Clinical assessment before starting PrEP
In HIV-positive patients, the use of tenofovir was reviewed in a meta-analysis and was associated with a statistically significant loss of renal function, with the effect being judged as clinically modest (12). Tenofovir use was not associated with increased risk of fractures, hypophosphataemia or severe proteinuria (12). Rarely, proximal renal tubular dysfunction (including Fanconi syndrome) may occur with TD* use (12-14).
Overall, tenofovir use in PrEP studies has not been associated with significant clinical renal problems (15-17). The Iniciativa Profilaxis Pre-Exposición (iPrEX) study showed a small but statistically significant mean decline in creatinine clearance (CrCL) from baseline but the decline in CrCL was reversible upon PrEP cessation (15). Factors associated with a decline in estimated Glomerular Filtration Rate (eGFR) include commencement of PrEP at age 40 years or over, a baseline eGFR below 90 mL/min/1.73m2, and good adherence (17). There are no data for people using PrEP who have an eGFR below 60 mL/min/1.73m2 therefore starting PrEP in individuals whose eGFR is well established to be below 60 mL/min/1.73m2 is not recommended. However, see comments below on managing individuals who are found to newly have an eGFR around 60 mL/min/1.73m2 at baseline testing.
Data from the iPrEx open-label extension (iPrEX-OLE) study found a significant increase in both urine alpha-1 microglobulin, a urine marker of impaired tubular reabsorption, and proteinuria after 6 months of TDF/FTC exposure suggesting that subclinical tubular injury occurs on PrEP (18).
There are limited data regarding whether on-demand† versus daily PrEP reduces the likelihood of renal toxicity. However, in the Intervention Préventive de l’Exposition aux Risques avec et pour les Gays (IPERGAY) study, no significant decline was observed in the mean slope of eGFR in the tenofovir and emtricitabine versus placebo arms over a median of 9.3 months follow-up (19), suggesting that on-demand† PrEP may not influence renal function. In the ADAPT study, a creatinine elevation was observed in 9% of 178 participants evaluated, but creatinine elevation did not differ between participants in the daily, time-driven and on-demand† PrEP study arms (P = 0.05) (20).
Recent data from the DISCOVER study where MSM and transgender women at risk of HIV were randomised to TDF/FTC versus tenofovir alafenamide (TAF)/FTC reported a significant difference in change in eGFR and tubular proteins during the study favouring TAF/FTC (21). More broadly the DISCOVER study found that TAF/FTC was non-inferior to TDF/FTC in terms of preventing HIV infection (21), however TAF/FTC has not been licensed yet in Australia for use as PrEP.
For all patients considered for PrEP, their risk factors for chronic kidney disease (CKD) should be assessed at baseline. These risk factors include diabetes, hypertension, smoking, concurrent medications and a known history of renal impairment or history of kidney injury or structural abnormality and Aboriginal and Torres Strait Islander status. Measurements of baseline serum creatinine, eGFR, the urine protein: creatinine ratio (PCR) and blood pressure should also be taken. The Cockcroft–Gault formula for estimating creatinine clearance (CrCl) (see Appendix 1) is regarded as the ideal way to measure the eGFR. However, for most practitioners, this is not practical. Instead, it is reasonable to measure the patient’s renal function using the eGFR as reported by the laboratories.
For individuals who are found to newly have an eGFR around 60 mL/min/1.73m2 at baseline, the eGFR should be repeated within 7 days because clinical situations occur when the eGFR may be unreliable, e.g. recent consumption of cooked meat. In this setting the clinician should ask the individual to fast or avoid a cooked meat meal within 4 hours of repeat eGFR testing. Exceptional dietary intake e.g. vegetarian diet, high protein diet, creatine supplements, and extremes of body size (e.g. high muscle mass) may underestimate eGFR. Being underweight or having low muscle mass may overestimate eGFR.
If after repeat testing an individual’s eGFR remains just below or just above 60 mL/min/1.73m2, it is recommended that the clinician speak to a specialist in PrEP as these patients may still be able to commence PrEP with close monitoring. Of note, this setting on-demand† PrEP may be a suitable option if the patient is a cis-gender MSM.
These guidelines recommend that creatinine, eGFR and urinary PCR measurements for each person are evaluated at baseline. The eGFR should be repeated 3 months after commencing PrEP then 6 monthly thereafter. However, based on currently available evidence, more intensive monitoring may be warranted in the following individuals:
- those over the age of 40 years
- those with a baseline eGFR of less than 90 mL/min/1.73 m2
- those with other comorbidities (e.g. hypertension, diabetes)
- those taking nephrotoxic drugs.
A minority of individuals may experience a decline in eGFR; the Australian CKD Management in General Practice recommends further investigations and consideration of a referral to a specialist renal service when there is sustained decrease in eGFR of 25% or more or a sustained decrease in eGFR of 15 mL/ min/1.73 m2 (22).
† The Therapeutic Goods Administration (TGA) has not approved this regimen in Australia.