The results of the Ipergay study of pre-exposure prophylaxis (PrEP) were published in the New England Journal of Medicine (NEJM) on December 1, World AIDS. The official newspaper published the results and little has changed since those presented by CROI in February of 2015 but the researchers do a number of additional observations and are especially cautious about non-interpretation of a study that only had 400 participants - too small for a prevention study - and an average of nine months of follow-up .
Despite this, Ipergay represents a major innovation in PrEP. It is the first, and so far only, randomized study to show that an intermittent PrEP scheme, only when anticipated to sex, may be as effective as taking PrEP daily.
To sum up the results: in Ipergay, 400 homosexual men and transsexual women were randomized to take Truvada (tenofovir / emtricitabine) or a placebo.
In the scheme participants were asked to take a double dose (two tablets) 24 to two hours before sex prediction and then a pill of both the two days after sex. If they continued to have sex, they were told to keep taking one pill a day until two days after the last sex. If they reiniciassem sex, they had to take a double dose last if more than one week from the sex.
The use of placebo was considered somewhat controversial in some activists and Ipergay considered that the efficacy of PrEP has been sufficiently demonstrated by the study 2010 iPrEx. However, the efficacy in iPrEx was only 42% of the total, and the researchers commented that "the use of a placebo was considered justifiable by the fact of the incoherent efficacy of PrEP in previous trials and the moderate efficacy according to the iPrEx test."
There was 19 HIV infections throughout the Ipergay trial period, but three of them were determined to have happened shortly before participants started PrEP / placebo. 14 infections were identified in men who were randomized to receive placebo and two men affected in use of PrEP.
In fact, none of these men had taken PrEP, or almost no PrEP, within two months before they tested positive (in Ipergay, outpatient appointments were done every eight weeks). A new detail added in the NEJM cohort is that participants were asked to return the unused tablets as well as those from the visit in which they were diagnosed, these two participants respectively returned 60 and 58 from the 60 tablets given to them two months earlier.
The 14/2 differences in infections represent an 86% (95% confidence interval: 40% -98%) reduction in the risk of infection by HIV study participants assigned to the Truvada. HIV incidence in the study was 6,6% per year in the placebo group and 0,91% in the group receiving Truvada. The 6,6% is more than double the 3% expected incidence before the study, although not as high as the 9% observed in the differentiated arm of PrEP in the PROUD study.
Study participants and sexual behavior
We learned a bit more about the participants in the study report. The average age was 34,5, with one in seven participants aged 18 to 24 years old and another seven from 25 to 29. Most (62%) aged 30 to 49 years. Just a quarter said they were in a more remarkable relationship - and this is probably one of the reasons for volunteering for the study - 30% of people in a relationship, the partner was HIV-positive (slightly more than in the arm of the Truvada).
Half of the participants were from Paris and 11% of Montréal in Canada, with others in Lyon, Nice, Nantes and Tourcoing, France. They had high levels of recreational drug use (44,5% last year, had used ecstasy, methamphetamine, amphetamine, cocaine, GHB or GBL) and 25% had more than five alcoholic drinks a day last month.
The men had a median number of eight sexual partners in the last two months - similar to the PROUD, where the average participants ten in the previous three months. This was the only behavioral indicator that changed a bit during the study: it fell from 7,5 partners for two months in the placebo arm and not in the Truvada arm, which was statistically significant but still likely to be found.
In addition to this slight drop in the number of partners in the placebo group participants, sexual behavior did not change during the study, with 70% throughout the study and in both arms having unprotected insertive anal sex in the previous two months, and two thirds of those who received unprotected receptive anal sex.
Adhesion was as previously described: while it is difficult to measure or even define 'adhesion' to an intermittent scheme, 86% of participants Truvada had tenofovir levels in their body consistent with what they would have taken at least one dose a week. The interesting thing is that so did eight men on the placebo; these three had taken post-exposure prophylaxis (PEP), mas provavelmente os outros cinco tinham tomado “informal PrEP”.
Only 43% self report, however, said they had taken PrEP in accordance with the study scheme the last time you had sex, while 28% had not taken at all.
On average, half of the participants were PrEP time, ie 15 days per month; 17% took PrEP over 26 days per month, or basically daily while 31% took for eleven days or less, or less than 2,5 days per week, a level which, according to the study data iPrEx would not be enough to protect them against HIV if it was a stable level of PrEP.
There was, however, a huge variability for each participant, "the bondline during the study, while some advantage on continuously and the other in practically all, many of the participants have stopped or restarted PrEP irregularly, many with gaps several months without Prep. Once irregular adherence (and the fact that 29% of sex was not covered by PrEP in all) was not associated with HIV infection, it probably means that the participants were able to correctly assess their risk levels and only if used PrEP when they judged the ratio as high risk.
Fourteen percent of participants had PEP during Ipergay (16% on Truvada and 12% in the placebo group), compared with an average of 18% of proud.
There were no serious adverse events related to study medication although one participant had to stop Truvada due to the suspicion of a reaction with the anticoagulant dabigatran. However, they were not significantly greater than gastrointestinal tract events, such as nausea, vomiting, abdominal pain or diarrhea, the group made more use of Truvada than the placebo group (14% versus 5%).
Creatinine levels, an indication of renal performance, were raised in 18% of participants Truvada versus 10% in the placebo group. Two participants from Truvada had declines in creatinine clearance lower than 60 ml / min, the definition of mild renal dysfunction, but these were transient rather than definitive.
The observations and conclusions
In their observations, the researchers Ipergay are especially cautious about their findings. They note that although the effectiveness of PrEP Ipergay was almost the most up to date, "short follow up time for our study may have increased the likelihood of an over-estimation of effectiveness due to high initial adhesion."
They add that "given that the participants had an average of 15 tablets per month, the results ... can not be extrapolated to [homosexuals] that have less frequent sex and therefore would be taking tenofovir / emtricitabine in a scheme yet more intermittent. "
By definition, men who had sex less times who have lower HIV incidence and therefore a much larger study would need to determine whether intermittent PrEP was effective for them.
Molina JM et al. On-demand preexposure prophylaxis in man at high risk for HIV-1 infection. NEJM beginning publication online, DOI: 10.1056 / NEJMoa1506273. Up to 2015. See full text here