Should event-driven PrEP be an option for women?

HIV pre-exposure prophylaxis (PrEP) could in theory stop the majority of HIV transmissions that still happen, and in some places, including England, is doing so. Yet worldwide, it is still only being used by a minority of those who could benefit from it.

A symposium during the recent Conference on Retroviruses and Opportunistic Infections (CROI 2024) saw presentations advocating changes in practice on what might be called opposite ends of the menu of PrEP options now on offer. Dr Rupa Patel of the US Centers for Disease Control and Prevention (CDC) asked why the roll-out of long-acting injectable PrEP had been so slow.

In the same session, Dr Jenell Stewart of  the Hennepin Healthcare Research Institute in Minneapolis, US argued that event-driven PrEP is demonstrably as effective as daily PrEP for gay men and trans women, and that there’s accumulating evidence that it could also work just as well for women and others who have vaginal sex. (Event-driven PrEP means taking PrEP pills not every day, but only around the time of a possible exposure to HIV.)

Event-driven PrEP should be included in guidelines as an option for everyone, she said. Failure to provide this cheap, accessible and convenient option for women who might want it is now a set of ‘dogmas’, she declared, depriving cisgender women of a choice many gay men have made and benefitted from.

The first ‘dogma’ Stewart challenged was that event-driven PrEP “only works for French men”.  This was because the only randomised placebo-controlled trial of this method, the IPERGAY trial, took place in France, where it proved to stop 86% fewer infections than placebo. (In the regimen used in IPERGAY, two pills were taken 24 hours before sex, then one 24 hours after, and another one 48 hours after the double dose.) This was exactly the same efficacy reported by the UK’s PROUD trial of daily PrEP, thus proving that the two methods were equally effective – but some PrEP guidelines continue to be cautious about it, and two influential guidelines still don’t recommend it for anyone.

Yet ‘2-1-1’ PrEP has since been widely promoted elsewhere to gay men from Australia to San Francisco without any apparent difference in HIV incidence compared to daily users.

Many PrEP users, given the choice, prefer event-driven PrEP. In PREVENIR, a French study that followed on from IPERGAY, at any one time in the 30-month study the split between daily and 2-1-1 users was roughly 50/50. But 41% of PREVENIR participants switched from one method to the other during the study, and often back again, showing that flexibility of method was desirable and appropriate. In other studies in high-income settings that allowed both methods, the proportion who chose event-driven PrEP varied from 12% to 48%, coverage appeared to be good and there were no HIV infections reported.

‘Coverage’ is a better measure of the usage of PrEP than adherence; it means the percentage of potential exposures to HIV covered by PrEP, rather than the number of pills taken. It was the key measure of success in the ADAPT studies, which provided a different event-driven PrEP regimen – just one pill 24 hours before sex and one 24 hours later – to gay and bisexual men in Bangkok and New York, and also to women in Cape Town. (Some participants were also randomised to a twice-weekly regimen, with an additional dose after sex.) 

In Bangkok, coverage did not differ by arm. In New York, coverage in the two non-daily arms was lower than in the daily PrEP arm, with 65% coverage in the daily PrEP arm, but only 41% in the non-daily arms. Nonetheless, the only HIV infection in New York happened in a man in the daily PrEP arm.

In a separate, pioneering study of PrEP among gay and bisexual men in west Africa, 74% of participants chose 2-1-1 dosing and only 26% chose daily dosing. There were 15 cases of HIV and only 41% coverage over the two arms. This was seen as showing that event-driven PrEP would not work in Africa. But in fact the overall efficacy, compared with no PrEP, was 79%, and because the number who took daily PrEP was small, there was no statistical difference between the efficacies of daily and event-driven PrEP.

What about women?

In the ADAPT study in women in Cape Town, there were four HIV infections. Coverage was 75% in the daily arm but only 52% in the non-daily arms – and the four infections were in the non-daily arms. “These events”, Stewart commented, “dampened enthusiasm for event-driven PrEP in cisgender women.”

It may be time to re-ignite this enthusiasm. The first thing to do is to address the hypothesis (or dogma) that women can’t use event-driven PrEP because their bodies handle the drugs differently.  

This derives from several studies that found that tenofovir levels in the mucosal cells lining the vagina and cervix took longer to reach steady-state drug levels, and never reached such high levels, as they did in the rectal mucosa. In the most influential study from 2016, the authors stated that “a minimum adherence to 6 of 7 doses/week (85%) was required to protect lower female genital tract tissue from HIV, while adherence to 2 of 7 doses/week (28%) was required to protect colorectal tissue.” This has been adopted as definitive by many PrEP guidelines.

