On Thursday July 26th, the formidable Jean-Michel Molina presented the latest HIV incidence data from the ANRS Prevenir Study, which is an ongoing prospective cohort HIV pre-exposure prophylaxis (PrEP) study conducted in the Paris region. Participants in this study can choose to either take on-demand PrEP or continuous daily PrEP. The main purpose of this presentation was to provide additional data on the effectiveness of on-demand PrEP.

To provide some background, the effectiveness of PrEP has mainly been studied as a continuous once-daily dosing regimen, where individuals take one pill of TDF/FTC every day to protect themselves against HIV. An alternative PrEP method is on-demand PrEP (or event-based PrEP), where participants take TDF/FTC pills around a single HIV exposure event. The effectiveness of such an approach has been studied in only a few trials to date, with the most solid evidence coming from the French IPERGAY trial and its open-label extension. In the IPERGAY trial, participants were instructed to take a double-dose of TDF/FTC (i.e. two pills) 2-24 hours prior to a potential HIV exposure, to take a second dose 24h later, and a final dose 48h after the initial dose. Thus participants would take four pills (in three doses) around a single potential HIV exposure. If they foresaw a repeat potential exposure within 7 days of the initial exposure, then they would take a single dose 2-24h before exposure, followed again by another dose 24h later, and a final dose 48h after the initial dose (see picture).














In Molina’s original IPERGAY trial, the 414 male participants were randomised 1:1 to receive either active TDF/FTC or placebo pills (double blinded). During the study period, they diagnosed 16 new HIV infections, of which 14 occurred in the placebo arm, and 2 in the TDF/FTC arm, thus producing a relative risk reduction of 86% (95% CI 40 to 98; P = 0.002) (ref: Molina et al. NEJM 2015, 373(23):2237-2246). In the subsequent IPERGAY open label extension, in which all participants took active TDF/FTC, they found a 97% relative risk reduction (95% CI 81 to 100) (ref: Molina et al. Conference presentation at AIDS 2016, Durban).

Molina’s presentation at AIDS 2018 backed up these findings with a much larger cohort study. The ANRS Prevenir study enrolled 1435 participants across 22 clinical sites, between 3rd May 2017 and 1st May 2018, of which 59% had previously taken PrEP, for a median of 10 months. Participants’ median age was 37 years, and 98.7% were men who have sex with men (MSM). At enrollment, 44% of participants chose to use PrEP every day, and 53% chose the on-demand regimen. The men who chose once-daily PrEP had more sexual partners than the men who chose on-demand PrEP (median 15 vs 10 sexual partners in the last 3 months; P <0.001). Similarly, the men who chose once-daily PrEP had more condomless anal sex acts than their buddies who chose event based-PrEP (median 3 vs 2; P <0.001). The current accumulated follow-up period is 302 and 361 person-years (PY) in the daily and on-demand groups, respectively.

The HIV incidence in this cohort study is 0 (95% CI 0 to 1.2) per 100 PY in the daily PrEP group, and 0 (95% CI 0 to 1.0) per 100 PY in the on-demand group (P = 1.0). Hence this study provides reassuring evidence that on-demand PrEP is indeed an effective HIV prevention strategy for MSM.

Since the results from the IPERGAY and IPERGAY-OLE were released, it has been questioned whether their results can be extrapolated to MSM who use on-demand PrEP infrequently. In IPERGAY, participants used an average of 15 pills per month, or about 4 per week. As we know from the iPrEX pharmacokinetic analyses, this dosing frequency provides quite good protection against HIV, regardless of whether it is timed around an HIV exposure. The IPERGAY investigators responded to this concern with an analysis of IPERGAY participants who used less than 15 pills per month, and found a relative HIV risk reduction of 100%. However, due to the small number of participants in this analysis, this result had a large confidence interval (95% CI 20 to 100). (Ref: Antoni et al. Conference presentation at IAS 2017, Paris). It will be interesting to see what proportion of participants in the Prevenir cohort study were infrequent users of on-demand PrEP, so that we will hopefully have further data to support the use of on-demand PrEP in MSM wish to use this strategy for infrequent potential exposures to HIV.

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