Low Risk of Proximal Tubular Dysfunction Associated With Emtricitabine-Tenofovir Disoproxil Fumarate Preexposure Prophylaxis in Men and Women

Abstract

Objective: Tenofovir disoproxil fumarate (TDF) is associated with proximal tubular dysfunction (tubulopathy) when used in the treatment of human immunodeficiency virus (HIV) infection. We evaluated whether TDF causes tubulopathy when used as HIV preexposure prophylaxis (PrEP) and whether tubulopathy predicts clinically relevant decline (≥25%) in the estimated glomerular filtration rate (eGFR).

Methods: A subgroup analysis of the Partners PrEP Study, a randomized, placebo-controlled trial of daily oral TDF, alone or with emtricitabine (FTC), in HIV-uninfected African men and women (Clinicaltrials.gov NCT00557245). Tubulopathy was assessed in concurrently obtained urine and serum samples at the 24-month or last on-treatment visit, predefined as ≥2 of the following: tubular proteinuria, euglycemic glycosuria, increased urinary phosphate, and uric acid excretion.

Results: Of 1549 persons studied (776 receiving FTC-TDF, 773 receiving placebo), 64% were male, and the median age was 37 years. Over a median 24 months of study-drug exposure, the frequency of tubulopathy was 1.7% for FTC-TDF versus 1.3% for placebo (odds ratio, 1.30; 95% confidence interval, .52-3.33; P = .68); Tubulopathy occurred in 2 of 52 persons (3.8%) with versus 3 of 208 (1.4%) without ≥25% eGFR decline (adjusted odds ratio, 1.39; .10-14.0; P > .99).

Conclusions: Daily oral FTC-TDF PrEP was not significantly associated with tubulopathy over the course of 24 months, nor did tubulopathy predict clinically relevant eGFR decline.

Keywords: PrEP; TDF nephrotoxicity; TDF toxicity; proximal tubular dysfunction.

Figure 1.

Study flow diagram. We used 2 complementary designs to answer 2 related questions; (1) a cohort analysis to determine whether emtricitabine (FTC)–tenofovir disoproxil fumarate (TDF) preexposure prophylaxis (PrEP) causes proximal tubulopathy, and (2) a nested case-control analysis of participants receiving either FTC-TDF or TDF PrEP to investigate whether proximal tubulopathy predicts a subsequent ≥25% estimated glomerular filtration rate (eGFR) decline from baseline. The cohort analysis considered persons randomized to FTC-TDF and placebo in the Partners PrEP Study. The primary selection criterion for inclusion in the cohort analysis was the possibility to have the 24-month visit by 10 July 2011, when the study placebo arm was suspended by the data and safety monitoring board (DSMB); this criterion is based on a baseline variable “date of enrollment into the study” and thus preserves the randomized group assignment. Persons selected into the cohort approach (n = 1549) tended to be female and older, with lower creatinine clearance and elevated blood pressure at baseline—characteristics indicating a high propensity for kidney toxicity—compared with those not selected (n = 1614). The nested case-control analysis considered persons assigned to active PrEP arms (FTC-TDF or TDF) who experienced a ≥25% eGFR decline (case patients). Controls were persons receiving active PrEP who never experienced a ≥25% decline in eGFR and who were frequency matched to case patients by study arm (either TDF or FTC-TDF) and duration of drug exposure. Abbreviation: HIV, human immunodeficiency virus.