A randomised controlled trial has found that the HIV infection rate in HIV-negative gay men who were given a daily preventative pill containing two HIV drugs was reduced by 44%, compared with men given a placebo.
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 iPrEx (Pre-exposure Prophylaxis Initiative) 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 calculate that if participants had taken their pills every time, the efficacy of the drug regimen would have been at least 92%, compared with placebo.
The trial
The iPrEx trial gave identical pills containing either the antiretroviral (ARV) drugs tenofovir (Viread) plus FTC (emtricitabine, Emtriva), or a dummy placebo pill, 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 the pills once a day.
The trial subjects were told there was a 50% chance they might be taking a placebo and were therefore 'instructed’ to maintain safer sex. The men paid study visits every four weeks during the two-year study. At every study visit they were tested for HIV, asked about their risk behaviour, given adherence and safer-sex counselling, and provided with condoms.
The subjects were followed for an average of 14 months between July 2007 and December 2009: 31% were followed for two years or more.
Who took part
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. Patients with high liver enzyme or creatinine levels, indicating liver or kidney damage, were excluded.
The average age of the men enrolled was 27 and three-quarters classed themselves as Hispanic and/or of mixed race (participants could choose more than one category). Nineteen subjects (1%) classed themselves as female transgenders. Sixty-eight per cent came from Lima or Iquitos in Peru or Guayaquil in Ecuador: iPrEx was initially launched in these two countries and other study sites added later.
At screening the average number of sexual partners reported by trial subjects in the past three months was 18. Sixty per cent reported 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. Thirteen per cent tested positive for syphilis and 35% for genital herpes (HSV-2), for which they received treatment, as did all subjects with STIs. A third had already had hepatitis B and were immune and two-thirds were offered hepatitis B vaccine.
One notable finding was a high level of alcohol use in the trial subjects: over half (54%) had more than five alcoholic drinks per day.
Safety
Few side-effects attributable to the study drug were observed. There was a higher level of nausea (9% versus 5%) in the first month in patients who took tenofovir/FTC, and the investigators advance this as a possible contributing factor to low adherence. Trial subjects gained weight, on average (due to maturing age in this young cohort), but in subjects on tenofovir/FTC the weight gain was delayed by three months relative to subjects on placebo. Nausea of grade 2 level or above (stronger or more long-lasting feelings of nausea) was experienced by 2% of the tenofovir/FTC group compared to 1% of the placebo group.
There were twice as many reports of raised creatinine levels in patients taking tenofovir, which is associated with kidney damage in a minority, though reports were rare: 25 (2%) in patients on tenofovir/FTC versus 14 (1%) on placebo. Five patients were taken off tenofovir/FTC due to raised creatinine levels but four of these re-started and creatinine levels did not rise again.
Resistance
During 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.
Of the ten participants who had acute HIV infection at baseline, three (one taking placebo) had HIV that was resistant to FTC when they were tested at week four of the study.The one taking placebo clearly had transmitted drug resistance (he had AZT and NNRTI resistance too): one appears to have acquired FTC resistance due to taking the PrEP drugs with a lot of HIV in his body (he had a viral load of 10 million at baseline): and one had a very low viral load at enrolment and could not be given a resistance test, so we cannot say if he developed resistance in response to PrEP.
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.
Efficacy
Of the 100 infected during follow-up, 36 infections occurred in men given tenofovir/FTC and 64 in men given placebo, yielding an overall efficacy of 44% (95% confidence interval, 15% to 63%: p = 0.005).
No HIV drug resistance was found in any subject who acquired HIV during follow-up.
On the basis of pill counts and self-reports, study subjects would have been judged as taking their pills at least 86% of the time and on average over 95% of the time.
In subjects reporting greater than 50% adherence, the efficacy of tenofovir/FTC was 50%. Efficacy in subjects reporting unprotected receptive anal intercourse at screening was 58%; in subjects reporting no receptive sex, efficacy was actually negative, indicating that PrEP may only make a significant difference to infection risk in the highest-risk men, namely ones who take the receptive role in unsafe sex.
Efficacy was also significantly greater than placebo in men reporting over 90% adherence (73% efficacy); 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%).
Adherence and drug levels
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, including 54% who reported over 50% adherence.
The drug level assays used could detect drug 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 missing 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 knowledge that they may be on placebo or by side-effects. However qualitative surveys found that some of the participants found the style of adherence counselling “overbearing”, according to Principal Investigator Bob Grant, and a new non-directive style of adherence counselling will continue into the rollover study.
In pre-exposure prophylaxis, poor adherence is of concern because it might give rise to HIV drug resistance, although in this trial it appears that adherence in those who did acquire HIV was so low this did not happen.
Conclusion
This is 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, its likely efficacy would be considerably greater.
As such, especially in conjunction with the result of the CAPRISA 004 microbicide trial, is a major advance in the study of HIV prevention methods and potentially adds new prevention options.
Bob Grant commented: "I hope this will inspire and galvanise an active discussion in people who care about HIV prevention.
"We now have four positive signals on new methods of HIV prevention - circumcision, a vaccine, microbicides and now PrEP; we have the possibility of constructing an active portfolio of prevention methods for individuals, with the support of an engaged community.
"These were mainly young guys in the trials who were finding out who they were. These are the people PrEP will be useful for. We can say 'We want you to develop your own ways to protect yourself, but meanwhile, here's a pill that can maybe protect you while you're doing that.'"
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.
Reference
Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men. New Engl Jour Med early online edition, 23 November 2010.
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
