The results of the PROUD study of HIV pre-exposure prophylaxis (PrEP) using daily tenofovir + emtricitabine (Truvada) have now been published in The Lancet scientific journal. PROUD, along with the other European randomised study of PrEP, Ipergay, demonstrated considerably higher levels of effectiveness of PrEP in preventing HIV infections than any previous study. The results from both studies were presented this February at the Conference on Retroviruses and Opportunistic Infections (CROI 2015).
There is little difference between the results in The Lancet and those presented at CROI but journal publication is important for the provision of PrEP in Europe as both the European Medicines Agency (EMA), which regulate the licensing of medicines, and the European Centre for Disease Prevention and Control (ECDC), which issues public health recommendations, both require journal publication for studies to be included in their evidence.
There were subtle differences. One statistically significant change in behaviour in men on PrEP was detected by the researchers (an increase in the proportion of men who had high numbers of condomless sex partners as the receptive partner) but, conversely, it is clearer than before that there was no change in the incidence of sexually transmitted infections (STIs) when men started PrEP.
The effectiveness of PrEP in PROUD remains 86% (meaning that PrEP prevented just over 17 out of every 20 HIV infections that would otherwise have happened), and the number of men needed to be treated with PrEP to stop one HIV infection remains at 13. However, the lower bound of the 90% confidence interval for the effectiveness of PrEP has been shifted upwards from 58% to 65%: what this means is that there is a less than one-in-ten chance that if the study was repeated, PrEP would turn out to be less than 65% effective.
The demographics remain almost the same as those reported in April 2014 when recruitment was complete: 544 men were enrolled at 13 sexual health clinics in England: 275 were randomly allocated to take daily Truvada as PrEP immediately and 269 to wait for a year before starting it.
Three HIV infections were observed in the men allocated to start PrEP immediately but one of these almost certainly contracted HIV just before he started PrEP (he tested HIV-positive at his second visit a month after starting) while the other two had stopped taking PrEP months before they acquired HIV.
There were also three men (not six as stated in the February aidsmap.com piece) who tested HIV-positive at their first clinic visit, the day they were first given PrEP, and must have contracted it, at most, 2-3 weeks before.
Two of the men who started PrEP while they already had HIV, including the one diagnosed on his second visit, developed resistance to emtricitabine: no-one developed resistance to tenofovir.
In contrast 20 (not 19 as originally thought) men in the deferred arm caught HIV during the year they were waiting for PrEP and this means the observed annual HIV incidence changed slightly to 9% in the deferred arm and 1.2% in the immediate arm. The 9% incidence seen in the deferred arm is very high; roughly seven times higher than the 1.34% seen in gay men attending English sexual health clinics in 2012.
This underlines that the men who came forward or were referred to PROUD were a highly selected group of the most at-risk gay men.
Another fact that supports this is that 64% of trial participants had had an STI diagnosed in the year before joining the study – an aggregate figure that was not reported at the spring 2014 BHIVA conference when baseline trial demographics were presented (only the figures for individual STIs were reported).
This means that there was clearly no increase in STIs in participants taking PrEP: 57% in the immediate arm and 50% in the deferred arm had an STI diagnosed during the study, but because men in the immediate arm had more tests, after adjustment, this 7% difference was not statistically significant. There was no difference at all in the one-third of men who caught a rectal bacterial STI, the most sensitive indicator of being the receptive partner in condomless anal sex, which is 17 times more risky than being the insertive partner when it comes to HIV infection.
There was one statistically significant difference in terms of behaviour. During the study a larger proportion of participants in the immediate-PrEP arm reported condomless receptive anal sex with ten or more partners in the previous three months than participants in the deferred arm (21% versus 12%, probability 0.03%). However while this was an increase over baseline it did not translate into more STIs and the number of partners with whom participants had any anal sex did not change.
The researchers conclude: “Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection.”
In an accompanying editorial, PrEP researcher Ken Mayer of Fenway Health in Boston, US, and Chris Beyrer, President of the International AIDS Society, comment: “The results from PROUD suggest that pragmatic deployment of PrEP must be part of any relevant primary HIV prevention strategy….PrEP should be part of the range of services offered by any clinical programme that focuses on sexual health. The time for cautionary speculation is over: HIV prevention services should be expanded worldwide by offering PrEP routinely to those who could benefit.”
McCormack S et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. The Lancet, early online publication. DOI: http://dx.doi.org/10.1016/S0140-6736(15)00056-2. 2015.
Mayer KH and Beyrer C. Antiretroviral chemoprophylaxis: PROUD and pragmatism. The Lancet, early online publication. DOI: http://dx.doi.org/10.1016/S0140-6736(15)00153-1. 2015.