The On-Demand Approach to PrEP, the HIV-Preventing Drug Regimen, Is Becoming More Popular. But Is It Safe?

Photo illustration of a shirtless man holding a bright blue PrEP Truvada pill.
Photo illustration by Slate. Photo by Marc Bruxelle/iStock/Getty Images Plus.

This post is part of Outward, Slate’s home for coverage of LGBTQ life, thought, and culture. Read more here.

An Australian man recently made headlines as the seventh reported case, worldwide, of a failure of PrEP (Pre-Exposure Prophylaxis), the groundbreaking drug regimen shown to be 99 percent effective at preventing HIV infection with daily adherence. While understandably disconcerting for users, PrEP failures are major news because they are so rare—and Truvada (tenofovir disoproxil fumarate/emtricitabine), the drug used for PrEP, is unquestionably one of the best tools we have for stopping the spread of HIV.

One notable detail of this case is that the individual, Steve Spencer (who is already undetectable and noninfectious with treatment and still an advocate for PrEP), was following what is known as an “on-demand” version of the regimen. This prescribed schedule is also known as event-driven PrEP, or PrEP 2-1-1. Essentially, when someone knows they are going to have condomless anal sex, they take a double dosage of PrEP between 2–24 hours before the encounter, and then a single pill each over the following two days. Official guidelines in Europe and Australia allow the on-demand approach, while the U.S. Food and Drug Administration has not yet approved it. Even so, some American doctors and health centers are already recommending the regimen to gay and bisexual men. While we don’t know the specific circumstances that precipitated Spencer’s seroconversion, it’s fair to ask: Is on-demand PrEP safe? And if so, who should consider using it?

To the first question, the short answer is that research shows on-demand PrEP offering significant protection against HIV with proper usage—and it is certainly better than no PrEP at all. But researchers and doctors disagree about whether it matches the effectiveness of the daily pill approach in practice.

Interest in on-demand PrEP began to grow in popularity among gay and bi men in the wake of a 2015 European study called IPERGAY. Subjects chosen because they already engaged in unprotected anal sex were told to take PrEP as-needed around sexual encounters on the 2-1-1 dosing schedule. In case of multiple consecutive episodes of sexual intercourse, participants were instructed to take one pill per day until the last instance of sexual intercourse in a given string, and then to take the final two post-exposure pills. Of the 414 subjects in the study, there were 16 cases of new HIV transmission: Two in the group taking PrEP and 14 in the placebo group, suggesting an 86 percent reduction in the incidence of HIV. Vitally, both transmissions in the group taking PrEP had stopped using PrEP many months prior to the time of transmission and were both still sexually active—in other words, they were not protected.

Another ongoing study from Europe called Prevenir has found even better results. This study, now in its third year, divides 1,435 subjects into daily and on-demand PrEP use (there is no placebo group) and has thus far found no HIV transmissions in either cohort. This suggests that on-demand PrEP can be as effective as daily PrEP use and has led the study’s authors to conclude that both dosing regimens could be recommended to the public.

These studies have led some American PrEP users and prescribers to experiment with the on-demand “disco dosing” schedule. But it’s worth being aware of the nuances of the science before trying it yourself. The original IPERGAY study has been criticized for perceived flaws, and some health advocates fear that doctors and users may be overestimating the efficacy of on-demand dosing. In particular, the major criticism of IPERGAY is that many of the subjects were having sex so often that they were essentially maintaining consistent levels of the drug in their body. The average subject in IPERGAY had five sexual encounters per month, which means on the 2-1-1 schema they took PrEP half the days each month. The question is: Can this data be extrapolated to someone who, say, has sex once per month and doesn’t have any consistent levels of the drug in his body?

Statistically speaking, it’s possible. A sub-study presented at the 9th International AIDS Society Conference in 2017 analyzed the original IPERGAY data of subjects who had three or fewer sexual encounters a month, and thus took fewer pills. Because there were no transmissions in this group (remember, the two HIV infections were in subjects who hadn’t taken their PrEP in months), it was concluded that the efficacy rate remained consistent across casual and regular on-demand PrEP users. Combine this with the Prevenir study, which showed no transmissions, and the data points to on-demand PrEP being highly effective.

But not all health professionals are rushing to recommend on-demand PrEP to their patients. According to Dr. Antonio Urbina at the Icahn School of Medicine at Mount Sinai, the results of IPERGAY and Prevenir seem to contradict medical understanding of how PrEP interacts with human tissue. But there are studies that assess PrEP users when they have varying levels of the drug in their body. The purpose of these tissue studies is to measure how long PrEP requires, and how many doses of PrEP are necessary, to reach maximal levels of saturation, and thus protection from HIV infection. These studies show it takes much longer than the “up to two hours before a sexual encounter” dosing schedule of on-demand PrEP to reach the safest levels. “To reach [maximal] protective levels of PrEP, you need to take it for one week for anal/rectal sexual encounters, and 21 days for cervical/vaginal sex,” says Urbina.

Additionally, there are variables that can influence the effectiveness of on-demand PrEP in ways statistical models can’t take into account. In terms of sex acts, “there are degrees of risk,” says Urbina. “The highest risk is receptive anal sex [bottoming] with ejaculation.” Oral sex or penetrative anal (topping) are less dangerous. Other risk factors include having other sexually transmitted infections, which can put you at greater risk of contracting HIV, receiving semen from someone with a high viral load (i.e., bottoming for someone who just contracted HIV, and doesn’t know it, and is shedding the virus at high levels), or having rough sex that may cause tears in tissues and increase the likelihood of transmission.

Beyond specific acts, some sexual situations are inherently riskier, and with those the maximal efficacy rate of daily PrEP taken for a longer period of time would be preferable. For example, if a patient was going into a situation where he might have multiple sexual encounters (possibly with internal ejaculation), like a sex party or gay cruise, Urbina would advise the patient to start PrEP as early as possible as a daily pill, and continue a month after coming back. But even that may not be ideal: Urbina says there still is not enough evidence to support “vacation dosing,” where PrEP is taken during a set period when subjects know they will be having risky sex.

This is why Urbina tends to push his patients toward daily adherence to PrEP. “The choreography of of 2-1-1 is hard, because sex is often spontaneous,” he says. “Daily PrEP is preferred because it is good for any surprise sexual encounters you may have.”

“But I do like studies of alternative models,” he adds.

Indeed, Urbina acknowledges that even if it may not provide optimal protection, there are patients who might benefit from on-demand PrEP. For example, it’s a good option for older patients who may have other medical issues (such as kidney problems) exacerbated by constant PrEP use, but still need protection for a handful of sexual encounters every year. For others the reason may be financial, given that a 30-day supply of the drug runs on the order of $1,500 a month absent any state sponsorship, insurance coverage, or copay assistance. And of course, there are always people who don’t like to take a daily pill, often because they are very sensitive to side effects, but still have risky sexual encounters that merit PrEP. (It’s worth noting that these patients might then repeatedly experience the common start-up side effects of diarrhea and nausea that usually fade after a week of daily use.) For any of these groups, 2-1-1 PrEP is better than nothing.

But what about everyone else? While studies of on-demand PrEP suggest it works effectively, there are many variables in the messiness of sex that arguably render it less dependable than the daily approach. For the majority or PrEP users, the safest, most confident approach remains swallowing that one blue pill a day.