Renal Function and Tenofovir Disoproxil Fumarate for Preexposure Prophylaxis: How Safe Is Safe Enough?

Recent studies have demonstrated that daily use of oral tenofovir disoproxil fumarate (TDF), with or without emtricitabine (FTC), for preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV) infection can decrease the incidence of HIV infection in diverse populations, including men who have sex with men (MSM), transgender women, at-risk heterosexuals, and persons who use injection drugs [1–4]. In these studies, efficacy was directly correlated with medication adherence. Based on the evidence from these studies, in 2012 the Food and Drug Administration approved oncedaily, coformulated TDF and FTC (TDFFTC) for use as PrEP, and in 2014 the Centers for Disease Control and Prevention issued guidelines recommending TDF-FTC PrEP for HIV prevention [5]. Subsequent studies of PrEP use by at-risk MSM in care settings have observed high levels of adherence and very low HIV infection incidences despite high rates of sexually transmitted infections, suggesting that PrEP can be highly effective under real-world conditions [6, 7]. As PrEP is a prophylactic intervention and not a treatment for established disease, potential PrEP users and their clinicians will need to weigh carefully the benefits of its use against the potential risks of experiencing medication toxicities from daily exposure to TDF-FTC. When used as treatment for HIV infection, TDF has been associated with acute and chronic kidney injury [8], including small decreases in the glomerular filtration rate and damage to renal proximal tubules. In the efficacy studies of PrEP, renal adverse events were rare and did not differ in frequency among participants randomly assigned to use active drug or placebo. However, a meta-analysis of randomized studies with TDF-based PrEP found that participants assigned to use PrEP had a 36% increased risk of an elevated creatinine level, although nearly all of these elevations were mild and normalized after discontinuation of PrEP [9]. While primary safety analyses from randomized studies have tended to focus on whether TDF-based PrEP affects rates of glomerular filtration, less attention has been given to its effect on proximal tubular function, which could also have important safety implications. In this issue of The Journal of Infectious Diseases, Mugwanya et al analyzed data from the Partners PrEP study, a randomized, placebo-controlled study of daily PrEP with TDF or TDFFTC amongHIV-uninfected Africanmen and women in HIV-serodiscordant partnerships, to ascertain rates of proximal tubular dysfunction and whether its occurrence predicts decreased renal function [10]. In an analysis that compared rates of proximal tubulopathy among participants assigned to receive TDFFTC or placebo, the authors found that, over a median drug-exposure period of 24 months, tubular damage was rare (occurring in <2% of participants) and that rates of tubular dysfunction did not differ by treatment assignment. In an additional, nested case-control analysis restricted to participants who received active drug (either TDF or TDF-FTC), the authors found that rates of proximal tubular dysfunction did not differ among participants who experienced a clinically significant decline in renal function (defined as a 25% decrease in estimated glomerular filtration rate) and those who did not experience declines in renal function. Based on these findings, the authors conclude that routine monitoring for markers of tubular damage to predict decreases in renal function is not likely to be an efficient strategy in care settings. However, because 1 participant assigned to TDFFTC developed severe Fanconi syndrome while using potentially nephrotoxic medications in addition to PrEP, the authors also suggest that monitoring for tubular dysfunction may be prudent for individuals at increased risk for renal injury. Although it is reassuring that TDFbased PrEP has not been associated with proximal tubular dysfunction or serious nephrotoxicity in randomized studies, caution is warranted when extrapolating these findings outside of controlled studies. These studies did not enroll individuals with abnormal renal function or risk factors for kidney disease, so the safety of TDF-based PrEP for such individuals is not known. Participants in these studies also generally received PrEP for <2 years, and some participants were not Received and accepted 19 April 2016; published online 27 April 2016. Correspondence: D. S. Krakower, Division of Infectious Diseases, Israel Deaconess Medical Center, 110 Francis St, WLMOB, Ste GB, Boston, MA 02215 (dkrakowe@bidmc. harvard.edu). The Journal of Infectious Diseases 2016;214:983–5 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup. com. DOI: 10.1093/infdis/jiw169