Reversibility of Glomerular Renal Function Decline in HIV-Uninfected Men and Women Discontinuing Emtricitabine-Tenofovir Disoproxil Fumarate Pre-Exposure Prophylaxis

Abstract

Background Tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis (PrEP) use is associated with a small but statistically significant decline in estimated glomerular filtration rate (eGFR). We investigated the reversibility of eGFR decline among HIV-uninfected adults discontinuing PrEP. Methods Data were from the Partners PrEP Study, a randomized trial of daily oral TDF and emtricitabine (FTC)-TDF PrEP among African HIV-uninfected men and women with baseline creatinine clearance ≥60mL/min. Serum creatinine was measured quarterly while on study medication and at month 1 and 2 after discontinuation. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration Equation. Results A total of 3924 individuals had a post-study drug serum creatinine measurement after the scheduled drug discontinuation (1271 for TDF, 1308 for FTC-TDF, and 1345 for placebo); 65% were male, median age was 35 (range 18–64) years. Median time on study drug was 33 (IQR 25–36) months overall, and 36 months (IQR 30–36) for TDF and FTC-TDF. Mean eGFR at the last on-treatment visit was 129 mL/min/1.73 m2 for TDF and 128 mL/min/1.73 m2 for FTC-TDF versus 131 mL/min/1.73 m2 for placebo (2-3 mL/min/1.73 m2 mean decline for PrEP versus placebo, p ≤0.01) and this difference reversed by 4 weeks after drug discontinuation (mean eGFR at the first post-drug visit: 130 mL/min/1.73 m2 in all groups). More than 96% of participants had a confirmed >75% eGFR rebound to baseline eGFR level by 8 weeks after drug discontinuation, with similar proportions across treatment groups. Conclusions In this large, placebo-controlled study of TDF-based PrEP, the small reduction in mean eGFR associated with PrEP reversed within weeks after discontinuation.

809 Reversal of Proximal Renal Tubular Dysfunction After Nucleotide Analogue Withdrawal in Chronic Hepatitis B

“…Previously, there have been a few case reports describing the reversal of ADV and TDF-related Fanconi's syndrome after TDF withdrawal in patients with CHB [12,26]. In contrast, our study showed that nucleotide analogue-related PRTD could be resolved in 16 CHB patients after discontinuation of nucleotide analogue similar to the phenomenon that occurs in HIV-infected patients [21][22][23][24][25]. The complete reversal of nucleotide analogue PRTD occurred in 81% of the patients at one year.…”

“…In contrast to these studies [4][5][6]17], PRTD and impaired phosphate renal tubular reabsorption were seen in 15-48% of CHB patients receiving long-term ADV and TDF therapy as in real world clinical experience [8,10,[18][19][20]. Reversibility of renal dysfunction has been shown in HIV-infected patients after cessation of TDF [21][22][23][24][25]. A few cases of reversible TDF or ADV-induced PRTD and Fanconi's syndrome have been reported in CHB patients after stopping treatment with nucleotide analogues [12,26].…”

“…The accumulation of TDF within proximal renal tubules can lead to mitochondrial injury, which has been proposed as a mechanism of TDF-induced nephrotoxicity and PRTD [36]. Discontinuation of TDF helps prevent the progression of TDF-induced nephrotoxicity despite incomplete reversibility [21,22,36].…”

Association of age, baseline kidney function, and medication exposure with declines in creatinine clearance on pre-exposure prophylaxis: an observational cohort study

“…The incidence of serious renal events in PrEP trials has been low. Moreover, in iPrEx and Partners PrEP, declines in renal function were mostly reversible 4–20 weeks after discontinuation 3,7 .…”

Safety of oral tenofovir disoproxil fumarate-based HIV pre-exposure prophylaxis use in lactating HIV-uninfected women

“…TDF, alone or with FTC, when used as PrEP is generally safe and well tolerated. Small but nonprogressive decreases in estimated creatinine clearance levels and decreases in bone mineral density can occur in a minority of persons taking TDF as PrEP but these quickly resolve within weeks of discontinuing PrEP (23–26). …”