PrEP is proven to reduce the risk of HIV acquisition. Drug levels (as markers of adherence) have been critical to interpreting disparate outcomes in PrEP trials, but can also be assessed (as markers of exposure) in relationship to adverse effects. Concentrations of tenofovir (TFV) and emtricitabine (FTC) in hair represent cumulative exposure and may be associated with toxicities in HIV-uninfected persons. We report for the first time, in a large PrEP demonstration study, the relationship between TFV/FTC levels in hair and renal function over time.
The iPrEx Open Label Extension (OLE) study enrolled HIV-negative MSM and transwomen and all were on PrEP. Hair samples were collected every 12 weeks and levels of TFV/ FTC measured via liquid chromatography/tandem mass spectrometry. Serum creatinine (Cr) was measured every 12 weeks and glomerular renal function (eGFR) estimated by Cockcroft-Gault (CG) or the MDRD equation. The association between change in eGFR over time (adjusted for baseline eGFR) and TFV/FTC levels (categorized into quartiles) was analyzed by generalized estimating equations.
Hair data and creatinine measures were available for 1144 person-visits in 202 participants followed for a median of 16.8 months. Median age 29 years (19-70); 91% MSM; 22% White, 11% Black, 6% Asian, 60% Latino/mixed. Baseline mean Cr level was 0.89mg/dL with a median baseline eGFR of 112mL/min (99-128). The eGFR for all participants on TFV/FTC decreased over 18 months, but there was a monotonic relationship between % decrease in eGFR with increasing quartile of hair level for TFV (p 0.008) and FTC (p 0.006) (Figure). For instance, mean % change in eGFR from baseline was -2.6ml/min (SE 0.8) in person-visits with TFV levels in the 1st quartile, but -5.6 (SE 0.7) when hair levels were in the 4th quartile. The odds of eGFR falling below 70 ml/min (6.1% of sample) increased with increasing quartile of TFV/FTC concentration (OR 4.4 (1.1-17.4) for 4th TFV hair quartile, p trend 0.045; OR 4.0 (0.9-17.2) for 4th FTC quartile, p trend 0.027).
We show for the first time that greater long-term exposure to TFV or FTC in patients on PrEP is associated with declining renal function over time. Hair levels of TFV/FTC were associated with decreases in eGFR and a higher likelihood of eGFR falling to <70mL/min in a monotonic fashion in iPrEX OLE. Establishing thresholds of TFV/FTC exposure that protect from HIV, but minimize the risk of toxicity, is essential to the real-world roll-out of PrEP.