The Steering Committee* of the PROUD trial of pre-exposure
prophylaxis (PrEP) in gay men in England announced today that participants currently
on the deferred arm of the study, who have not yet started PrEP, will be recalled to their clinics and offered the
opportunity to begin PrEP ahead of schedule. This is because the effectiveness seen
in the trial has exceeded the threshold set for trial continuation.
Although the exact effectiveness seen in the trial is yet to
be established pending analysis and follow-up of participants, the indications
are that it is considerably in excess of that originally anticipated by the
In PROUD, 545 gay men at high risk of HIV infection have been recruited
through 13 sexual health clinics in London, Brighton, Manchester, Birmingham,
Sheffield and York.
Participants have all been offered a package of regular testing for HIV
and sexually transmitted infections (STIs), condoms, safer sex support,
and behavioural surveys and monitoring, and have been randomised into two
groups. One group has also received tenofovir + emtricitabine (Truvada) immediately (the ‘immediate arm’) while the other has, up till now, been
offered it a year into the study (the ‘deferred arm’).
The object of this design is to establish whether participants
who know they are taking PrEP will change their HIV risk behaviour (such as
using condoms less or even not using them at all) and, if so, whether this will reduce
or even cancel out the beneficial effect of PrEP.
This trial design is being used because some critics of PrEP
have forecast that PrEP will have an overall negative effect: in August, the
Chief Executive of the AIDS Healthcare Foundation, Michael Weinstein said:
“We want the public to know that the government-sanctioned widespread scale up
of PrEP appears to be a public health disaster in the making.” It is therefore
very important to know if people like Weinstein are right or wrong, and whether
PrEP will have a negative effect if people know they are taking it.
The PROUD pilot has not been designed to establish the effectiveness
of PrEP as such. At the time it was designed, it was thought that a large trial
of 5000 participants would be needed to generate the number of HIV infections required
to establish a clear measurement for the effectiveness of PrEP in reducing (or
not) HIV infections in participants.
However, in April 2014, it became clear that the offer of PrEP
had appealed to a subset of gay men characterised by a higher HIV infection
rate than had originally been taken into account when calculating trial size. This
implied that the pilot trial would be potentially capable of producing a clear
answer on effectiveness, in spite of its small size. An Independent Data and Safety Monitoring
Committee (IDMC) was therefore set up.
IDMCs have a privileged position in randomised trials: they
are the only people to see the unblinded data before the end of the trial, and their
job is to monitor the data to see if there are signs that the trial should be
stopped. Grounds for stopping include that it has become clear that the
intervention being trialled causes harm, that the trial will never produce a
clear result (so-called ‘futility’) or that the intervention is so beneficial
it would be unethical to withhold it from people in the study. The PROUD IDMC met three times and in the
third meeting on 6 October decided that the intervention was clearly
beneficial; it found that the effectiveness of immediate PrEP appeared to have
passed a threshold they had previously set.
This threshold will not be the actual effectiveness: it is the
lowest-possible likely effectiveness allowing for chance results or, in
technical terms, the lower bound of the 95% confidence interval. In terms of
the actual numbers of infections seen, the observed effectiveness is likely to
be higher. The final difference will not become clear until the clinics have recalled
as many participants as possible as there will no doubt be some other previously
undetected HIV infections in both groups. Currently 130 people in the deferred
arm are yet to be offered PrEP.
Full results are expected early next year.
The PROUD trial has not stopped: it will continue because it
is still important to find out longer-terms trends: will participants’
adherence to PrEP, which must clearly have been high, fall over time? Will
levels of risk behaviour stay unchanged? Will drug resistance feature to any
significant extent? These are still important questions to answer and the
English NHS is likely to want them answered before making a decision as to
whether to provide PrEP. This development opens up opportunities to study other drugs or regimens too –
but above all it opens up an opportunity to make a big impact on the HIV
epidemic in gay men in the UK and elsewhere.
Dr Adrian Palfreeman, Vice
Chair of the British HIV Association, said: "We welcome the news that we
have made significant progress in efforts to prevent HIV in men who
have sex with men, where ongoing transmission in the UK remains
unacceptably high, and look
forward to seeing the results when they are available. BHIVA, along with
other key stakeholders, are working with NHS England to devise a policy
to consider the future availability of pre-exposure prophylaxis,
alongside existing measures to prevent infection,
within the NHS in the future”
* Gus Cairns is co-chair
of the Steering Committee of the PROUD trial.