Changes in kidney function among men having sex with men starting on demand tenofovir disoproxil fumarate - emtricitabine for HIV pre-exposure prophylaxis

Abstract

Introduction: Daily pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is associated with a small but statistically significant decrease in estimated glomerular filtration rate (eGFR). We assessed the renal safety of on-demand PrEP with TDF/FTC in HIV-1 uninfected men.

Methods: We used data from the randomized double-blind placebo-controlled ANRS-IPERGAY trial and its open-label extension conducted between February 2012 and June 2016 among HIV-uninfected MSM starting on-demand PrEP. Using linear mixed model, we evaluated the mean eGFR decline from baseline over time and determined risks factors associated with eGFR decline during the study.

Results: During the blind phase, with a median follow-up of 9.4 months, the mean decline slope of eGFR from baseline was -0.88 and -1.53 mL/min/1.73 m² per year in the placebo (n = 201) and the TDF/FTC group (n = 198) respectively, with a slope difference of 0.65 mL/min/1.73 m² per year (p = 0.27). Including both phases, 389 participants started on-demand TDF/FTC with a median follow-up of 19.2 months and a mean decline of eGFR from baseline of -1.14 mL/min/1.73 m² per year (p < 0.001). The slope of eGFR reduction was not significantly different in participants with baseline eGFR ≤ 90 mL/min/1.73 m² (p = 0.44), age >40 years (p = 0.24) or hypertension (p = 0.21). There was a dose-response relationship between recent tenofovir exposure and lower eGFR when considering the number of pills taken in the two months prior the visit (eGFR difference of -0.88 mL/min/1.73 m² between >15 pills/month vs. ≤15 pills/month, p < 0.01) or plasma tenofovir concentrations at the visit (eGFR difference compared to ≤2 ng/mL: >2 to ≤10ng/mL: -0.98 mL/min/1.73 m² , >10 to ≤40ng/mL: -1.28 mL/min/1.73 m² , >40 ng/mL: -1.82 mL/min/1.73 m² , p < 0.001). Three participants discontinued TDF/FTC for eGFR < 60 mL/min/1.73 m² during the OLE phase. No case of Fanconi syndrome was reported.

Conclusions: The renal safety of on-demand PrEP with TDF/FTC was good. The overall reduction and intermittent exposure to TDF/FTC may explain this good renal safety.

Keywords: HIV; PrEP; eGFR; intermittent; kidney; on-demand; tenofovir.

Figure 1

Variation over time of estimated glomerular filtration rate according to treatment arms in the blind phase of the IPERGAY trial. The figure depicts the change over time in eGFR estimated by CKD‐EPI equation (first panel) and the change of eGFR from baseline (second panel) by study months and treatment arm. Boxes encompass all data points between the 25th and 75th percentiles. Thick bars in boxes indicate the median data value. The upper whisker extends from the hinge to the largest value no further than 1.5 * Inter‐Quartile Range (IQR). The lower whisker extends from the hinge to the smallest value at most 1.5 * IQR of the hinge. Data beyond the end of the whiskers (‘outliers’) are plotted individually. The declining slope of eGFR from baseline was −0.88 mL/min/1.73 m² per year in the placebo group (p = 0.04) and −1.53 mL/min/1.73 m² per year in the TDF/FTC group (p < 0.01) and was no different between the two arms (p = 0.27). TDF denotes tenofovir disoproxil fumarate and FTC denotes emtricitabine.

Figure 2

Distribution of estimated glomerular filtration rate changes from baseline at four weeks and six months according to treatment arms in the blind phase of the IPERGAY trial. The y‐axis and the percentages depicted inside the bars are the proportion in each treatment arm falling within the range of change in eGFR depicted to the right of the bars. TDF denotes tenofovir disoproxil fumarate and FTC denotes emtricitabine.

Figure 3

Markers of proximal tubulopathy according to treatment arms in the blind phase of the IPERGAY trial. ^aMedian of follow‐up of 9.4 months (IQR 5.1 to 20.6). Proportion of study visits with protein and glucose in urine dipsticks at baseline and during the follow‐up (median of 9.4 months) in the placebo and TDF/FTC arm. Numbers inside the bars are the number of urine dipstick accumulated after starting treatment.

Figure 4

Markers of proximal tubulopathy among all participants initiating on‐demand TDF/FTC based PrEP. ^aMedian of follow‐up of 19·2 months (IQR 18·0 to 26·9). Proportion of study visits with protein and glucose in urine dipsticks at baseline and during the follow‐up (median of 19·2 months) in all participants initiating TDF/FTC. Numbers inside the bars are the number of urine dipsticks accumulated after starting TDF/FTC.