. (b) Percent change in serum creatinine and 95% confidence intervals from baseline, to week 24 (TAF n = 271, TDF n = 141), and to week 84 (TAF n = 265, TDF n = 138). Creatinine was significantly higher in the TDF group at week 24 and 84 and there was a significant difference between the groups in serum creatinine change from baseline to week 84.
Fig 3. No association between serum creatinine…
Fig 3. No association between serum creatinine and plasma NfL.
No significant correlation between plasma NfL and serum creatinine at baseline (r = -0.07, p = 0.18). TAF: tenofovir alafenamide fumarate; TDF: tenofovir disoproxil fumarate; NfL: neurofilament light protein.

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