All participants in PROUD study to be offered PrEP early

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 researchers.

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.

Glossary pilot study Small-scale, preliminary study, conducted to evaluate feasibility, time, cost, adverse events, and improve upon the design of a future full-scale research project. Independent Data Monitoring Committee (IDMC) An independent committee of clinical research experts that reviews data not available to the study team while a clinical trial is in progress to ensure that participants are not exposed to undue risks. A DSMB can recommend that the study be stopped if the intervention is not effective, is causing harm to participants or the study is not likely to serve its scientific purpose. Also known as an Independent Data Monitoring Committee (IDMC). 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. drug resistance A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus. safer sex Sex in which the risk of HIV and STI transmission is reduced or is minimal. Describing this as ‘safer’ rather than ‘safe’ sex reflects the fact that some safer sex practices do not completely eliminate transmission risks. In the past, ‘safer sex’ primarily referred to the use of condoms during penetrative sex, as well as being sexual in non-penetrative ways. Modern definitions should also include the use of PrEP and the HIV-positive partner having an undetectable viral load. However, some people do continue to use the term as a synonym for condom use.

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.