Renal Impairment in a Large-Scale HIV Preexposure Prophylaxis Implementation Cohort

Douglas Drak; Hamish Mcmanus; Tobias Vickers; Jack E. Heron; Stefanie Vaccher; Iryna Zablotska; Rebecca Guy; Benjamin Bavinton; Fengyi Jin; Andrew E. Grulich; Mark Bloch; Catherine C. O'Connor; David M. Gracey


AIDS. 2021;35(14):2319-2326. 

In This Article

Abstract and Introduction


Background: HIV preexposure prophylaxis (PrEP) with fixed-dose tenofovir disoproxil fumarate (TDF) and emtricitabine has been associated with low rates of renal impairment in clinical trials. Large-scale PrEP implementation may result in higher rates, as the prevalence of associated risk factors may be higher than in trial populations.

Methods: A posthoc analysis of EPIC-NSW, a large Australian multicentre PrEP implementation trial for patients at high risk of HIV infection. Participants were eligible for inclusion if they commenced PrEP between 1 March 2016 and 30 April 2018, and had renal function assessed at baseline and at least once more before the censor date. The primary outcome was new-onset renal impairment, defined as an estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2.

Results: A total of 6808 participants were eligible for inclusion. Almost all were male (99%), with a median age of 35 years [interquartile range (IQR): 28–44]. Approximately one-quarter (26%) had a baseline eGFR <90 ml/min per 1.73 m2. Over a median follow-up period of 1.2 years (IQR: 0.6–1.7), the rate of renal impairment was 5.8 episodes per 1000 person-years [95% confidence interval (CI): 4.0–7.8]. In multivariable Cox regression, there was a higher risk of renal impairment in participants aged ≥50 years [hazard ratio (HR) 14.7, 95% CI: 5.0–43.3, P < 0.001] and those with an eGFR <90 ml/min per 1.73 m2 (HR 28.9, 95% CI: 6.9–121.9) at baseline.

Conclusion: In a large-scale implementation study, TDF-containing PrEP was associated with a low risk of renal impairment overall, whereas older patients and those with preexisting renal dysfunction were at substantially increased risk.


Preexposure prophylaxis (PrEP) with fixed-dose tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) has been shown to be efficacious in preventing HIV infection in clinical trials and, more recently, to be effective at a population level in the large-scale EPIC-NSW implementation study.[1–4] Although TDF is generally well tolerated, it is a potential nephrotoxin.

The use of TDF for PrEP is associated with a small and generally nonprogressive reduction in estimated glomerular filtration rate (eGFR), with a minority of patients developing clinically significant renal impairment.[5–7] Earlier placebo-controlled trials and subsequent implementation studies have differed, however, in the reported incidence of this TDF-associated renal impairment. A meta-analysis of the former found the risk of creatinine elevations no greater in PrEP patients than those receiving placebo.[8] In contrast, implementation studies have generally reported between two to ten-fold higher rates of renal impairment than in randomised trials, depending on how renal impairment was defined.[5,7,9–11]

These differences in the risk of renal impairment may be due to the placebo-controlled studies, and their open-label extensions, having included fewer older patients and/or patients with preexisting renal dysfunction as compared to later implementation studies, two patient groups known to be at increased risk of TDF-induced renal impairment.[7,9–11] The implementation studies have tended to be smaller than the earlier placebo-controlled trials, however.[7,8,10] The incidence of renal impairment in 'real world' PrEP populations therefore may not be well characterised.

Despite the potential for nephrotoxicity, daily dosing with TDF-containing PrEP is currently recommended by major international societies for HIV prevention and uptake of TDF-containing PrEP is increasing.[12–15] Alternatives to daily dosing with TDF-containing PrEP exist, including event-driven PrEP, which offers reduced TDF exposure, and the novel prodrug tenofovir alafenamide (TAF), with less renal toxicity.[16]

With the continued uptake of PrEP and the emergence of alternatives to daily TDF dosing, a more precise estimation of the risk of renal impairment in a 'real world' population would aid in clinical decision making. Here, we report the incidence and predictors of new-onset renal impairment in patients taking once daily PrEP for HIV prevention in EPIC-NSW, a prospective large-scale PrEP implementation study in Australia.