Mentored Scientist Award

Effects of Emtricitabine/tenofovir Disoproxil Fumarate Use on Kidney Health in HIV Pre-exposure Prophylaxis

Headshot of Vasantha Jotwani, MD
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Pre-exposure prophylaxis (PrEP) with once-daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)
prevents acquisition of HIV infection [1-4]. Although well tolerated, [5, 6] cases of nephrotoxicity have occurred
during TDF use, especially in HIV-infected individuals. [7-23] Such cases have resolved in most [7, 22, 24-26] but
not all [15, 19, 23, 27] persons after drug discontinuation, and may involve proximal tubular dysfunction [7-13, 16,
17, 19-22, 24, 26, 28], Fanconi syndrome, [16, 24, 25], or glomerular dysfunction.[7, 10, 11, 14, 15, 21-23, 26, 27].
The iPrEx trial demonstrated a small yet statistically significant decrease in glomerular filtration rate (GFR) as
estimated by creatinine clearance associated with FTC/TDF, but found no evidence for proximal tubular injury using
conventional markers such as urinary protein, glucose, fractional excretions of phosphorus and glucose (Fig 1 and
2) [1, 29]. No statistically significant difference in incidence of renal dysfunction was observed in heterosexual men
and women on FTC/TDF as compared to placebo in African PrEP studies [33, 34]. However, creatinine-based
estimations of GFR are less sensitive than estimations of GFR using cystatin C due to bias caused by differences in
muscle mass and race, especially in HIV patients [35]. In the general population, cystatin C better predicts both
cardiovascular disease and mortality [36]. Furthermore, renal injury such as proximal tubular damage precedes
renal dysfunction and may also portend worsened renal prognosis in HIV-infected persons [31].
TDF is known to be associated with proteinuria, and proximal tubule dysfunction may be the earliest sign. It is
important to investigate the potential risks of TDF in healthy individuals in the context of PrEP trials. The known
renal effects associated with TDF use in HIV-infected individuals may not occur in HIV-uninfected persons.
Alternatively, renal toxicity due to PrEP-related TDF use may not have been detected thus far due to the use of
assays with limited sensitivity for detecting renal changes. Newer biomarkers more sensitive for injury including IL-
18, albumin-to-creatinine ratio (ACR), neutrophil gelatinase-associated lipocalin (NGAL), alpha-1 microglobulin, and
kidney injury molecule-1 (KIM-1) [30-32] are not typically assessed clinically; in recent research studies, however,
they have been used as an approach for heightened surveillance and they are associated with subsequent decline
in estimated glomerular filtration rate [31, 35] and renal allograft rejection after transplant [37].
The detection of early kidney damage using urine biomarkers may have important implications for predicting future
renal dysfunction and for PrEP safety monitoring in healthy individuals where heightened surveillance is critical.
Among randomized participants in iPrEx who contributed stored urine and blood specimens, we propose to test the
hypotheses that: (1) compared to placebo, individuals randomized to daily FTC/TDF will have higher levels of serum
cystatin C; and (2) compared to placebo, individuals randomized to FTC/TDF will have higher urine levels of
biomarkers of kidney damage.