Renal Function Changes With TDF/FTC Used as PrEP
Renal Function Changes With TDF/FTC Used as PrEP
Objective: Tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis decreases sexual acquisition of HIV infection. We sought to evaluate the renal safety of TDF in HIV-uninfected persons.
Design and methods: The Iniciativa Profilaxis Pre-Exposición (iPrEx) study randomly assigned 2499 HIV-seronegative men and transgender women who have sex with men (MSM) to receive oral daily TDF coformulated with emtricitabine (FTC/TDF) or placebo. Serum creatinine and phosphorus during randomized treatment and after discontinuation were measured, and creatinine clearance (CrCl) was estimated by the Cockcroft–Gault equation. Indicators of proximal renal tubulopathy (fractional excretion of phosphorus and uric acid, urine protein, and glucose) were measured in a substudy.
Results: There was a small but statistically significant decrease in CrCl from baseline in the active arm, compared to placebo, which was first observed at week 4 (mean change: -2.4 vs. -1.1 ml/min; P = 0.02), persisted through the last on-treatment visit (mean change: +0.3 vs. +1.8 ml/min; P = 0.02), and resolved after stopping pre-exposure prophylaxis (mean change: -0.1 vs. 0.0 ml/min; P = 0.83). The effect was confirmed when stratifying by drug detection. The effect of FTC/TDF on CrCl did not vary by race, age, or history of hypertension. There was no difference in serum phosphate trends between the treatment arms. In the substudy, two participants receiving placebo had indicators of tubulopathy.
Conclusions: In HIV-seronegative MSM, randomization to FTC/TDF was associated with a very mild nonprogressive decrease in CrCl that was reversible and managed with routine serum creatinine monitoring.
Pre-exposure prophylaxis (PrEP) with once-daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) prevents acquisition of HIV infection. In July 2012, the US Food and Drug Administration approved oral FTC/TDF HIV PrEP and the US Centers for Disease Control and Prevention and WHO issued guidance for its use. Although well tolerated with an excellent safety profile when used in HIV-infected individuals, FTC/TDF has been associated with nephrotoxicity, resolving in most, but not all, after drug discontinuation. When present, TDF's nephrotoxicity often involves proximal tubular dysfunction, occasionally presenting as Fanconi syndrome, although declines in glomerular filtration rate (GFR) as estimated by creatinine clearance (CrCl) may also occur.
Most studies evaluating the role of TDF in renal dysfunction have been conducted in participants living with HIV, hepatitis B, and other chronic diseases that may be independently associated with kidney disease. The Iniciativa Profilaxis Pre-Exposición (iPrEx) study offers an opportunity to assess the unique effects of TDF on renal function in HIV-seronegative individuals.
Abstract and Introduction
Abstract
Objective: Tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis decreases sexual acquisition of HIV infection. We sought to evaluate the renal safety of TDF in HIV-uninfected persons.
Design and methods: The Iniciativa Profilaxis Pre-Exposición (iPrEx) study randomly assigned 2499 HIV-seronegative men and transgender women who have sex with men (MSM) to receive oral daily TDF coformulated with emtricitabine (FTC/TDF) or placebo. Serum creatinine and phosphorus during randomized treatment and after discontinuation were measured, and creatinine clearance (CrCl) was estimated by the Cockcroft–Gault equation. Indicators of proximal renal tubulopathy (fractional excretion of phosphorus and uric acid, urine protein, and glucose) were measured in a substudy.
Results: There was a small but statistically significant decrease in CrCl from baseline in the active arm, compared to placebo, which was first observed at week 4 (mean change: -2.4 vs. -1.1 ml/min; P = 0.02), persisted through the last on-treatment visit (mean change: +0.3 vs. +1.8 ml/min; P = 0.02), and resolved after stopping pre-exposure prophylaxis (mean change: -0.1 vs. 0.0 ml/min; P = 0.83). The effect was confirmed when stratifying by drug detection. The effect of FTC/TDF on CrCl did not vary by race, age, or history of hypertension. There was no difference in serum phosphate trends between the treatment arms. In the substudy, two participants receiving placebo had indicators of tubulopathy.
Conclusions: In HIV-seronegative MSM, randomization to FTC/TDF was associated with a very mild nonprogressive decrease in CrCl that was reversible and managed with routine serum creatinine monitoring.
Introduction
Pre-exposure prophylaxis (PrEP) with once-daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) prevents acquisition of HIV infection. In July 2012, the US Food and Drug Administration approved oral FTC/TDF HIV PrEP and the US Centers for Disease Control and Prevention and WHO issued guidance for its use. Although well tolerated with an excellent safety profile when used in HIV-infected individuals, FTC/TDF has been associated with nephrotoxicity, resolving in most, but not all, after drug discontinuation. When present, TDF's nephrotoxicity often involves proximal tubular dysfunction, occasionally presenting as Fanconi syndrome, although declines in glomerular filtration rate (GFR) as estimated by creatinine clearance (CrCl) may also occur.
Most studies evaluating the role of TDF in renal dysfunction have been conducted in participants living with HIV, hepatitis B, and other chronic diseases that may be independently associated with kidney disease. The Iniciativa Profilaxis Pre-Exposición (iPrEx) study offers an opportunity to assess the unique effects of TDF on renal function in HIV-seronegative individuals.