Preventing long-term tenofovir renal toxicity by pharmacokinetic assessment

Abstract

Tenofovir is the active metabolite of tenofovir disoproxil fumarate (TDF), a commonly used antiretroviral agent in HIV treatment and in HIV preexposure prophylaxis. After a long-term exposure, TDF is associated with kidney impairment. In the D:A:D study cohort of HIV-infected patients (22 603 HIV-infected patients with baseline estimated glomerular filtration rate (eGFR) 90 ml/min per 1.73 m), tenofovir exposure was associated after adjustment with an increased relative risk (1.18 a year) of developing chronic kidney disease (CKD) defined by the occurrence of an eGFR below 70 ml/min per 1.73 m [1]. Recent studies also suggested that tenofovir use in preexposure prophylaxis might also be associated with a weak decline in eGFR, a mean decrease in eGFR after 60 months of treatment was 6 ml/min in the Bangkok Tenofovir study [2], and around 2 ml/min per 1.73 m during a median follow-up of 18 months in Partners Prep Study [3]. The decline in eGFR associated with tenofovir use is not always reversible after treatment cessation [4]. Tenofovir has a mitochondrial toxicity in tubular cells, leading to kidney tubular dysfunction (KTD) [5]. KTD affects 10.6–19% of the patients receiving tenofovir [6,7]. Tubular tenofovir toxicity is probably dose dependent. Indeed, an association between high-trough tenofovir plasma concentrations and KTD (defined by hypophosphatemia, hypouricemia, nondiabetic glucosuria, b-2 microglobulinuria, or a-1 microglobulinuria) was previously observed [6,7]. However, a decrease in eGFR may be observed without evidence for KTD. It is crucial to identify mechanisms and risk factors of tenofovir renal toxicity. Tenofovir penetrates in tubular cells by several tubular transporters. Polymorphisms in genes encoding for tubular transporters organic cationic transporter 1, multidrug resistant protein 2 (MRP-2) and 4 (MRP-4) were associated with increased tenofovir plasma concentrations and increased risk of KTD or of decrease in eGFR [8–11].