Injectable PrEP clearly works at least as well for cisgender women having vaginal sex as it does for people having anal sex. But there remains some uncertainty as to whether the much lower effectiveness of oral PrEP seen in most studies in women is entirely due to poorer adherence, or whether biological differences in drug absorption and elimination also contribute.
These doubts continue to affect dosing recommendations for women using PrEP and have prevented event-driven or ‘on demand’ PrEP for women from being adopted in guidelines. One 2017 paper concluded that event-driven PrEP could not work for women.
However, a modelling study presented by Dr Mackenzie Cottrell of the University of North Carolina at last week's Conference on Retroviruses and Opportunistic Infections (CROI 2025), has found that, based on studies of drug absorption and clearance, event-based dosing for women using tenofovir disoproxil / emtricitabine (TDF/FTC) should be effective. The model related drug levels in tissues in women to observed efficacy cells taken from the female genital tract, circulating lymphocytes and rectal tissue.
The recommended on-demand dose of PrEP for people having anal sex is ‘2-1-1’: a double dose of TDF/FTC before sex, then if sex happens a single dose 24 hours after the first dose, and another 48 hours later. This had exactly the same efficacy in the IPERGAY study as daily PrEP did in the contemporaneous PROUD study.
However, because drug levels are lower in the female genital tract than they are in the rectum and also fall more quickly below the concentration needed to prevent HIV, Cottrell and colleagues suggest that for event-based dosing, women would need to take an extra pill 72 hours after the first two, or ‘2-1-1-1’ dosing. This regimen, Cottrell said, would probably be even more effective than ‘2-2-2’ dosing, though it involves taking one less pill.
She noted that her findings from modelling should be tested in a clinical trial.
In detail, the efficacies the model predicts for women are that with standard 2-1-1 dosing, drug levels within five days of exposure to HIV should be enough to prevent 80% of infections in women, but that taking an extra pill (2-1-1-1 dosing) would increase this to 94% efficacy within six days after exposure, and 80% after seven.
Increasing the pill burden to a double dose on all four days (2-2-2-2 dosing) would only extend the 94% efficacy level by one more day.
The model posits what happens when just one event-driven regimen is taken, to protect against one possible exposure to HIV. The assumption is that, in situations where adherence to event-driven PrEP is imperfect, cisgender women having vaginal sex would not be protected from a second exposure to HIV for as many days as people having anal sex.
Cottrell told aidsmap: “In the HPTN084 study, for people in the oral PrEP arm, you really don’t see a difference in risk reduction between gay and bi men and trans women taking 2-3 doses a week, compared with those taking seven a week. In HPTN083 however, 2-6 doses a week offered considerably less risk reduction for women than taking seven doses.”
Cottrell’s model puts together two separate areas of study: pharmacokinetic studies that investigate drug levels reached in different tissues, and pharmacodynamic studies that show the degree of protection that is offered by different doses and timings of them.
Levels of both tenofovir and its metabolite (tenofovir diphosphate: i.e. the form cells convert it into when they absorb it) are 10-50 times lower in the female genital tract than in the rectum.
In the case of emtricitabine, its metabolite actually reaches 10-fold higher levels in cells than outside them. But whereas one model of how PrEP works (the Zhang model in this report) finds that extracellular levels of PrEP are less important than those in cells, Cottrell disagrees with this.
She agrees with the previously mentioned 2017 paper in one key aspect: within cells, naturally occurring nucleotides similar to TDF and FTC may compete with them, potentially reducing their intracellular efficacy. Therefore, drug levels outside the cell remain important, but she does not think this rules out event-driven dosing.
Cottrell told aidsmap that her model agreed with a recent study by Professor Jeanne Marrazzo that showed that taking 4-6 pills a week offered 87% protection for women, but that taking seven afforded 99%.
“I believe that seven days a week PrEP is 100% effective at stopping HIV, including in women,” she said. “And that taking a 2-1-1-1 regimen ‘on demand’ would come very close to that in women who might prefer it.”
Dumond JB et al (presenter Cottrell ML). Optimizing on-demand tenofovir disoproxil fumarate/emtricitabine dosing in women for HIV prevention. Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 157, 2025.