Early Safety of Tenofovir Alafenamide in Patients With a History of Tubulopathy on Tenofovir Disoproxil Fumarate

A Randomized Controlled Clinical Trial

L Hamzah; D Williams; AC Bailey; R Jones; F Ibrahim; CG Musso; K Burling; B Barbini; L Campbell; FA Post

Disclosures

HIV Medicine. 2020;21(3):198-203. 

In This Article

Abstract and Introduction

Abstract

Objectives: The aim of the study was to assess the effect of tenofovir alafenamide (TAF) on kidney and bone biomarkers in patients who developed proximal renal tubulopathy (PRT) while receiving tenofovir disoproxil fumarate (TDF).

Methods: Individuals with a history of TDF-associated PRT and currently suppressed HIV infection on a tenofovir-sparing regimen were randomized 1:1 to continue current antiretroviral therapy or initiate emtricitabine (F)/TAF with discontinuation of nucleoside reverse transcriptase inhibitors (NRTIs) as appropriate. Renal and bone biomarkers were analysed at baseline, week 4 and week 12. The primary outcome was the mean difference between study arms in urine retinol-binding protein:creatinine ratio (RBPCR) change from baseline to week 12. Data were analysed using linear regression, with robust standard errors (primary outcome), and repeated measures mixed effects models (secondary outcomes). The trial was registered under European Union Drug Regulating Authorities Clinical Trials Database 2016–003345-29.

Results: We randomized 31 individuals [mean age 52.4 (standard deviation 0.3) years; 97% male; 90% white); all completed the study. At 12 weeks, there was no difference in change in RBPCR (β 19.6; 95% confidence interval −35.3, 74.5; P = 0.47), and no difference in change in estimated glomerular filtration rate (eGFR) (based on creatinine or cystatin C), albuminuria, proteinuria, renal phosphate or urea handling, (fasting) urine osmolality, parathyroid hormone and bone turnover markers in the control versus the F/TAF exposed groups. No cases of PRT were observed.

Conclusions: In people with a history of proximal renal tubulopathy while on TDF, 12-week exposure to TAF did not adversely affect renal tubular function. These data support continued evaluation of the long-term safety of TAF in this group of patients.

Introduction

Tenofovir disoproxil fumarate (TDF) is among the most widely used components of antiretroviral therapy (ART). Renal toxicity is a recognized complication of TDF and may manifest as acute kidney injury, progressive estimated glomerular filtration rate (eGFR) decline, chronic kidney disease (CKD) and/or proximal tubulopathy (PRT).[1,2] PRT is characterized by normoglycaemic glycosuria, proteinuria, renal phosphate wasting and/or metabolic acidosis which may progress to Fanconi syndrome and be accompanied by reductions in bone mineral density, osteomalacia and/or fragility fractures.[3,4] Based on data from the UK Collaborative HIV Cohort, the incidence of renal toxicity with TDF use is estimated to be around 5% and the incidence of treatment-limiting PRT around 0.4%.[5,6] Reported risk factors for PRT include older age, white ethnicity, immunodeficiency, more prolonged exposure to TDF and co-exposure to didanosine or ritonavir- and cobicistat-boosted agents.[5] The pathological hallmark of TDF-associated PRT is acute tubular injury (ATI), with prominent mitochondrial dysmorphia.[3,7,8] Although kidney function generally improves upon TDF discontinuation, some 20–30% of patients may be left with residual renal impairment.[3,7]

Tenofovir alafenamide (TAF) is a novel tenofovir pro-drug formulation that achieves high intracellular tenofovir diphosphate concentrations despite 90% lower systemic exposures. Clinical trials have demonstrated similar rates of viral suppression compared with TDF, with reduced effects on kidney and bone biomarkers.[9,10] A clinical trial in people with HIV infection and renal impairment (creatinine clearance 30–70 mL/min) supports the use of TAF in this group and suggests that TAF is generally safe across a broad range of renal pathologies.[11] Individuals who developed PRT while receiving TDF, however, may be uniquely susceptible to the adverse effects of tenofovir on the kidneys and bone. While TAF has been used in a small number of individuals who developed PRT on TDF,[12–15] it remains to be confirmed whether TAF can be used safely in this group of patients.

We conducted a clinical trial of TAF in people with HIV infection and a history of PRT on TDF. We hypothesized that TAF exposure in this group of individuals would be safe and have minimal impact on renal and bone biomarkers. In this report, we compare the early changes in these biomarkers with exposure to TAF versus continued exposure to tenofovir-sparing ART.

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