Last December, France became the second country in the world after the United States to approve pre-exposure prophylaxis (PrEP) for HIV prevention. Since then, four more countries have given PrEP the green light, but France remains a pioneer on at least two counts.
It's the first country to make PrEP widely available at no financial cost to those who need it.
And it's the first to offer PrEP on an event-driven dosing schedule, otherwise known as intermittent PrEP.
Men who have sex with men (MSM) and transgender women whose primary route of exposure to HIV is through anal sex may choose between daily dosing or event-driven dosing. Briefly, the latter involves taking a double dose of Truvada (tenofovir/FTC) in the 24 hours before sex, another pill 24 hours after having sex and a fourth pill 48 hours afterwards. This is the approach to PrEP that French researchers found reduced HIV transmissions by 86% in the IPERGAY study.
But the event-driven schedule is only available for MSM and trans women. It has not been studied in heterosexual men, women, trans men, or people who inject drugs -- there is simply no evidence available that it would work for these groups. Moreover, due to biological differences, the approach is unlikely to work for those whose primary route of exposure to HIV is vaginal sex.
France's neighbors are also interested in the potential of event-driven PrEP. Belgium and the Netherlands are both running demonstration projects in which MSM are offered a choice of daily or event-driven PrEP and can switch between the two. In England, the draft PrEP policy that was abruptly shelved last month would have suggested event-driven dosing as the default for MSM.
But in the United States, both the FDA approval of Truvada for prevention purposes and the Centers for Disease Control and Prevention (CDC)'s guidelines only sanction daily dosing.
Might this change? If the Europeans demonstrate event-driven PrEP to be durable and effective in everyday use, could practice evolve in the United States?
An Attractive Option
There are a number of reasons why someone might want to take PrEP less frequently than daily, focusing their use of the medication on periods when they may be exposed to HIV.
First, many people have short and variable periods of being at increased exposure to HIV. Risk may be concentrated in particular moments -- such as trips away from home or time spent with particular partners. While some people find that sex is often unplanned, others tend to have a good idea of when it will occur.
Second, Truvada can cause side effects and fewer doses may lower the chances of problems occurring. The drug's impact on the kidneys may be a particular concern as people get older and for people who have health conditions.
Third, less frequent dosing could lower the cost for both the health care system and the end user. Some people might only need a handful of pills a month rather than 30.
The strongest evidence to support event-driven PrEP comes from the IPERGAY study. In this randomized clinical trial, 399 MSM and one trans woman in France and Quebec were offered either PrEP or a placebo.
The event-driven dosing that was tested went like this. Sometime between 24 and two hours before you think you might have sex, you should take two pills. If you do actually have sex, you should take another pill 24 hours after the time you took the first pills, then a pill 48 hours afterwards. You'd therefore be taking four tablets over a period of two to three days. If you continue to have sex, you're advised to continue taking PrEP once every 24 hours until 48 hours after your last encounter.
The schedule's complexity might make some people prefer daily dosing. Indeed, based on the self reporting of those in the study, adherence was hit and miss. For example, 43% had taken their pills the last time they had sex, 29% had taken some of their pills and 28% had not taken any pills at all. It seems that most people in the study stopped and restarted PrEP according to their perception of whether they were at risk -- for example, based on what they guessed or knew about a sexual partner's health status.
Whatever they were doing, it worked. In the half of men given dummy tablets, 14 acquired HIV. In those men given PrEP, only two did -- and these individuals had in fact stopped taking their tablets.
And event-driven PrEP is continuing to work for the study participants. Results from ongoing follow-up, released at this year's Conference on Retroviruses and Opportunistic Infections (CROI), shows that there have still been no new transmissions in people taking their tablets. The results actually suggest that event-driven PrEP has a higher level of efficacy than the 86% originally calculated -- probably closer to 94%.
Questions About Effectiveness
Despite the high level of efficacy seen, American officials have expressed caution.
Jonathan Mermin, M.D., of the CDC said that the study "provides the first evidence that an event-driven regimen is effective among high-risk MSM with frequent sex." But he said that attention should be given to the characteristics of those taking part.
"Since available data suggest that men in this study were taking PrEP an average of three to four days per week, CDC cautions that researchers do not yet know if this regimen will work among MSM who have sex less frequently and would therefore be taking PrEP less often."
