Research in context
Evidence before this study
Daily oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine is recommended by WHO and the US Centers for Disease Control and Prevention as an additional prevention tool for people at substantial risk of HIV infection, including men who have sex with men (MSM), heterosexual men and women, intravenous drug users, and HIV-negative partners in serodiscordant couples. PrEP efficacy is strongly associated with adherence, but some individuals might not be able to take daily pills for long periods of time. On-demand PrEP, taken at the time of sexual activity, might represent an interesting option for people willing to use oral PrEP without being committed to a daily regimen. A single efficacy trial, the ANRS IPERGAY trial, done among high-risk MSM in France and Canada showed an 86% (95% CI 40–98) relative reduction of HIV incidence with on-demand tenofovir disoproxil fumarate and emtricitabine compared with placebo. However, because this single trial was prematurely discontinued after a median follow-up of only 9·3 months, one cannot dismiss the possibility of an overestimation of PrEP efficacy due to high initial adherence to PrEP, and more data are needed to confirm the efficacy of PrEP on demand.
We searched PubMed with no language restrictions until Jan 27, 2017, with the terms “on demand pre exposure prophylaxis and HIV” or “intermittent”, “event driven”, “sex driven”, “time driven”, “pre exposure prophylaxis”, and “HIV”. This search yielded 91 publications. We also reviewed all trials of non-daily (event or time-driven) oral PrEP listed in the AVAC HIV Prevention Research and Development Database, which has comprehensive information on clinical trials of HIV prevention either planned, ongoing, or completed. We identified several completed and ongoing studies and demonstration projects designed to assess acceptability, safety, people preferences, pharmacokinetic models, and adherence to intermittent PrEP, but none were designed to assess efficacy. Numerous cost-effectiveness studies with intermittent PrEP have also been done.
Added value of this study
This open-label extension of the ANRS IPERGAY trial immediately followed the end of the double-blind phase of the study and all participants were offered to receive open-label on-demand PrEP. With approximately twice the number of individuals using on-demand PrEP (n=361) for a median duration of follow-up, which was also twice that of the double-blind phase (18·4 months), these results confirm and extend the effectiveness of on-demand PrEP previously reported. Indeed, the incidence of HIV infection among MSM in our study was low (0·19 case per 100 person-years), representing a 97% (95% CI 81–100) relative reduction of HIV incidence compared with the incidence in the placebo group of the double-blind phase. Additionally, the safety of on-demand treatment was good, with only 1% of participants discontinuing PrEP mainly because of a reduced plasma creatinine clearance. Furthermore, despite a reduced use of condoms, the incidence of sexually transmitted infections did not increase during this open-label extension study.
Implications of all the available evidence
On-demand tenofovir disoproxil fumarate and emtricitabine is an effective and safe alternative to daily oral PrEP with tenofovir disoproxil fumarate and emtricitabine among MSM and will expand their choices for PrEP. Research is ongoing to assess this on-demand regimen in other high-risk groups (heterosexual men and women). On-demand PrEP is recommended only in Europe and Canada among MSM, but results of this study might also inform guidelines.