The success of the iPrEx
study of pre-exposure prophylaxis (PrEP) in gay men opens up as many urgent
questions as it has answered. This became clear as the results of the study
were discussed by Anthony Fauci, head of the US National Institute of Allergies
and Infectious Diseases (NIAID), who were the biggest funders of the trial, and
Bob Grant, the iPrEx study’s Principal Investigator.
To summarise, the iPrEX
study gave half of a group of men who have sex with men (MSM) who were at high
risk of HIV infection one Truvada (tenofovir+FTC)
pill a day and the other half a placebo. After an average 14 months on the
regimen there were 44% fewer infections in men taking Truvada than in men taking placebo.
How do we support adherence to PrEP?
The other interesting
finding was that adherence in the study was not only lower than
expected, it
was also a lot lower in reality than it was on the basis of
participants’ own reports or by counting the number of pills dispensed.
Participants
claimed at least 90% adherence but a substudy, in which drug levels in
participants’ blood and immune cells were measured, suggested that in
reality
it was about 50%.
Subanalyses were done
suggesting that, based on pill counts and self-reports, the efficacy of
PrEP in
people who took more than half their doses was 50% and in people who
took 90%
of their doses was 74%. However the significantly lower ‘real’ adherence
levels make analyses based on pill counts unreliable, as they assumed
all pills dispensed
were taken.
We can’t really say, therefore, that PrEP will definitely work if
you have perfect adherence, nor can we say (as one agency concluded) that PrEP
definitely won’t work if your
adherence is less than 90%.
“All we can say,” Susan Buchbinder,
one of the iPrEx investigators told Aidsmap, “is that it does look like
people who were able to take their drug more regularly were more likely
to be protected."
This on the one hand is
discouraging as it suggests adherence will be a big challenge in making PrEP
work; on the other hand it suggests that the potential efficacy of PrEP
is very high – as efficacious as condoms if not more so – and if we can help patients
achieve high adherence it could offer significant protection against infection.
Bob Grant, the study’s
global Principal Investigator, said: “Although daily use of a pill to prevent
something is challenging, it is feasible. We know from the use of statins to
prevent high cholesterol and, perhaps more relevantly, oral contraceptives to
prevent pregnancy, that people will adhere to preventative regimens if they see
enough benefit in them.”
He said that the iPrEx
researchers would be looking into the adherence and efficacy question much more
deeply, and would be checking thousands of other stored samples for drug levels
to get a much more accurate idea of the true adherence levels in the trial. These investigations
would not only help establish a truer picture of efficacy but also look at
whether people gave up taking their pills at characteristic times: if those who
stopped taking Truvada did so very
soon after starting, for instance, it might suggest that the reason was
side-effects.
He emphasised that one of
the most promising aspects of the trial was that efficacy was highest in the
highest-risk people: the men who had significant levels of unprotected anal sex
as the passive partner. In fact there was little measurable efficacy in men who
denied being receptive in anal sex.
“It became apparent early in the trial,” he said, “that IPrEx was
attracting the highest risk individuals. Many had never had an HIV test
before or come
forward for help with prevention, yet here they were volunteering to be
part of
a prevention initiative. It was also just as effective in the youngest
men in
the study as in anyone else.”
A rollover study offering
every participant in the study open-label Truvada
will start in early 2011. This study, which will last till 2013, will allow the
investigators to monitor for longer-term side effects and long-term changes in
behaviour.
Importantly the study will also use a completely different style of
adherence counselling, which was piloted in the last few months of iPrEx.
Feedback from interviews with participants showed that they found being
reminded about adherence by the same people who were giving them blood tests
was not conducive to being honest about adherence problems. The rollover study will
therefore feature adherence counsellors who are completely separate from the
staff doing monitoring tests, and who will not be informed of
patients’ adherence levels as assessed by blood tests: all patients
will be treated equally and asked about what factors are making it easy or hard
to take the pills.
Should PrEP become standard of care in prevention trials?
One thorny question
resulting from iPrEx is whether, given that the intervention appears to
be potentially very effective, forthcoming or ongoing prevention
trials should now start using Truvada as
their control arm instead of an inactive placebo.
Anthony Fauci said that
this was a difficult question and the answer would depend on the trial. iPrEx
had only established the efficacy of PrEP in one population and it might be
very different in others: if studies started using Truvada instead of placebo they might have to become
unrealistically large, and we might fail to demonstrate whether PrEP had
universal efficacy. He said that NIAID would approach this question on a
case-by-case basis, going through every trial protocol to decide if a placebo
arm was still ethical.
Possible answers to this
included re-consenting trial participants so that they were informed of
the iPrEx results and asked if they still wished to remain in the trial,
or adding a
third arm comparing oral Truvada to whatever other intervention was being
studied, but he could not predict what was going to happen without an
investigation of all studies.
Community recommendations
The same cautions also
applied to what messages to send out to affected communities and the people who
care for them.
Anthony Fauci said that, on the one
hand, because Truvada was already
available, the formulation of new guidelines was
urgently needed so that potential providers, from individual physicians to insurers, understood what iPrEx told us and, more
importantly, did not tell us about PrEP in case patients asked for it.
