Event-based PrEP dosing for women: a challenge to guidelines and an activist issue
5 January 2026. Related: Early access, Guidelines, HIV prevention and transmission.
Simon Collins, HIV i-Base
Several recently published articles, including two papers in JID, look at whether PrEP efficacy is more likely to be driven by systemic drug levels in peripheral blood mononuclear cells (PBMCs) rather than by drug levels in genital and rectal mucosal tissue. [1, 2, 6]
The difference is important and not just academic.
This is because drug levels in immune cells including in PBMCs are not affected by either sex or gender or exposure risk.
Both papers support even simpler event-based dosing (sometimes called on-demand dosing) as an option for everyone – and including for cisgender women, transgender men and non-binary people, and when the exposure risk is related to injecting drugs.
Event-based dosing
Event-based 2:1:1 dosing has been an option for gay and bisexual men and transgender women for over ten years, based on results from the French/Canadian IPERGAY study. This involved taking two doses of oral TDF/FTC 24 to 2 hours before sex followed by a single dose 24 and 48 hours after. [3]
Although no randomised controlled studies (RCTs) have looked at event-based dosing in other populations, in 2025, both UK and European PrEP guidelines recommended wider use of event-based PrEP using 2:7 dosing by other people: taking a double dose of oral PrEP 24 to 2 hours before sex followed by daily single dose PrEP for seven days after. This noted that fewer than seven post doses might be just as effective. [4, 5]
The new modelling studies reported below both support only needing PrEP for either 2 or 3 days after sex, with only 4 or 5 rather than 9 tablets for coverage.
Unfortunately, other PrEP guidelines, despite also being updated in 2025, including those from WHO, IAS-USA and Canada, still only recommend event-based dosing for gay and bisexual men and for transgender women. This shows the difficulty in changing guidelines in the absence of Grade 1 and 2 data, even when the efficacy of these randomised studies is only explained by later analyses from PK/PD substudies. [6, 7]
Hypothesis 1: Drug levels in vaginal and rectal tissue
The first paper in JID, by Nathan Engel and colleagues, proposes that cisgender women could safely use event-based PrEP by using a new 2:1:1:1 dosing regimen (total five pills). [1]
This would involve taking daily PrEP for only three days after sex (2:3) rather the seven days after sex (2:7) recommended in UK and European guidelines.
Engel and colleagues used pharmacokinetic/pharmacodynamic (PK/PD) data to model rates of protection from several 3- and 4-day PrEP dosing options. This looked at different combinations of double and single doses, including 2:1:1:1, basing efficacy on maintaining EC90 levels at 5, 7 and 10 days after sex. Although levels at 10 days matched to earlier studies in rectal tissues, drug levels at 7 days was judged to be sufficient based on the 3-6 day timeframe for exposure to vaginal tissue to reach regional lymph nodes.
This research group, led by Mackenzie Cottrell at University of North Carolina, previously reported extensive modelling data that linked to women needing higher levels of adherence to daily PrEP than men and was largely based on tenofovir levels being roughly 10-fold lower in vaginal compared to rectal tissue. The new data proposing 2:1:1:1 dosing is mainly driven by higher drug levels of emtricitabine (FTC) rather than tenofovir in female genital tissue.
However, this hypothesis cannot explain the positive results from the Partner PrEP study where TDF monotherapy in cisgender women had >70% efficacy of compared to placebo, despite tenofovir concentrations never reaching effective levels in vaginal tissue.
While the authors do not recognise that drug concentrations in PBMCs would explain the Partner PrEP results, they are not able to scientifically refute the PBMC hypothesis.
Hypothesis 2: Drugs levels in PBMCs
A second paper in JID, by Susan Buchbinder and Peter Anderson, also both experienced PrEP researchers, argues for the urgency of easier dosing options for women. In reviewing the different hypotheses for PrEP efficacy this article generally supports the importance of drug levels in PBMCs. [2]
The authors stress that it is unacceptable that there have been no RCTs of event-based dosing in cisgender women over the ten years since the IPERGAY study. They note that many women might not want to use injectable PrEP, even if it does become widely available, and that event-based dosing is so significantly different to daily dosing in helping to de-medicalise PrEP, that it could potentially increase the uptake of oral PrEP in women.
As well as analysing data supporting 2:1:1:1 dosing in the Engels paper, the article also reviews research by Max von Kleist and colleagues from the Robert Koch Institute in Berlin. This group published results from two complex modelling approaches, showing that the variable clinical results reported from large RCTs of daily oral PrEP in women were more accurately explained by categorising undetectable drug levels as zero rather than low adherence. [8]
These analyses showed that drug levels in PBMCs more closely and convincingly predict the efficacy of PrEP observed in RCTs rather than reduced drug exposure in genital tissue. Importantly, similar results have now been reported when the group looked at results from large RCTs in men and transgender women, in a paper just published online ahead of peer-review. [9]
Although these results are compelling, this approach is not able to rule out that drug levels in mucosal tissue might also play a contributing role. This might just be a theoretical limitation however, as achieving target levels in PBMCs will always also imply distribution in tissue sites.
