The iPrEx study

The first randomised controlled trial of PrEP in humans to produce a statistically meaningful result announced its findings on 23 November 2010. The iPrEx (Pre-exposure Prophylaxis Initiative) trial found that the HIV infection rate in HIV-negative gay men who were given a daily pill containing two HIV drugs was reduced by 44%, compared with men given a placebo.¹

The efficacy in subjects who, by self-report and pill count, took the drugs more than 90% of the time was 73%.

The other big finding of the trial was that while 93% of trial subjects reported taking the pills correctly, on the basis of drug-level monitoring in blood tests only 51% actually did so. The investigators calculated that if participants had taken their pills every time, the efficacy of the drug regimen would have been at least 92%, compared with a placebo.

The trial gave Truvada (tenofovir/FTC) pills or placebo pills of identical appearance to 2499 initially HIV-negative men who have sex with men at high risk of HIV infection, in nine cities in four continents. The men were told to take one pill once a day. They were followed for an average of 14 months between July 2007 and December 2009 and 31% were followed for two years or more.

The trial subjects were told there was a 50% chance they might be taking a placebo and were therefore, in the words of the researchers, 'instructed’ to maintain safer sex. The provision of safer-sex counselling and condoms was very effective in itself. At the time potential participants were screened for possible participation in the trial, the average number of sexual partners reported in the past three months was 18. By the time of trial enrolment, by which time participants had already been introduced to the trial concept, had preliminary discussions and signed a consent form, participants were reporting an average of seven partners in the last three months. During the trial itself, this went down to two partners in the previous three months. The efficacy reported for PrEP in the study was, therefore, demonstrated in a setting in which behaviour change was already reducing the risk of HIV infection relative to baseline.

Over 4900 subjects were screened, of whom 2406 were ineligible or never joined the study, 410 (8.5%) because they turned out already to have HIV. The average age of the men enrolled was 27. Nineteen subjects (1%) classed themselves as female transgenders. Sixty-eight per cent came from Peru or Ecuador - iPrEx was initially launched in these two countries, while study sites in Brazil, the United States, South Africa and Thailand were added later.

These men were at very high risk of HIV infection. At screening, the average number of sexual partners reported by trial subjects in the past three months was 18. Sixty per cent reported any unprotected anal intercourse (UAI) in the last three months, 77.5% reported UAI with a partner of unknown HIV status in the last six months and 2.5% with a partner known to have HIV. One other notable finding was a high level of alcohol use in the trial subjects: over half (54%) had more than five alcoholic drinks per day.

During the follow-up, 110 men tested HIV-antibody positive. It was subsequently found, by doing viral-load tests on stored blood, that ten of these subjects actually had acute HIV infection at the time of recruitment, which was not detected using HIV-antibody tests. Doctors’ notes showed that at least seven of these ten subjects had symptoms suggestive of acute HIV infection.

No-one in the trial developed resistance to tenofovir, and none of the 100 people who became HIV-positive during the trial developed any drug resistance. However, two of the subjects who joined the trial with acute infection apparently developed resistance to FTC.

Of the 100 infected during follow-up, 36 infections occurred in men given tenofovir/FTC and 64 in men given a placebo, yielding an overall efficacy of 44% (95% confidence interval, 15% to 63%: p = 0.005).

The researchers estimated adherence on the basis of the number of pill bottles dispensed and empty ones returned, and via self-report – though, as discussed below, this turned out not to be a reliable indicator of adherence. Average adherence reported by study subjects on this basis was between 86 and 95%, depending on whether pills in unreturned bottles were regarded as having been taken or not. In subjects reporting greater than 50% adherence, the efficacy of tenofovir/FTC was 50%. In subjects reporting over 90% adherence, efficacy was 73%.

Efficacy in subjects reporting unprotected receptive anal intercourse at screening was 58%; in subjects reporting no receptive sex, there was no significant efficacy, indicating that PrEP was only making a significant difference to infection risk in the highest-risk men.

Efficacy was also significantly greater than placebo in men: aged over 25 (59%); with at least secondary education (54%); who took fewer than five alcoholic drinks a day (57%); who were circumcised (77%); and who did not have HSV-2 (54%).

A surprise awaited researchers when they tested for drug levels. They did not do this with every trial subject, but tested every subject who became infected with HIV and compared them with two uninfected, matched controls.

They found that drug levels were detectable in either the blood or cells of only 9% of subjects who became infected. But they also found that drug levels were detectable in only 51% of the HIV-negative controls.

The drug-level assays used could detect drug levels in the cells up to two weeks after a dose, indicating not only that far fewer subjects than reported were actually taking their pills, but that this was a long-term pattern and not caused by sporadically missed doses.

The investigators calculate, on the basis of these figures, that if all subjects had taken the study drug exactly as prescribed, the efficacy would be at least 92% and possibly up to 95%.

Why not only the poor efficacy, but the concealment of it? Other HIV-prevention trials have shown that trial subjects adhere to their medication considerably less than they report. This may be influenced, the iPrEx investigators speculate, by side effects and participants’ knowledge that they may be on placebo. Moreover, qualitative surveys found that some of the participants found the style of adherence counselling used in the trial ‘overbearing’, so a new non-directive style of adherence counselling had replaced it. An open-label rollover study, with all participants in the original study who wish to continue PrEP, will start in early 2011 and will report in 2013.

This was the first study to definitively prove that pre-exposure prophylaxis, as a concept, works. Under study conditions, it protected nearly half of a group of high-risk gay men who would otherwise have caught HIV. With good adherence, it’s likely that efficacy would be considerably greater. As such, especially in conjunction with the result of the CAPRISA 004 microbicide trial, it was a major advance in the study of HIV-prevention methods and potentially adds new prevention options.