Abstract Body

Tenofovir disoproxil fumarate (TDF) is infrequently associated with proximal tubular dysfunction in HIV-infected persons when used as part of combination antiretroviral therapy, but limited data are available for HIV-uninfected persons on TDF for pre-exposure prophylaxis (PrEP).

Data are from the Partners PrEP study, a randomized trial of daily oral TDF and emtricitabine (FTC)-TDF PrEP among African HIV-uninfected men and women (ClinicalTrials.gov:NCT00557245). We conducted: 1) a cohort analysis to determine whether FTC-TDF PrEP causes proximal tubular dysfunction among HIV-uninfected persons randomized to FTC-TDF versus placebo, and 2) a nested case-control analysis of persons on TDF or FTC-TDF to determine whether tubular dysfunction predicts subsequent clinically relevant decline in estimated glomerular filtration rate (eGFR). The primary outcome was subclinical proximal tubulopathy (PT), pre-defined as any two of the following markers of tubular dysfunction: tubular proteinuria, euglycemic glycosuria, increased urinary phosphate excretion, or increased urinary uric acid excretion. PT was assessed in concurrently obtained urine and serum samples at the 24-month visit or last on-treatment visit. For the nested case-control analysis, cases were persons on TDF or FTC-TDF with confirmed ≥25% eGFR decline from baseline and controls were persons with similar drug exposure without the ≥25% eGFR decline.

Of 1549 persons included in the cohort (776 on FTC-TDF, and 773 on placebo), 64% were male. Median age was 37 years (range 18-64) and median duration of study drug exposure was 24 months (range 3-27). The frequency of PT was 1.7% in FTC-TDF versus 1.3% in the placebo arm [odds ratio 95% confidence interval: 1.30 (0.52, 3.33); p=0.68]. PT occurred in 2 of 52 (3.8%) persons who experienced ≥25% eGFR decline versus 3 of 208 (1.4%) controls (adjusted odds ratio, 95% confidence interval: 1.40 (0.10, 14.1); p >0.99]. One person on FTC-TDF and potentially nephrotoxic co-medications developed features indicative of Fanconi syndrome.

In this large placebo-controlled study, proximal tubular dysfunction was rare and was not significantly associated with daily oral FTC-TDF PrEP over up to 24 months of observation, nor did it predict a subsequent clinically relevant decline in eGFR. These findings support the safety of TDF-based PrEP as a component of HIV prevention in healthy HIV-uninfected individuals.