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