The US Centers
for Disease Control (CDC) moved particularly fast to counsel caution about
immediately assuming we had a new prevention tool for gay men.
Pointing out
that one implication of the findings was that anything under 90% adherence might be ineffective, the CDC said: “PrEP
should never be seen as the first line of defence against HIV. It was only proven
to be partially effective when used in combination with regular HIV testing,
condoms and other proven prevention methods, and it does not protect against
other sexually transmitted infections”.
It emphasised that the
cornerstones of HIV prevention for gay men remained using condoms consistently
and correctly, getting tested to know their status, getting treated for STIs,
getting support to reduce drug use and sexual risk behaviour, and trying to
reduce the number of sexual partners.
Fauci said that the CDC
should now get together with other stakeholders to produce a unified set of
recommendations for prevention in light of these new findings. “Is [taking
PrEP] something we want people to do,” he asked, “given that we don’t know
anything about its effects in women or men, and we know nothing about its
long-term implications?”
In terms of moving forward
to licensing Truvada as a
preventative drug, Bob Grant said that because tenofovir and FTC had been used
as treatment for eight or nine years and their safety profile well-known, a
completely new marketing authorisation would not be necessary and all that was
needed would be a change of indication on the label. It would, however,
probably take at least one more convincing trial result in a different population
before this could be considered.
Resistance and acute infection
One of the acknowledged
problems with PrEP is that it is almost impossible to eliminate the possibility
that some people might come forward for it who already have HIV, especially
acute HIV infection that does not yet show up on antibody tests. This happened to ten
people in the study, and one or two of them appear to have developed drug
resistance as a result. Routine HIV RNA testing to detect viral load in people yet to form
antibodies would be prohibitively expensive.
Bob Grant said that there
were cheaper alternatives such as p24 antigen testing, already used in the UK,
but noted that at least seven out of the ten participants who
had acute HIV infection had symptoms that were severe enough for them to seek medical
attention. Although it would not eliminate all acute infections, he said, a
guideline should be adopted that said that PrEP should under no circumstances
be started if people have flu-like symptoms, a rash, a sore throat or any other symptoms suggestive
of a viral infection.
Cost and practicality
The list price for Truvada in the US is $14,000 a
year and even in heavily-discounted public schemes still costs thousands. Fauci
and Grant were asked how using a ‘chemical condom’ that cost $38 a day could be
justified when condoms themselves cost a few cents each.
Fauci said that he thought
that the iPrEx results might change the pricing structure of the drugs. “We
might start seeing a whole range of prices,” he said, “and we have to remember
that generics are available in many countries.” He was, however, concerned
whether downward pressure on the prices of tenofovir and FTC might increase
disparity between different countries.
At this point Javier Lama,
the local principal investigator for Peru, said that, ironically, neither
generic not branded Truvada was yet
available for HIV treatment in Peru, though he hoped it would be next month,
and the separate drugs were available.
In the developed-world
context, further cost-effectiveness analyses, such as computing the cost of the
intervention per infection averted, would be needed to convince insurers [and,
in the case of countries like the UK with universal-access healthcare,
evaluation agencies like NICE], that paying for PrEP was worthwhile.
The biggest question around
cost and practicality is the concern that providing antiretrovirals
for HIV prevention could be seen as a distraction or as competing for scarce
resources in a world where, as Anthony Fauci re-emphasised, only 36% of people
with HIV have access to ARVs to save their lives.
Bob Grant said that he
could see increasing “synergy” between HIV treatment and prevention approaching. “We
have to have something to slow the spread of HIV in these communities,” he
said, “and only treating the already-infected does not seem to be slowing the
rate of new infections enough.” He foresaw antiretrovirals being provided in
integrated prevention-and-treatment programmes that would also feature testing,
prevention advice and so on. “Might using these drugs for prevention also
encourage people to test, reduce stigma, and encourage treatment uptake?” he
asked.
Fauci also thought that
PrEP might only be necessary for short periods of people’s lives. “We think it
may become a bridge to other protective behaviours,” he said.
HIV treatment advocates
also expressed caution about the implications of IPrEX for people with HIV, but
also emphasised that the treatment experience of people with HIV might be
crucial in helping people come forward for testing.
Kevin Moody, Chief Executive
Officer of the Global Network of People Living with HIV (GNP+) said: “As
treatment and prevention come together, it is important to involve HIV-positive
people in discussions about how PrEP can and should be made available in the
future.
"People living with HIV have a crucially important role to play in HIV
prevention, both for the development of new HIV prevention tools and in
advocating for improved access to existing prevention options.”
Further information
See also Anti-HIV drugs prevent HIV infection, trial shows - if you take them. (23 November
2010).
We have previously reported research from the iPrEx trials on adherence
to PrEP, presented at the Fifth International Conference of HIV
Treatment Adherence in Miami. See Adherence to ARV prevention methods is challenging, partly because they don’t
treat illness (27 May 2010).
For more information on pre-exposure prophylaxis (PrEP), visit the PrEP pages of our website.
For more information on the iPrEx trial, visit the iPrEx website: www.globaliprex.com