How safe is TDF/FTC as PrEP? A systematic review and meta-analysis of the risk of adverse events in 13 randomised trials of PrEP

Tenofovir/emtricitabine (TDF/FTC) used as pre-exposure prophylaxis (PrEP) has proven benefits in preventing HIV infection. Widespread use of TDF/FTC can only be justified if the preventative benefits outweigh potential risks of adverse events. A previous meta-analysis of TDF/FTC compared to alternative tenofovir alafenamide (TAF)/FTC for treatment found no significant difference in safety endpoints when used without ritonavir or cobicistat, but more evidence around the safety of TDF/FTC is needed to address concerns and inform widespread use. A systematic review identified 13 randomised trials of PrEP, using either TDF/FTC or TDF, versus placebo or no treatment: VOICE, PROUD, IPERGAY, FEM-PrEP, TDF-2, iPrEX, IAVI Kenya, IAVI Uganda, PrEPare, PARTNERS, US Safety study, Bangkok TDF study, W African TDF study. The number of participants with grade 3/4 adverse events or serious adverse events (SAEs) was compared between treatment and control in the meta-analysis. Further analyses of specific renal and bone markers were also undertaken, with fractures as a marker of bone effects and creatinine elevations as a surrogate marker for renal impairment. Analyses were stratified by study duration (1 year of follow up). The 13 randomised trials included 15,678 participants in relevant treatment and control arms. Three studies assessed TDF use only. The number of participants with grade 3/4 adverse events was 1306/7504 (17.4%) on treatment versus 1259/7502 (16.8%) on control (difference=0%, 95% confidence interval [CI] -1% to +2%). The number of participants with SAEs was 740/7843 (9.4%) on treatment versus 795/7835 (10.1%) on no treatment (difference=0%, 95% CI -1% to +1%). The number of participants with creatinine elevations was 8/7843 on treatment versus 4/7835 on control (difference=0%, 95% CI 0%-0%). The number of participants with bone fractures was 217/5789 on treatment versus 189/5795 on control (difference=0%, 95% CI 0% to 1%). There was no difference in outcome between studies with 1 year of randomised treatment. In this meta-analysis of 13 randomised clinical trials of PrEP in 15,678 participants, there was no significant difference in risk of grade 3/4 clinical adverse events or SAEs between TDF/FTC (or TDF) and control. Furthermore, there was no significant difference in risk of specific renal or bone adverse outcomes. The favourable safety profile of TDF/FTC would support more widespread use PrEP in populations with a lower risk of HIV infec