PrEP, the big issues: iPrEx study directors discuss unanswered questions

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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.

Glossary

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

acute infection

The very first few weeks of infection, until the body has created antibodies against the infection. During acute HIV infection, HIV is highly infectious because the virus is multiplying at a very rapid rate. The symptoms of acute HIV infection can include fever, rash, chills, headache, fatigue, nausea, diarrhoea, sore throat, night sweats, appetite loss, mouth ulcers, swollen lymph nodes, muscle and joint aches – all of them symptoms of an acute inflammation (immune reaction).

oral

Refers to the mouth, for example a medicine taken by mouth.

generic

In relation to medicines, a drug manufactured and sold without a brand name, in situations where the original manufacturer’s patent has expired or is not enforced. Generic drugs contain the same active ingredients as branded drugs, and have comparable strength, safety, efficacy and quality.

risky behaviour

In HIV, refers to any behaviour or action that increases an individual’s probability of acquiring or transmitting HIV, such as having unprotected sex, having multiple partners or sharing drug injection equipment.

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