Oral PrEP using TAF compared to TDF
Buchbinder and Anderson also review data linked to important PK differences between TAF and TDF.
PrEP was originally developed using daily oral TDF/FTC but in 2019 the US FDA approved TAF/FTC which uses a different formulation of tenofovir. Although the application was for a broad indication, approval was only granted for gay and bisexual men and transgender women. The FDA panel was divided, voting 10 to 8 against a wider general indication because the DISCOVER study had not included cisgender women. [10, 11]
Although Gilead committed to further studies of TAF/FTC in women, these never materialised, despite data suggesting a better PK profile of TAF in vaginal tissue.
Importantly, TAF/FTC produced similar efficacy to the TDF/FTC control arm in the phase 3 DISCOVER RCT despite 10-fold lower tenofovir exposure in rectal tissue – and 7-fold higher levels in PBMCs. Also, no HIV infections occurred in people taking 2 or more daily doses of TAF/FTC a week.
Animal studies also show that two doses of TAF/FTC would reach protective levels in vaginal tissue that are higher than with TDF/FTC and better levels in PBMCs.
Additional PK data led to IAS-USA updating their PrEP guidelines in June 2025 to include the option for cisgender women to use daily TAF/FTC off-label as PrEP. This was based on an analysis of results in the TAF/FTC control arm in the phase 3 PURPOSE 1 study – a registrational RCT for injectable lenacapavir PrEP). IAS-USA still don’t recommend broader use of event-based dosing however. [12]
Although women in the oral TAF/FTC arm had a similar incidence of HIV to the background population with no PrEP, this result was explained by low adherence. Women who took two or more doses of oral TAF/TFC a week had an 89% reduced risk of HIV compared to women who only took one or fewer weekly doses. Only 2 of the 39 incident infections in the TAF/TFC arm showed good drug levels and one of these was through likely exposure to drug-resistant HIV. [13]
An impressive and detailed dose-finding study using 2:1:1 dosing for insertive sex reported higher tenofovir-DP concentrations in ex-vivo foreskin tissue and PBMCs with prolonged protection from TAF/FTC compared to TDF/FTC. [14]
These and other studies supported UK guidelines to recommend that TDF and TAF can both be used as oral PrEP with the same dosing options.
Of note, the increased intracellular drugs levels from TAF compared to TDF have also led to a new study by Jean-Michel Molina (who led the IPERGAY study) that only uses two doses of TAF/FTC. The SimpPrEP study uses 1:1 dosing, taking one dose of TAF/FTC 24 to 2 hours before sex and the second dose 24 hours later. This randomised open-label study being run in France and Thailand with a control arm of TAF/FTC using 2:1:1 dosing. Unfortunately, the study is only enrolling cisgender gay and bisexual men and results are unlikely to be available for at least two years. [15]
Contradictory guidelines: modelling and PK data need to be universally discussed
Currently there are important differences between PrEP guidelines, including over event-based dosing and starting with a double dose. Although guidelines don’t generally claim to be prescriptive, only offering guidance, in practice they are used to determine whether or not services are commission and provided.
Although different guidelines often use different methodologies with approaches to grading their recommendations, they should still be based on the same body of research. This isn’t currently the case though with some guideline panels not analysing PK/PD studies.
As an example, the 2025 UK guidelines produced using the GRADE system include a strong recommendation for event-based for all populations, but recognise that data from some specific population groups is limited. This led to evidence ratings of 1A if the exposure risk is receptive anal sex, IC for receptive vaginal sex and 1D for receptive neovaginal sex. This is a limitation of the way GRADE methodology recognises different types of evidence, even though receptive anal sex is accepted as a significantly higher risk than receptive vaginal sex.
Although WHO guidelines were also updated in 2025 using GRADE, cisgender women are only recommended to use daily dosing. This is because PK/PD research into the mechanism of protection has low recognition, even when the results from a large review of observational cohorts support high efficacy based on only four or more doses a week. [16].
A simpler example could be the decision by WHO to not routinely recommend that everyone could start PrEP with a double dose to have protection within two hours. This is something that would immediately improve the acceptability of PrEP and the related quality of life from rapid protection, and potentially reduce infections.
