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Background:  Tenofovir DF (TDF) is a nucleotide analog reverse transcriptase inhibitor (NRTI) used for the treatment of HIV disease. Despite demonstrated renal safety in several clinical trials, case reports, and observational data suggest that it may be associated with nephrotoxicity.

Methods:  We analyzed data from a large prospective observational cohort, comparing all patients who initiated TDF (n = 344) or an alternative NRTI (n = 314) after January 1, 2001 and who had at least 2 blood samples drawn to test for serum creatinine (Cr) within 90 days of initiation. We assessed change and percentage change in calculated creatinine clearance (CL_Cr) over the study period for each subject. Baseline CL_Cr was calculated using the Cockcroft-Gault equation using the average of the 2 serum Cr measurements obtained closest to the start of therapy.

Results:  TDF recipients had greater increases in Cr and greater absolute and percentage declines in CL_Cr than those in the NRTI group, although there was no difference in rates of discontinuation coincident with maximum decline in CL_Cr. Median baseline Cr and CL_Cr were 0.8 mg/dL and 117.5 mL/min, respectively, with no differences between groups. Median Cr change was +0.15 and +0.10 in the TDF and NRTI groups, respectively (p = 0.01). Median CL_Cr change was –13.35 and –7.5 mL/min (p = 0.005). The changes were apparent by 90 days of therapy and persisted over the entire year. The percentage change in CL_Cr was also associated with longer duration of treatment with TDF or the NRTI, diabetes, higher baseline Cr, and CD4 count <50 cells/mm³ (p <0.05). In a multivariate analysis only TDF use and lower CD4 count were associated with CL_Cr decline (p < 0.05), with a trend toward association with lower baseline CL_Cr and diabetes. In this analysis, hypertension, use of ritonavir-boosted lopinavir or any other concomitant ART, viral load, previous use of adefovir, age, sex, race, and HIV transmission risk group were not associated with CL_Cr decline.

Conclusions:  Use of TDF is associated with a modest decline in CL_Cr, especially in patients with baseline renal insufficiency, diabetes, or low CD4 count. While the differences were statistically significant, they were small in magnitude and of unclear clinical significance. Patients at risk for renal dysfunction should be carefully monitored when taking TDF, and the dosing interval should be adjusted when indicated by a reduced Cr clearance.

Keywords: tenofovir; nephrotoxicity; renal function