On-demand PrEP may need a longer dosing schedule for cisgender women

A recently published study challenges the notion that on-demand pre-exposure prophylaxis (PrEP) isn’t suitable for people assigned female at birth, suggesting instead that the dosing schedule might just look different.

“There is a possibility that on-demand PrEP dosing should be tailored to women, and that [a] fourth dose may be really important,” said study author Mackenzie Cottrell, M.S., Pharm.D., a clinical pharmacologist at the University of North Carolina’s Eshelman School of Pharmacy. The research was published online on Sept. 11, 2025, in The Journal of Infectious Diseases.

Event-driven PrEP involves taking two doses of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) between two and 24 hours before sex, then a single dose 24 hours and again 48 hours after sex. This 2-1-1 approach has been well-tested in cisgender men and transgender women but no clinical trials have been conducted with cisgender women.

Prior study data evaluating daily PrEP has suggested that protection against HIV may be less forgiving when cisgender women miss doses compared to cisgender men and transgender women. Ever since, there’s been a long-standing idea that people assigned female at birth must perfectly adhere to a daily PrEP regimen for it to be effective, said Jenell Stewart, D.O., M.P.H., an infectious disease specialist with Hennepin Healthcare in Minneapolis, who was not part of the study.

“In more recent years, we’re seeing a growing body of evidence—both in terms of mathematical modeling studies, adherence effectiveness analyses, some more complex analyses of drug levels, and thinking about drug levels in different locations in the body, not just right there in the mucosa—that has led to a deeper understanding of what it takes to be protected against HIV,” Stewart said. “And a lot of these models demonstrate or suggest that fewer doses in a week are enough to be protective for people who are assigned female sex at birth.”

Cottrell and team’s pharmacokinetic model was built by giving different doses of TDF and FTC to cisgender women and measuring the change in drug levels over time in various tissues, including the rectum, vagina, and cervix. The pharmacodynamic model was built by pre-treating CD4+ cells isolated from human blood to TDF and FTC then exposing to HIV to determine what drug levels stopped infection. Coupling the models allowed the team to estimate the percentage of women protected from HIV given a particular on-demand PrEP dosing scheme—and how long the simulated cohort retained protective drug levels. The threshold for this study corresponded to drug levels that stopped 90% of viral infections, called the EC90.

This simulation study compared several on-demand, three-day dosing regimens (2-1-1, 2-2-1 and 2-2-2 regimens) and four-day dosing regimens (2-1-1-1, 2-2-1-1, 2-2-2-1, and 2-2-2-2). All of the three-day schemes resulted in above 80% of women achieving EC90 five days after sex, but the percentages dropped quickly thereafter. At seven days, only 46% of the women simulated to have taken 2-1-1 dosing reached EC90. About 69% achieved EC90 with 2-2-1 dosing and 77% with 2-2-2.

A fourth day of on-demand PrEP extended the estimated seven-day protection significantly. The 2-1-1-1 dosing schedule showed approximately 84% of women achieving EC90 after seven days while the highest result was 95% with the 2-2-2-2 dosing.

Cottrell said that while it’s unknown how long drug levels need to be maintained after exposure to HIV, seven days may be enough considering how long it takes for HIV to spread once it’s in the body. “It takes about three days for a cell to [get infected] and then start producing new virus,” she said. “And then it takes, up to six-ish days for cells around that cell to become infected and produce new virus and then to propagate all the way up to the lymph node and then to hit the blood compartment.”

As for why the modeling predicts such a big jump with a fourth day of dosing, Cotrell theorizes it comes down to FTC levels. While rectal tissue shows higher concentrations of TDF than FTC, vaginal tissue has higher FTC, but it metabolizes at a higher rate. “And so I think that the reason why that fourth day of dosing is important is because emtricitabine is clearing out more quickly,” she said, adding that the extra 24-hours of the drug seems to carry cisgender women further.

Stewart expressed concern that strategies with multiple days of taking two PrEP pills might not be well-tolerated, but said she’s open to discussing 2-1-1-1 with patients who express that daily PrEP isn’t fitting into their lifestyles. “We don’t yet have clinical trial data to really show that efficacy, but I think it’s an exciting step in the right direction for providing more choice for people, because we know when people are able to choose a method that works for their life, they’re more likely to take it and take it well,” she said.

Cottrell agrees that 2-1-1-1 should be the focus moving forward. “I think you get your biggest bang for your buck by just adding that fourth day of dosing,” she said, noting that when you add double doses on top of that, the gain is small. “We should design a clinical trial with the fourth dose to give us the best chance for proving that on-demand PrEP will work for women.

“We need it now, or yesterday.”

By Andy Carstens