Study predicts that PrEP efficacy in men is driven by drug levels in cells: matching earlier results in women

Simon Collins, HIV i-Base

A new modelling study published as an open-access paper in Nature Communications, provides further evidence that the efficacy of oral PrEP is driven by drug levels in immune cells (PBMCs), rather than levels in blood, genital or rectal tissue. [1]

These results directly affect the practical advice about adherence and how often different people need to take PrEP, supporting recent UK guidelines.

For example, lower drug levels in vaginal compared to rectal tissue led to early guidelines recommending greater adherence for receptive vaginal compared to receptive anal sex. If efficacy is driven by drug levels in PBMCs however, dosing could be the same, irrespective of sex and gender.

The new study used complicated computer modelling to analyse results from two large studies in gay and bisexual men (HPTN 083 and DISCOVERY) based on drug levels in blood, rectal tissue and PBMCs.

The modelling used two different assumptions.

One was that HIV protection was related to drug levels in rectal tissue and the other was that protection came from drug levels in immune cells circulating in blood.

When models ran each study based on these data, drug levels in rectal tissue underestimated the protection seen in the real-life studies but the actual results were predicted when using drug levels in PBMCs.

Importantly, these results complement an earlier study from 2023 that analysed results of PrEP studies in cisgender women. [2]

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These results, together with those from large observational studies, led to UK and European PrEP guidelines to expand the option of on-demand dosing to situation when the HIV risk is from receptive vaginal sex. However, this is based on using 2:7 dosing (2-dose start following by 7 daily post sex doses) rather than 2:1:1 dosing, together with a comment that this was a cautious approach and that fewer post-sex dose might be just as effective. [3, 4]

A more recent pharmacokinetic study by researchers who have previously reported the importance of drug levels in vaginal tissue, recommended that 2:1:1:1 dosing (ie using only 3 post sex daily doses) would be sufficient (rather than needing to use 2:7 dosing). [5, 6]

Other guidelines, including from WHO and US CDC still only recommend daily dosing for people having receptive vaginal sex, wanting evidence from RCTs. This is even though these studies have not been run over the last 12 years, making pharmacokinetic and modelling studies essential for bringing equity to this question.

References

Iannuzzi S et al. Pharmacological markers of HIV prevention for oral pre-exposure prophylaxis in men who have sex with men.Nat Commun 17, 4213 (2026). doi: 10.1038/s41467-026-72907-6
https://www.nature.com/articles/s41467-026-72907-6
Pharmacological markers of HIV prevention for oral pre-exposure prophylaxis in men who have sex with men. (10 May 2026).
https://www.clearskyscience.com/en/10.1038/s41467-026-72907-6/
BASHH/BHIVA. Guideline on the Use of HIV Pre-exposure Prophylaxis (2025)
https://www.bashh.org/resources/5/hiv_preexposure_prophylaxis_2025 (webpage)
https://www.bashh.org/_userfiles/pages/files/prep_2025.pdf (PDF)
EACS guidelines major update: ART, OIs, on-demand PrEP for women, weight gain, HIV-2, pregnancy, infant feeding, sleep disorders and more. HTB (25 October 2025).
https://i-base.info/htb/52581
Engel N et al. Optimizing On-Demand Tenofovir Disoproxil Fumarate/Emtricitabine Dosing in Women for HIV Prevention. J Inf Dis, 2025 jiaf459.
academic.oup.com/jid/advance-article-abstract/doi/10.1093/infdis/jiaf459/8251364
Event-based PrEP dosing for women: a challenge to guidelines and an activist issue. HTB (6 January 2026).
https://i-base.info/htb/52959