Renal Safety of Tenofovir Alafenamide vs. Tenofovir Disoproxil Fumarate

A Pooled Analysis of 26 Clinical Trials

Samir K. Gupta; Frank A. Post; José R. Arribas; Joseph J. Eron Jr; David A. Wohl; Amanda E. Clarke; Paul E. Sax; Hans-Jürgen Stellbrink; Stefan Esser; Anton L. Pozniak; Daniel Podzamczer; Laura Waters; Chloe Orkin; Jürgen K. Rockstroh; Tatiana Mudrikova; Eugenia Negredo; Richard A. Elion; Susan Guo; Lijie Zhong; Christoph Carter; Hal Martin; Diana Brainard; Devi SenGupta; Moupali Das

Disclosures

AIDS. 2019;33(9):1455-1465. 

In This Article

Abstract and Introduction

Abstract

Objective: Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has been associated with improvement in markers of renal dysfunction in individual randomized trials; however, the comparative incidence of clinically significant renal events remains unclear.

Design: We used a pooled data approach to increase the person-years of drug exposure analysed, maximizing our ability to detect differences in clinically significant outcomes.

Methods: We pooled clinical renal safety data across 26 treatment-naive and antiretroviral switch studies to compare the incidence of proximal renal tubulopathy and discontinuation due to renal adverse events between participants taking TAF-containing regimens vs. those taking TDF-containing regimens. We performed secondary analyses from seven large randomized studies (two treatment-naive and five switch studies) to compare incidence of renal adverse events, treatment-emergent proteinuria, changes in serum creatinine, creatinine clearance, and urinary biomarkers (albumin, beta-2-microglobulin, and retinol binding protein-to-creatinine ratios).

Results: Our integrated analysis included 9322 adults and children with HIV (n = 6360 TAF, n = 2962 TDF) with exposure of 12 519 person-years to TAF and 5947 to TDF. There were no cases of proximal renal tubulopathy in participants receiving TAF vs. 10 cases in those receiving TDF (P < 0.001), and fewer individuals on TAF (3/6360) vs. TDF (14/2962) (P < 0.001) discontinued due to a renal adverse event. Participants initiating TAF-based vs. TDF-based regimens had more favourable changes in renal biomarkers through 96 weeks of therapy.

Conclusion: These pooled data from 26 studies, with over 12 500 person-years of follow-up in children and adults, support the comparative renal safety of TAF over TDF.

Introduction

Tenofovir (TFV) disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor that is highly efficacious and generally well tolerated. However, TDF is associated with renal adverse events, including proximal renal tubulopathy (PRT), which occurs in less than 1% of individuals.[1,2] TFV alafenamide (TAF), a TFV prodrug, is associated with a mean 91% lower plasma TFV exposure compared with TDF.[3] As higher plasma TFV levels have been associated with nephrotoxicity,[4,5] reduced circulating TFV levels are hypothesized to result in fewer renal adverse events. In phases 2 and 3 clinical trials of both treatment-naive and virologically suppressed adults and children,[3,6–35] TAF-containing regimens have demonstrated high efficacy and favorable changes in renal biomarkers including creatinine clearance (CrCl), total and tubular proteinuria, and albuminuria compared with a variety of unboosted and ritonavir (RTV)-boosted or cobicistat (COBI)-boosted TDF-containing regimens. It has been more challenging to determine whether the favourable biomarker profile of TAF translates into improved renal clinical outcomes, due to the low rates of renal events in individual trials, although the 144 week follow-up of the pooled pivotal trials for elvitegravir (EVG)/COBI/emtricitabine (FTC)/TAF had zero cases of PRT and zero renal discontinuations compared with four cases of PRT and 12 renal discontinuations in the EVG/COBI/FTC/TDF group.[8] To better understand the renal clinical outcomes in TAF vs. TDF-containing HIV regimens, we conducted a large integrated analysis of people living with HIV (PLH) from 26 TAF clinical trials. These trials included cumulative exposures of 12 519 person-years to TAF and 5947 person-years to TDF, thereby providing increased statistical power to evaluate the comparative impact on renal adverse events and renal function over time.

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