Interestingly, in the case of injectable PrEP, the evidence points the other way. An early dose-finding study of long-acting cabotegravir found drug levels in the cervical and vaginal mucosal cells were very similar to those in blood plasma, but were very low in rectal mucosal cells. Yet no one disputes the findings of the HPTN 083 study – that injectable cabotegravir was 68% better at preventing HIV infection in gay and bisexual men and trans women than oral PrEP – or has argued that guidelines should not recommend it for gay men.

An answer to this puzzle came in two elegant modelling studies in Nature Medicine last November. You can read about them here but, in brief, one showed that, in oral PrEP, if tenofovir levels in the vaginal mucosa were crucial for HIV prevention, even 100% PrEP adherence in women wouldn’t be more than 50% efficacious. If, on the other hand, the levels of tenofovir inside white blood cells were what mattered, then four or more doses a week should exceed 95% efficacy.

In other words, we may have been chasing the wrong target all this time. There’s no biological reason event-driven PrEP can’t work just as well in women. It’s all about coverage.

Jenell Stewart raised a laugh when she asked, rhetorically, “Does the vagina demand perfection?”. She answered it by citing this recently published study, which, by pooling the results of PrEP studies in women, found that taking four or more pills a week was 90% effective for women – and that two to three pills was 63% effective.

Stewart said she was not suggesting that most women would prefer event-driven PrEP. But it would be a desirable option for some, especially women who are only episodically at risk (for instance, those with partners who are seasonal workers), women who know when they are going to have sex, sex workers who see clients at specific times, and any woman who wishes to minimise cost or side effects.

She compared it with contraceptives: numerous studies have shown that different people want different things, and those preferences change over time.

Event-driven PrEP for women should be reconsidered and researched further, Stewart argued. One line of research would be to compare 2-1-1 and daily PrEP. She argued that tenofovir alafenamide (TAF) rather than tenofovir disoproxil (TDF) should be tested, as TAF may work slightly better than TDF-based PrEP when 2-4 pills a week are taken.

But even in the absence of more data, the evidence is now strong enough to suggest that differences in the efficacy of event-driven versus daily PrEP are not due to intrinsic factors, but purely in how closely people tie their PrEP use to their times of risk. Guidelines should recognise this, she said.

Most guidelines – including ones from the World Health Organization, the European AIDS Clinical Society, the British HIV Association (BHIVA), the Australian body ASHM, IAS-USA, and several city and state public health departments in the United States – support event-based dosing as an option for gay and bisexual men and trans women. Many of these guidelines actually support the use of event-driven PrEP by cisgender men of any sexual orientation, even if these recommendations have not been widely publicised. And some, including BHIVA also support its use in what must be a tiny group of cisgender women who exclusively have anal sex. But none have as yet re-evaluated the evidence for people having receptive vaginal sex. And the CDC and South African guidelines still don’t recommend event-driven PrEP at all, for anyone.

This talk, as others in the session, opened with a video from a user of the PrEP method concerned. In this case, Frédérique, a French trans woman, explained how when younger and out on the ‘scene’ in Paris, she had needed daily PrEP as her lifestyle had been quite ‘chaotic’. “But now I am settled down and living in the country…I know when I’m going to have sex.” The only recommendation she wanted to make concerning even-driven PrEP was to design tough and practical PrEP packs that could easily be carried in a pocket rather than the conventional blister packs.

During the Q&A session, Professor Angela Kashuba of the University of North Carolina commented that the tissue and white blood cell concentration figures quoted did not necessarily rule out subtle but significant differences in body distribution that could have an effect. Jenell Stewart agreed, but said “We can’t exclude people from a method purely on the basis of mucosal drug levels.”

UK activist Simon Collins commented that some clinics now recommend that everyone starts PrEP with a double dose, which can be followed by a week of daily dosing.

Dr Alison Castle, who practises in rural KwaZulu Natal, commented that regardless of drug levels, the primary reason event-driven PrEP might not be suitable for many women is because gender power difference meant that women were often not in a position to predict when they might have sex. Jenell Stewart said she totally agreed, but added: “It is not up to us as practitioners to decide who can and cannot plan and predict sex.”