The pharmacodynamics (drug absorption and elimination rates) of the two drugs that comprise Truvada may favour the efficacy of intermittent pre-exposure prophylaxis (PrEP) more than previously thought, at least when it comes to protection from transmission via anal sex, the Eighth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015) heard on Monday.
A new study, HPTN 067 or ADAPT, received a lot of attention at the conference and one of its main conclusions was that its participants found it easier to adhere to PrEP if it was taken daily than when it was taken every few days or only when sex was anticipated.
Despite this, we have evidence from the only randomised controlled trial of intermittent PrEP so far conducted, Ipergay, that this way of taking PrEP can be highly effective. In Ipergay, a two-pills-before-sex-plus-two-pills-after regimen of intermittent PrEP proved to be just as effective at preventing HIV – stopping 86% of potential infections – as the daily regimen in a near-simultaneous study of daily PrEP, PROUD. The question delegates were asking at IAS this week was: Why did Ipergay work?
Adherence in Ipergay was good, but not spectacular: 81% of participants said in self-interview that they used PrEP the last time they had sex, but only 53% said they took all doses as required. Detectable plasma levels of tenofovir, the longer-lasting of the two drugs in Truvada, were found in samples from 82 to 91% of participants in their two-monthly visits. Tenofovir levels indicated that 80 to 85% of Ipergay participants had taken PrEP at least once in the week before a sample was taken.
Was this enough to protect? Jean-Michel Molina, Ipergay’s principal investigator, said that in previous studies, 96% protection from HIV was reached after just three doses of Truvada PrEP and 99% after five doses. Adequate concentrations in blood of both of the drugs in Truvada, tenofovir and emtricitabine, were reached as soon as two hours after taking a pill but that while similar levels of emtricitabine were reached in rectal secretions in the same timespan, tenofovir did not become detectable in rectal secretions until 24 hours after the first dose. This may mean, Molina commented, that emtricitabine offers the sole protection against HIV very early on after a first dose.
In a substudy of Ipergay, volunteers were given one double dose of Truvada. Drug levels in their blood were taken before the dose and then at 30 minutes, one hour, and 2, 4, 8 and 24 hours after it. Rectal biopsies were collected from participants over the same timespan. These biopsies were also cultured along with HIV to see if they were protected from it. In rectal tissue, similarly to the findings from rectal secretions in the previous study, protective levels of emtricitabine were found as early as 30 minutes after the double dose. Adequate levels of tenofovir, however, were only found 24 hours after the dose.
Was a double dose necessary? And how about the post-sex doses? Molina said that the double dose did indeed offer twice the overall drug exposure as a single dose would. In the rectal biopsies, however, the protection offered by only one isolated double dose was just 40% – indicating that if only taken occasionally, the post-sex doses were very necessary.
David Glidden of the University of California, San Francisco, presented separate studies of the pharmacodynamics of tenofovir and emtricitabine as measured in 19 HIV-negative volunteers.
He found that tenofovir only ever reached one-tenth the levels in cervical tissue cells as it did in rectal tissue cells and that, furthermore, it took longer to approach such maximum levels – about five days in the rectum versus 10-12 days in the cervix.
In terms of protection from transmission via anal intercourse, Glidden calculated that 77% protection against HIV was reached after one dose of tenofovir. This is higher than the 38% suggested by a rectal explant study, although the lower bound of the confidence interval in this study is 40%. Estimated protection is 89% after two doses, and 98% after three: a previous substudy of the iPrEx PrEP study concluded that four doses a week would be enough to offer essentially 100% protection from HIV.
In terms of stopping PrEP, after 30 days of daily dosing, the estimated protection offered by the PrEP remaining in the body from HIV transmission via anal intercourse was 97%, 24 hours after the time of the first missed dose, 96% after three days, 93% after five days, and was still 90% a week later. However, it is not known yet how estimated protection would build up and decay when starting and stopping PrEP, in the case of HIV transmission via vaginal sex.
What does this tell us about the protectiveness of the Ipergay regimen – and of the intermittent regimens in ADAPT?
Firstly, we still do not know enough about protection in vaginal and cervical tissues to say whether or to what degree intermittent PrEP would be effective in women, or trans* men who have vaginal sex. At present, it is therefore best to recommend daily dosing for vaginal sex.
For anal sex, however, it does look as if significant protection lasts anything up to a week after the previous dose of PrEP, if people have been taking it steadily, and would be rapidly ‘topped up’ by the emtricitabine within hours of a subsequent double dose as long as the interval was no longer than that. If PrEP is taken before sex but after a long time gap, however, the post-sex doses – both of them – are very important to take too.
In this context, it is notable that the Ipergay regimen offers much greater timing flexibility, as the first post-sex dose can be taken any time in the next 24 hours; this is much easier than taking it two hours after sex, something the ADAPT participants found difficult.
There is more information to come out on the adherence patterns and individual ‘PrEP careers’ of participants in Ipergay. Until then, most experts, including the World Health Organization in their forthcoming guidelines, are likely to recommend daily PrEP as the best option. However, given that many PrEP users are unlikely to take it strictly daily in the same way as HIV-positive people have to take HIV treatment, and that many appear to alter their PrEP taking to fit around what iPrEx Principal Investigator Bob Grant called “seasons of risk”, it is important to try and set the safety limits on the efficacy of intermittent PrEP as clearly as possible.
Molina J-M and the Ipergay study team. Coitally-Dependent TDF/FTC in MSM: Updates on PrEP Efficacy in Ipergay. Symposium presentation, eighth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Presentation no MOSY0102. 2015.
Glidden D et al. How to start and stop PrEP: a pharmacology perspective (HPTN 067 and more). Symposium presentation, eighth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Presentation no MOSY0109. 2015.
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