Equivalent Decline in Inflammation Markers with Tenofovir Disoproxil Fumarate vs. Tenofovir Alafenamide

Nicholas T Funderburg, Grace A McComsey, Manjusha Kulkarni, Tammy Bannerman, Jessica Mantini, Bernadette Thornton, Hui C Liu, Yafeng Zhang, Qinghua Song, Liang Fang, Jason Dinoso, Andrew Cheng, Scott McCallister, Marshall W Fordyce, Moupali Das, Nicholas T Funderburg, Grace A McComsey, Manjusha Kulkarni, Tammy Bannerman, Jessica Mantini, Bernadette Thornton, Hui C Liu, Yafeng Zhang, Qinghua Song, Liang Fang, Jason Dinoso, Andrew Cheng, Scott McCallister, Marshall W Fordyce, Moupali Das

Abstract

Background: Initiation of antiretroviral therapy (ART) and subsequent virologic suppression reduces immune activation and systemic inflammation.

Methods: We examined longitudinal changes in biomarkers of monocyte activation (sCD14, sCD163), and systemic (IL-6, hsCRP, sTNFR-I and D-dimer) and vascular (Lp-PLA2) inflammation in a subgroup (N=100 per arm) of participants enrolled in a randomized, placebo-controlled trial comparing elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF; TAF) to E/C/F/tenofovir disoproxil fumarate (E/C/F/TDF; TDF) in treatment-naïve adults.

Results: For 194 participants (TAF, 98; TDF, 96), baseline levels of biomarkers did not differ by treatment arm; there were no differences in biomarker values between groups at weeks 12, 24, or 48 (p>0.05), except IL-6 at week 12 (p=0.012). Among all participants (combining groups), there were statistically significant declines from baseline observed for D-dimer, sCD163, and sTNFR-1 by week 12 and IL-6 by week 24. The proportion of participants with Lp-LA2 levels<200ng per mL (p=0.250) or hsCRP levels <3000mg per L (p=0.586) was unchanged through week 48.

Conclusions: We observed equivalent declines in biomarkers of monocyte activation and systemic inflammation in treatment-naïve adults treated with TAF or TDF for 48weeks, suggesting that TAF and TDF have equivalent impact on immune activation and inflammation.

Keywords: Biomarkers; Immune activation; Inflammation; Tenofovir alafenamide.

Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
Fasting lipids at baseline and week 48. P-values calculated using Wilcoxon rank-sum test for treatment comparison of change from baseline at Week 48.
Fig. 2
Fig. 2
Percent changes in markers of inflammation and immune activation. Plasma samples were thawed and levels of A) soluble CD14 (sCD14), soluble CD163 (sCD163), B) C reactive protein (hsCRP), tumor necrosis factor receptor type 1 (TNFr-I), D-dimer, interleukin-6 (IL-6) and C) lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured by ELISA. Differences in percent changes were assessed by Wilcoxon rank-sum test.
Fig. 3
Fig. 3
Changes in levels of biomarkers: equivalence by two one-sided test. Using TOST, equivalence is established at α significance level if a (1–2α) ∗ 100% confidence interval (CI) for the ratio of treatment 1/treatment 2 is contained within a range around 100%, such as (80%–125%).
Fig. 4
Fig. 4
Changes in levels of biomarkers: equivalence by Random Forest. Machine learning algorithm Random Forest with receiver operating characteristic (ROC) curve and variable importance was used to assess the biomarkers' ability to differentiate between arms (Breiman, 2001). BL, baseline; Hb, hemoglobin; CLcr, creatinine clearance.

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