Switching to Abacavir Versus Use of a Nucleoside-Sparing Dual Regimen for HIV-Infected Patients With Tenofovir-Associated Renal Toxicity

JL Casado; C Santiuste; MJ Vivancos; M Monsalvo; A Moreno; MJ Perez-Elías; JM del Rey; S Moreno

Disclosures

HIV Medicine. 2018;19(8):541-550. 

In This Article

Abstract and Introduction

Abstract

Objectives: We investigated the reversibility of tenofovir disoproxil fumarate (TDF)-associated renal decline and tubular dysfunction using different antiretroviral strategies.

Methods: A successive evaluation of renal [estimated glomerular filtration rate (eGFR)] and tubular (phosphataemia, proteinuria, albuminuria, phosphaturia, uricosuria, glycosuria and tubular proteinuria) parameters was performed in 231 patients, before and after switching from TDF to abacavir (n = 60), using dual therapy (n = 49), or continuing the same regimen including TDF (n = 122).

Results: In a successive evaluation after a median of 8.86 months, or less time if treatment was switched (4.8 months vs. 13.3 months to second evaluation; P < 0.01), a significant improvement in eGFR (median change +0.3 vs. −2.91 mL/min/1.73 m2 in patients who did not discontinue TDF; P = 0.04) and tubular dysfunction (median change −40% vs. +30%, respectively; P < 0.01) was observed. Lineal regression showed that age (β = −0.14; P = 0.04), previous eGFR decline (β = –0.42; P < 0.01), and time on TDF (β = −0.19; P = 0.04) were associated with impaired eGFR recovery. There were no differences in eGFR slopes between patients using abacavir instead of TDF and those using a dual therapy, who showed similar improvement in proteinuria (−22% vs. −19%, respectively), phosphaturia (+10.1% vs. +9.4%, respectively), and urinary beta-2-microglobulin (−9% vs. −15%, respectively; P > 0.1 for all), although patients receiving the dual regimen were more heavily pretreated. A eGFR decrease (−6.17 mL/min/1.73 m2) was observed in patients taking dolutegravir or rilpivirine, but with similar improvement to that observed in the rest of switching patients in tubular abnormalities.

Conclusions: Tenofovir disoproxil fumarate discontinuation was associated with a rapid and significant improvement in eGFR and tubular abnormalities, regardless of whether abacavir or dual therapy was chosen. Switching to a regimen that included dolutegravir and/or rilpivirine was associated with a eGFR decrease without differences in the rate of tubular dysfunction improvement in comparison with the rest of patients who discontinued tenofovir.

Introduction

Renal toxicity is an important issue in HIV-infected patients. Cohort studies have shown an increase in the incidence of chronic kidney disease (CKD) and a decrease in the estimated glomerular filtration rate (eGFR) in this population, related to traditional risk factors, advanced immunosuppression and the effects of various antiretroviral drugs.[1,2] Among antiretroviral drugs, tenofovir disoproxil fumarate (TDF) has been found to be associated with a high rate of tubular renal dysfunction and a mild but progressive kidney function decline in clinical cohorts, and these effects have been attributed to mitochondrial toxicity in proximal tubule cells.[3–5]

Several studies have shown a partial improvement after TDF withdrawal, which was associated with several factors such as eGFR at treatment initiation and interruption, age, and time on TDF.[6,7] We recently showed that switching from TDF was associated with a significant decrease in various tubular abnormalities and a significant improvement in eGFR.[8] However, no studies have evaluated the best combination antiretroviral therapy (cART) option in these patients with TDF-associated renal and tubular toxicity.

Hypothetically, because TDF causes tubular disease, stopping TDF switching from TDF to another treatment option should produce a renal outcome that is independent of the chosen option. However, studies enrolling large cohorts found an independent role for protease inhibitors (PIs) such as lopinavir or atazanavir as a cause of eGFR deterioration.[1,9] Using TDF together with a boosted PI was shown to produce more marked renal deterioration, which was attributed to higher plasma drug levels and intracellular TDF concentration in tubule cells. However, it is possible that using abacavir, which is also a nucleoside reverse transcriptase inhibitor (NRTI), could be less effective in reversing mitochondrial toxicity after TDF use. Moreover, the recent introduction of different antiretroviral drugs known to alter tubular secretion of serum creatinine, such as dolutegravir (DTG), rilpivirine (RPV) or cobicistat, could interfere with the evaluation of renal outcome after TDF withdrawal.[10,11]

To date, there is no consensus on the best option to use when discontinuing TDF, if several antiretroviral options are available, or whether it is safe to change if treatment options are limited. Thus, we analysed the evolution of renal and tubular disease in a cohort of patients who discontinued TDF, and were switched to an NRTI-sparing dual regimen or only changed from TDF to abacavir.

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