Background:  A growing number of case reports have associated tenofovir (TDF) use with nephropathy, in particular proximal renal tubulopathy and impaired calculated glomerular filtration rates (cGFR). Data from larger observational HIV cohorts is limited.

Methods:  Changes of the cGFR were retrospectively analyzed for patients in the Swiss HIV Cohort Study (SHCS). We defined 2 endpoints:  time to a sustained decrease in cGFR over at least 1 month of ≥10 mL/minute, and ≥10% from cGFR at initiation or re-initiation of combined ART (cART). We compared treatment-naïve patients initiating cART with (group 1, n = 100) or without TDF (group 3, n = 357), as well as patients re-initiating cART after at least 1 year with (group 2, n = 113) and without TDF (group 4, n = 137). The endpoints were analyzed with Kaplan-Meier plots. The effect of TDF was investigated with a multiple Cox proportional hazard model adjusted for baseline variables such as demographic parameters, HIV RNA, actual and nadir CD4 count, AIDS status, cART exposure, risk factors for arteriosclerosis, and cotrimoxazole co-medication. Also, we specifically analyzed all the patients who had to stop TDF because of drug-related nephrotoxicity.

Results:  Results based on the Cockcroft-Gault and the modification of diet in renal disease (MDRD) equation for cGFR were highly consistent. For Cockcroft-Gault, endpoint A (B) was reached in 33.0% (30.0%) in group 1, 35.4% (35.4%) in group 2, 17.9% (19.1%) in group 3, and 19.7% (19.0%) in group 4 (p <0.001 for group (1+2) vs (3+4)). The probabilities not to reach a 10 mL/minute reduction in cGFR at 6, 12, and 24 months for group (1+2) vs (3+4) were 0.79 vs 0.89, 0.67 vs 0.85, and 0.48 vs 0.79, respectively. In the multiple Cox regression analysis, patients on TDF had a significantly increased risk to reach both endpoints (hazard ratio [HR] 2.63, 95%CL 1.87 to 3.69). The HR for baseline cGFR was 1.03 (1.02 to 1.04). Diabetes mellitus (HR 2.50, 0.87 to 7.17) was not significant probably due to the small sample size. Prior AIDS was an independent risk factor for both endpoints for MDRD, but not for Cockcroft-Gault data. Altogether, 46 (1.6%) of 2592 TDF-treated patients had to stop TDF because of drug-related nephrotoxicity after a mean of 442 (±324) days.

Conclusions:  Initiating cART was associated with a substantial decrease in cGFR in all subpopulations studied. This decrease was significantly more frequent in patients treated with TDF. HIV-related patient characteristics had little impact on cGFR dynamics.