IPERGAY's principal investigator, Jean-Michel Molina, M.D., also says that the results cannot be generalized to people having less frequent sex. But it's worth noting that while the average number of pills taken each month was 15 (i.e., three or four a week), this is just an average. There was considerable variation -- 23% of participants took fewer than five pills a month while 17% took over 25 pills.
Jonathan Mermin said that we do not know whether the regimen will work if taken only a few hours or days before sex, without any buildup of the drug from prior use. As he pointed out, studies suggest that it may take several days for tenofovir (one of the components in Truvada) to build up to maximum levels. Peak levels are reached in the rectum after five to seven days of daily dosing, while it may take 20 days to reach maximum levels in vaginal tissues.
But are maximum levels actually required before exposure? The event-driven schedule is not only working by providing a maximal level of drug before exposure to HIV, but also through the two following doses taken 24 and 48 hours afterwards.
As Jean-Michel Molina told last year's International AIDS Society conference, "The pre- and post-exposure doses both appear to be critical for providing full protection against HIV acquisition."
Molina also pointed to one intensive study of how Truvada is distributed in the body, known as Cell-PrEP.
The researchers correlated the observed levels in blood with levels that previous studies had found to be protective against HIV. They found that, after three days of daily dosing, participants had drug levels in their blood that were consistent with a 96% level of protection against HIV. After five days, there was 99% protection.
This suggests that high levels of protection are achieved quite quickly: For someone using event-based dosing when having sex for the first time in a while, the four pills may prevent most transmissions.
The CROI conference also heard from Dave Glidden, Ph.D., statistician on the iPrEx study. Glidden suggested that there were three types of data that, put together, indicated that event-driven dosing can work for people whose HIV risk is through rectal infection: first, the drug distribution data just mentioned; second, the evidence of efficacy in IPERGAY; and third, the adherence data from French MSM in IPERGAY and from Thai MSM in the smaller ADAPT study.
For her part, Sheena McCormack, M.Sc., principal investigator on the English PROUD trial, told me that she found IPERGAY's results highly persuasive. Despite the considerable variety of sexual behavior and of levels of adherence among the trial participants, event-driven PrEP was effective across the board. "It worked well for those guys who were having sex all the time and it worked well for the guys who were not having sex very often," she said.
And she sees other advantages to the approach. "It emphasizes the message that you take PrEP when you're at risk, not for the rest of your life," she said. Rather than letting people get used to a daily medication they no longer really need, the event-driven schedule encourages people to take breaks when appropriate, while clearly indicating how they can re-start.
Could these arguments lead some Americans to try event-driven dosing of PrEP? Particularly if European countries produce more data showing the safety and effectiveness of the approach, might some American doctors start to prescribe Truvada PrEP "off-label," in other words outside the terms of the FDA license?
At the same time, some individuals may learn more about the event-based dosing schedule and decide to follow it themselves, regardless of their health care provider's advice. Less consciously, someone's adherence to daily dosing may simply wane during a period in which they aren't having sex they consider to be risky.
Already on the Facebook group PrEP Facts, you can read posts from individuals interested in event-driving dosing, perhaps because they would prefer to avoid taking unnecessary medication or because they sometimes go for periods without sex. There are others who face problems with their health coverage, struggling with deductibles and co-pays, wondering if it would make more sense to spread their medication out over a longer period of time.
Although event-driven use is being raised with increasing frequency, it's fair to say that the consensus among the most active members of PrEP Facts is that daily dosing has many advantages. Being much better researched than event-driven dosing, the daily schedule is the only one approved by the CDC and FDA. And rather than being an option only for MSM and trans women, there is good evidence that daily dosing also works for women and heterosexual men. Moreover, the daily routine makes adherence easier for many people, and you don't need to be able to predict when you'll have sex.
But event-driven PrEP may look like an attractive option for some people who feel that their personal circumstances correspond with those of the participants in the IPERGAY study. In other words, it may be an option for MSM and for trans women whose main HIV risk is through being the receptive partner in anal sex, in particular individuals who have sex quite frequently and with some degree of planning or predictability.
Not for everyone certainly -- but if PrEP can be an adaptable measure better tuned to different people's needs and circumstances, it probably stands a better chance of being widely used and put into practice.