www.hivandhepatitis.com

IPERGAY Pre-exposure Prophylaxis Results Published

Results from the IPERGAY study of intermittent pre-exposure prophylaxis (PrEP) were published in the New England Journal of Medicine on December 1, World AIDS Day. The published results are little changed from those presented at the Conference on Retroviruses and Opportunistic Infections last February by principal investigator Jean-Michel Molina, but the researchers make a number of additional comments and are notably cautious about not over-interpreting a study that only had 400 participants -- very small for a prevention study -- and an average of 9 months’ follow-up.

[Produced in collaboration with Aidsmap.com]

Despite this, IPERGAY represents a major innovation in PrEP. It is the first -- and so far only -- randomized study to show that "on demand" PrEP can be just as effective as daily PrEP if it is given as an intermittent regimen that users only take when anticipating sex.

To summarize the results, in IPERGAY 400 men who have sex with men (defined to include transgender woman) were randomized to either take Truvada (tenofovir/emtricitabine) or a placebo. The regimen that participants were told to take was a double dose (2 pills) at 2 to 24 hours in advance of anticipated sex, and then a pill on both of the 2 days following sex. If they continued to have sex, they were to keep taking 1 pill a day until 2 days after the last time they had sex. If they restarted sex, they again were told to take a double dose if more than a week had passed since the previous sex.

The use of a placebo was somewhat controversial in IPERGAY, as some activists felt that the effectiveness of PrEP had already been sufficiently demonstrated by the iPrEx study, first published in 2010. However, effectiveness in iPrEx was only 42% overall (compared with 92% for those who took Truvada consistently), and the authors commented that, "The use of a placebo was deemed to be justified because of the inconsistent efficacy of PrEP in previous trials and the moderate efficacy in the iPrEx trial."

There were 19 new HIV infections during the whole IPERGAY trial period, but 3 of those were determined to have happened shortly before participants started taking PrEP or placebo. Besides those, there were 14 infections among men allocated to placebo and 2 among men allocated to PrEP.

In fact, neither of these 2 men had taken PrEP -- or hardly any -- in the 2-month period before they tested HIV-positive (in IPERGAY, clinic visits were every 8 weeks). One new detail added in the NEJM article is that participants were asked to return unused pills, and at the visit when they were diagnosed these 2 participants returned, respectively, 60 and 58 out of the 60 pills given to them 2 months previously.

The 14 versus 2 difference in new infections represents an 86%reduction in the risk of HIV infection for the trial participants allocated to take Truvada (95% confidence interval 40%-98%). HIV incidence in the trial was 6.6% per year among placebo recipients and 0.91% among Truvada recipients. The 6.6% is more than double the 3% incidence anticipated before the trial, though not as high as the 9% seen in the deferred PrEP arm in the English PROUD study.

Study Participants and Sexual Behavior

We learn a little more about the study participants from the NEJM report. Their average age was 34.5, with 1 in 7 participants aged 18-24 and another 1 in 7 being 25-29. The majority (62%) were aged 30-49. Only a quarter said they were in a relationship but remarkably -- and this is presumably one reason for volunteering for the study -- 30% of those in a relationship said their partner was HIV-positive (slightly more in the Truvada arm).

Half the participants were from Paris and 11% from Montreal in Canada, with the others from Lyon, Nice, Tourcoing, and Nantes in France. They reported high levels of recreational drug use (44.5% in the last year had used ecstasy, methamphetamine, amphetamine, cocaine, GHB, or GBL) and 25% had had more than 5 alcoholic drinks per day in the past month.

The men had had a median of 8 sexual partners in the past 2 months -- similar to PROUD, in which participants averaged 10 partners in the previous 3 months. This was the one behavioral indicator that changed slightly during the study: it fell to 7.5 partners per 2 months in the placebo arm but not the Truvada arm, and this was statistically significant but nonetheless likely to be a chance finding.

Apart from this slight drop in the number of partners among participants on placebo, sexual behavior did not change during the study, with 70% throughout and in both arms having condomless anal sex in the previous 2 months, and two-thirds of those having receptive sex.

Adherence

Adherence in IPERGAY has been described before; while it is challenging to measure or even define "adherence" to an intermittent regimen, 86% of participants on Truvada had levels of tenofovir in their body consistent with taking at least 1 dose a week. Interestingly, so did 8 men in the placebo arm; 3 of these had taken post-exposure prophylaxis (PEP), but presumably the other 5 had taken "informal PrEP" not provided by the trial.

Only 43% in self-reports, however, said they had taken PrEP in accordance with the study regimen last time they had sex, while 28% had not taken it at all.

On average, participants took PrEP half the time, i.e., 15 days per month; 17% took PrEP more than 26 days a month (essentially daily), while 31% took it for 11 days or fewer, i.e., less than 2.5 days per week, a level that, according to data from the iPrEx study, would not be enough to protect them from HIV if it represented a steady level of PrEP taking.

There was, however, tremendous variability in individual participants’ adherence  throughout the study. While some  took it steadily and others scarcely at all, many participants stopped or restarted PrEP irregularly, many with gaps of several months off PrEP. Since irregular adherence -- and the fact that 29% of sex was not covered by PrEP at all -- was not associated with HIV infection, this presumably means that participants were correctly judging their levels of risk and only taking PrEP when they judged it as high. 14% of participants took PEP during IPERGAY (16% on Truvada and 12% on placebo), compared with an average of 18% in PROUD.

Safety

There were no serious drug-related adverse events in the study, though 1 participant had to stop Truvada due to a suspected reaction with the anticoagulant drug dabigatran. However, there were significantly more gastrointestinal events such as nausea, vomiting, abdominal pain, or diarrhea in the Truvada group than the placebo group (14% versus 5%).

Creatinine levels -- an indication of kidney performance -- were raised in 18% of participants on Truvada versus 10% on placebo; 2 participants on Truvada had drops in creatinine clearance to below 60 mL/minute, definitive of mild kidney dysfunction, but these were transient and did not last.

Comments and Conclusions

In their comments the IPERGAY researchers are notably cautious about their findings. They commented that although the effectiveness of PrEP seen in IPERGAY was nearly the highest to date, "the short follow-up for our study may have increased the likelihood of an exaggerated estimate of efficacy due in part to high initial adherence."

They add that "given that participants took a median of 15 pills a month, the results…cannot be extrapolated to [gay men] who have less frequent sexual intercourse and thus would be taking tenofovir/emtricitabine on a more intermittent regimen." By definition, men who had sex less often would have lower HIV incidence, and so a much bigger study would be needed to establish whether intermittent PrEP was effective for them.

12/2/15

Reference

J-M Molina, C Capitant, B Spire, et al. (ANRS IPERGAY Study Group). On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection. New England Journal of Medicine 373(23):2237-2246. December 3, 2015.