Modelling study challenges links between gender and PrEP: event-based dosing and easier daily dosing should work for all

­Simon Collins, HIV i-Base

A detailed and complex modelling study published online in Nature Medicine challenges the view that there are gender differences in the relationship between drug levels and efficacy of PrEP. [1]

The researchers analysed results from five large PrEP studies in cisgender women and found that PrEP efficacy closely correlates with drug levels in peripheral blood mononuclear cells (PBMCs) which also contain a higher proportion of CD4 cells. Previously, PrEP efficacy was explained by levels of PrEP in blood plasma or in vaginal or colorectal tissue, and this was used to guide dosing recommendations in guidelines.

The researchers propose that different patterns of pill-taking behaviour explain inconsistent efficacy rates, rather than the current attribution to biological factors which doesn’t actually fit with the results observed in clinical data.

The study by Lanzin Zhang from the Robert Koch Institute, Berlin and colleagues was published online in the journal Nature Medicine in November 2023.

The exciting practical outcomes from their results will relax the longer lead-in for daily dosing and enable all populations to now have the option of event-based dosing.

Study design and results

The study used a top-down analysis of efficacy results from five large randomised PrEP studies (HPTN 084, FEM-PrEP, VOICE, Partners-PrEP and TDF2) to define efficacy and a bottom-up modelling approach to understand the role of adherence, exposure route (vaginal or anal) and drug pharmacokinetics using in vitro and ex vivo data to explain the mechanisms of efficacy.

Although low efficacy in the clinical trials was closely linked to adherence, this was driven by the large numbers of women who were either not taking any PrEP at all or who were only taking one tablet a week or less. This group ranged from 19% in Partners-PrEP to 71% in VOICE. The new analyses showed that any level of PrEP still provided some protection and high levels of protection were seen with 3 or 4 daily doses each week. This is significantly fewer than the 6 to 7 weekly doses that up until now has been consistently recommended.

In addition to a more sophisticated understanding of adherence, the study confirmed the early protective role of FTC, which reaches intracellular steady-state within 24 hours compared to seven days needed for tenofovir disoproxil. These data also confirm that tenofovir levels do not need to be at steady-state for optimal protections given the clinical efficacy from using 2:1:1 dosing in gay and bisexual men and transgender women in the IPERGAY and PREVENIR studies.

Simulation results for partial adherence in women showed median efficacy of 65% (IQR : 35 to 90%), when only one dose was taken weekly, increasing to 90% (IQR: 75 to 96%) and 96% (IQR:  90 to 98%) with either two or three weekly doses respectively.

The study was also able to show that levels of PrEP drugs in vaginal and colorectal tissue were not the mechanism for protection, as previously believed – otherwise PrEP efficacy would have been significantly lower than observed in the clinical trials, and women with perfect adherence taking seven daily pills every week would still not be able to achieve total protection.

Finally, the simulations highlighted that the VOICE, FEM-PrEP and TDF2 studies were underpowered to determine average efficacy because the observation times when women were actually taking PrEP were too short.

The strength of this study is that it included the five largest randomised controlled trials and that the modelling fits the wide range of outcomes they produced. The complex methodology included all permutations of multiple possible simulations in more models than summarised in this short article.

Two limitations noted by the authors include the need to test their methods in PrEP studies conducted in men and that event-based dosing in women needs to be formally assessed.


This impressive paper has the potential to increase the options for women taking PrEP and provide reassurance when pills are missed.

However, the authors caution that clinical studies are still needed and similar modelling needs to be performed for studies in gay men.

There is a need to formally study event-based dosing in cisgender women and also to evaluate shorter regimens in all populations currently advised to use the longer lead-in and daily dosing. This includes some situations for people who are transgender and non-binary.

We now need to see whether, and how quickly, these results will be integrated into PrEP guidelines, which now need to be reviewed.

This study supports earlier research into the pharmacology of PrEP, showing that everyone starting PrEP using a double dose (two pills) can achieve optimal protection within two hours, so long as the post-sex daily doses are taken as recommended. The paper by Garrett et al is notable for modelling that expands protection to percutaneous HIV exposure where the risk comes from injecting drugs. [2, 3]

As this paper proposes that 2:1:1 should be appropriate for everyone based on drugs levels achieved in PBMCs, the use of 2:7 dosing by transgender and non-binary people who want to use event-based dosing might be an overly conservative recommendation. 2:7 dosing involves taking a double dose before sex followed by daily dosing for seven days after sex.

Data supporting everyone achieving rapid protection by starting with an initial double dose is supported by the very high levels of protection observed in the IPERGAY and PREVENIR studies. [4, 5]

Updated community guide to PrEP (Feb 2024)

The latest edition of the UK guide to PrEP has been fully revised to include this latest information. It is available online and printed booklets can also be ordered online. All i-Base resources are free to individuals and UK clinics.

Thanks to Professor Sheena McCormack for discussions and comments on this paper and report.


  1. Zhang L et al. Model-based predictions of protective HIV pre-exposure prophylaxis adherence levels in cisgender women. Nat Med. 2023 Nov;29(11):2753-2762. doi: 10.1038/s41591-023-02615-x. (13 November 2023).
  2. Cottrell ML et al. A translational pharmacology approach to predicting outcomes of preexposure prophylaxis against HIV in men and women using tenofovir disoproxil fumarate with or without emtricitabine. J Infect Dis. 2016 Jul 1;214(1):55-64. doi: 10.1093/infdis/jiw077. Epub 2016 Feb 24.
  3. Garrett KL et al. A pharmacokinetic/pharmacodynamic model to predict effective HIV prophylaxis dosing strategies for people who inject drugs. J Pharmacol Exp Ther. 2018 Nov;367(2):245-251. doi: 10.1124/jpet.118.251009. Epub 2018. (27 August 2018).
  4. Molina JM et al for the IPERGAY Study Group. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med. 2015 Dec 3;373(23):2237-46. doi: 10.1056/NEJMoa1506273. Epub 2015 Dec 1. (1 December 2015).
  5. Molina JM et al for the ANRS PREVENIR Study Group. Daily and on-demand HIV pre-exposure prophylaxis with emtricitabine and tenofovir disoproxil (ANRS PREVENIR): a prospective observational cohort study. Lancet HIV. 2022 Aug;9(8):e554-e562. doi: 10.1016/S2352-3018(22)00133-3. (27 June 2022).
  6. UK Guide to PrEP. 10th edition. (February 2024). (website) (PDF)­

Links to other websites are current at date of posting but not maintained.