The initial double dose is supported by data showing rapidly achieving target concentrations in all compartments and practical advantages of reducing overall drug use, together with a lack of safety concerns. (As a note, HIV PEP could also arguably be improved by starting with a double dose, given the critical importance of starting as early as possible and that access is invariably delayed by many hours).
Or that the current recommendation for women to need daily dosing for a week based to reach the same target levels. This historical data is forcing women wanting to access PrEP to overcome significantly higher adherence hurdles before they even decide to start.
Transgender and non-binary people – and injection-related risks
Although many PrEP studies included transgender women, very few have actively enrolled transgender men and/or people who are non-binary, with the PURPOSE 5 lenacapavir study being the only exception.
Limited of lack of direct data however doesn’t mean that PrEP will not be just as effective in all people. This is especially the case, if the mechanism behind protection is from drug levels in PBMCs, as discussed above.
Also, all guidelines recommend that PrEP can be widely used by cisgender heterosexual men – rightly so – even though they were not included in any registrational PrEP studies.
Studies in transgender women have not reported any differences compared to cisgender gay and bisexual men, so long as adherence is as good, even though studies were likely under-powered to show differences. This includes the option to use 2:1:1 dosing. Although some biological changes could potentially be linked to higher risks for transmission, and continued research is important, these are likely to also be overcome if efficacy is significantly driven by PrEP levels in PBMCs. Importantly, there are no drug interactions between PrEP meds and gender affirming hormones.
PrEP is also rightly recommended when the exposure risk is from injecting drug rather than sexual risk, even though there is little direct evidence proving protection. This includes many problems with the Bangkok Tenofovir Study despite it being an RCT with a primary endpoint results supporting access to PrEP. If efficacy is driven by systemic distribution due to drug levels in PBMCs also favours efficacy with relatively low rates of adherence. [17]
Future research
Future research into newer formulations of PrEP include even longer acting injections: annually for lenacapavir and four-monthly for cabategravir.
Studies are also already ongoing of a single monthly oral dose of MK-8527, with a potential to work as both PrEP and PEP.
The excitement for these compounds needs to also be tempered with practical experience of access, including issues of costs and pricing, especially given the new financial climate for international funding.
It is also appropriate here to highlight the data gaps that future research is unlikely to address. If an RCT of event-based doing of oral PrEP in women has not been funded and studied over the last ten years, this certainly won’t be supported now that the priority for PrEP research has broadly shifts to long-acting formulations, which will drive commercial research.
The international funding crisis for global health issues also reduce the risk of reduced research.
comments
Greater equity of access to event-based dosing should become an urgent issue in 2026. This should be driven by the current low uptake of PrEP in main populations.
For example, currently, less than 5% of people using PrEP across Europe are women. [18]
The decision by some guidelines to limit discussion of evidence from PK/PD studies is a bottleneck that stops easier options for PrEP, both from more rapid protection by starting with a double dose and for wider use of event-based dosing. Also, although PrEP is approved based on results from large RCTs, the actual impact has always depended on secondary PK/PD analyses. This started from the first i-PrEX study in 2010 where the 43% efficacy from the primary analysis was only really understood to be closer to 95% after drug levels data was also included. [19]
Just deferring to the need for new RCTs for all recommendations avoids the significant issue that these new studies will never be either funded or run. Although the evidence level should ideally be the same for all populations, this is actually unrealistic, given studies are never powered to demonstrate efficacy in sub-groups. This aspect of the interpretation of the GRADE process for PrEP needs urgent review.
Guidelines could acknowledge that both daily and event-based PrEP is being widely recommended for cisgender heterosexual men who have never been included in any PrEP efficacy trials. To a similar extent this is also the case for transgender men. Also, that the current recommendation for transgender women to use 2:1:1 dosing – definitely a good thing – is likely only supported by data that is under-powered to be able to show efficacy.
All guidelines have a responsibility to discuss the broad range of data supporting PrEP efficacy, including event-based dosing and starting with a double dose for all populations.
Although long-acting formulations – whether injectable or oral – offer incredible promise, oral PrEP – whether TDF- or TAF-based – is highly effective, affordable and is likely to be the only available option for millions of people for years to come.
Guidelines also have a responsibility to facilitate access based on all available evidence and not to withhold access waiting for idealised research that will never be run.
References
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academic.oup.com/jid/advance-article-abstract/doi/10.1093/infdis/jiaf459/8251364 - Buchbinder SP and Anderson PL. On-Demand Dosing of HIV Preexposure Prophylaxis for Women: Has Their Time Finally Come? J Inf Dis, 2025 jiaf507.
oi.org/10.1093/infdis/jiaf507 - IPERGAY PrEP study shows early efficacy in protecting gay men from HIV: all participants to switch to active drug. HTB (29 October 2014).
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