Changes in Glomerular Kidney Function Among HIV-1–Uninfected Men and Women Receiving Emtricitabine–Tenofovir Disoproxil Fumarate Preexposure Prophylaxis

Abstract

IMPORTANCE Tenofovir disoproxil fumarate (TDF) use has been associated with declines in the estimated glomerular filtration rate (eGFR) when used as part of antiretroviral treatment by persons with human immunodeficiency virus (HIV) type 1, but limited data are available for risk when used as preexposure prophylaxis (PrEP) for HIV-1 prevention.OBJECTIVE To determine whether TDF-based PrEP causes eGFR decline in HIV-1-uninfected adults. DESIGN, SETTING, AND PARTICIPANTSA per-protocol safety analysis of changes in eGFR in the Partners PrEP Study, a randomized, placebo-controlled trial of daily oral TDF and emtricitabine (FTC)-TDF PrEP among heterosexual HIV-1-uninfected members of serodiscordant couples in Kenya and Uganda. The trial was conducted from 2008 to 2012. MAIN OUTCOMES AND MEASURESPredefined outcomes of this analysis were mean eGFR change and a 25% or greater eGFR decline from baseline. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTSOf 4640 participants in the once-daily TDF (n = 1548), FTC-TDF (n = 1545), or placebo (n = 1547) groups, 63% were men. At enrollment, median age was 35 years (range, 18-64 years), and mean eGFR was 130 mL/min/1.73 m 2 . During a median follow-up of 18 months (interquartile range 12-27 months), mean within-group eGFR change from baseline was +0.14 mL/min/1.73 m 2 for TDF, −0.22 mL/min/1.73 m 2 for FTC-TDF, and +1.37 mL/min/1.73 m 2 for placebo, translating into average declines in eGFR attributable to PrEP vs placebo of −1.23 mL/min/1.73 m 2 (95% CI, −2.06 to −0.40; P = .004) for TDF and −1.59 mL/min/1.73 m 2 (95% CI, −2.44 to −0.74; P < .001) for FTC-TDF. The difference in mean eGFR between PrEP and placebo appeared by 1 month after randomization, was stable through 12 months, and then appeared to wane thereafter. The respective proportions of persons who developed a confirmed 25% or greater eGFR decline from baseline by 12 and 24 months was 1.3% and 1.8% for TDF and 1.2% and 2.5% for FTC-TDF, and these frequencies were not statistically different from the confirmed decline in the placebo group (0.9% and 1.3% by 12 and 24 months, respectively). CONCLUSIONS AND RELEVANCEIn this large randomized, placebo-controlled trial among heterosexual persons, with median follow-up of 18 months and maximum follow-up of 36 months, daily oral TDF-based PrEP resulted in a small but nonprogressive decline in eGFR that was not accompanied by a substantial increase in the risk of clinically relevant (Ն25%) eGFR decline. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00557245

Reversibility of Glomerular Renal Function Decline in HIV-Uninfected Men and Women Discontinuing Emtricitabine-Tenofovir Disoproxil Fumarate Pre-Exposure Prophylaxis

“…As reported previously 10 , TDF and FTC-TDF use was associated with a small, nonprogressive decline in eGFR, and in the current analysis crude mean eGFR was 2-3 mL/min/1.73 m 2 lower in the active PrEP arms (representing annual eGFR loss of ≤1 mL/min/1.73 m 2 per year) compared to placebo at the last on-study drug visit: 129 mL/min/1.73 m 2 for TDF and 128 mL/min/1.73 m 2 for FTC-TDF versus 131 mL/min/1.73 m 2 for placebo (Table 2; p<0.01 for both TDF and FTC-TDF vs placebo). By 4 weeks after study drug discontinuation, mean eGFR were similar across the three groups (Figure): 130.1 mL/min/1.73 m 2 for TDF, 129.9 mL/min/1.73 m 2 for FTC-TDF, and 130.1 mL/min/1.73 m 2 for placebo (p>0.05 for both TDF and FTC-TDF vs placebo).…”

“…The World Health Organization and the US Centers for Disease Control and Prevention recommend TDF-based PrEP as part of a comprehensive package to prevent HIV infection in high-risk individuals 5,6 . Although generally well tolerated, TDF exposure has been associated with small but statistically significant decline in estimated glomerular filtration rate (eGFR) in HIV infected adults receiving TDF-containing antiretroviral regimens 7-9 and in HIV uninfected persons receiving TDF-based PrEP for HIV prevention 10,11 . Among HIV infected adults, kidney function returns to baseline level in a majority who discontinue TDF, but cases of less than optimal recovery have been reported 9,12 .…”

Tenofovir: What We Have Learnt After 7.5 Million Person-Years of Use

“…Small declines in eGFR after TDF initiation were again seen [32, 33]. A drawback is the limited duration of TDF use in these PreP studies to date, in conjunction with a short follow-up time.…”

Preventing long-term tenofovir renal toxicity by pharmacokinetic assessment

“…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 2 ), 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 2 [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 2 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].…”