Results of the United Kingdom PROUD study were published in the September 9th issue of the Lancet, following their earlier presentation at the Conference on Retroviruses and Opportunistic Infections 2015, in Seattle . As reported at CROI, pre-exposure prophylaxis (PrEP) dramatically reduces the risk of HIV infection in gay men and transgender females by 86%. In addition, there was no evidence of increased high risk sex in those receiving PrEP and there was also no increase in drug resistant HIV among those receiving PrEP.
PrEP consists of a daily dose of the anti-HIV drug, Truvada, which is a combination of two antiretroviral drugs, tenofovir and emtricitabine (FTC) and is normally used to treat HIV infection. Studies such as PROUD and others, clearly demonstrate that it is also highly effective at preventing infection with HIV when taken by people who are HIV negative.
PROUD is an open label, randomised clinical trial conducted at 13 sexual health clinics in England. Participants were randomised to receive PrEP either immediately, or after one year deferral. In order to be effective the study had to recruit participants at very high risk of infection. This was ensured by selecting HIV negative men and transgender women who have sex with men and who reported receptive anal sex without a condom in the previous 90 days. Participants were prescribed PrEP on a rolling 90 day basis, after an initial 30 day prescription and asked to attend clinic every three months in which they would be tested for HIV and bacterial STIs. In addition participants were asked to complete monthly questionnaires and daily diaries about sexual behaviour and PrEP adherence.
Unlike other clinical trials of PrEP which were placebo controlled, the PROUD study was designed to test the effectiveness of PrEP in a real-life setting i.e. where people’s knowledge that they are receiving the drug might affect either their compliance (because there is less incentive to adhere to a regimen if you might be getting a placebo), or their sexual risk taking behaviour. There have been fears that use of PrEP might cause people to abandon condom use. PROUD tested this theory by allowing everyone in the study to know if they were on PrEP or not.
The results presented in the Lancet are from a pilot phase of PROUD, intended to assess feasibility of recruitment and retention for a large clinical trial. However, the unexpectedly large difference in HIV infections between the immediate and deferred arms of the study enabled determination of the effectiveness of PrEP. PROUD was originally designed to have a sample size of 5000 participants, powered to detect a 50% reduction in new HIV infections. The pilot study had a sample size of 500. As a result of the striking protection conferred by PrEP in the pilot phase, the trial steering committee recommended that the study design was changed in October 2014 to close recruitment and give immediate access to PrEP to all participants in the deferred PrEP group (n = 163). While the trial has been stopped, participants are still receiving PrEP and longer term data is being collected until the final enrolled participant has completed 2 years follow up.
The study recruited 544 participants, of which 275 were in the immediate group and 269 were in the deferred group. At the time of reporting, HIV incidence follow up data was complete for 243 (94%) of 259 patient years in the immediate group and 222 (90%) of 245 patient years in the deferred group. Three HIV infections occurred in the immediate group (1.2/100 person years) as compared to 20 in the deferred group (9/100 person years). This represents a relative a reduction of 86% (90% CI 64-96, p = 0.0001). Put more simply, these figures mean that 13 individuals in a similar group would need to be taking PrEP for one year to avert one new acquisition of HIV infection. The new infections in the deferred group occurred despite 174 prescriptions of post-exposure prophylaxis (PEP). Of the twenty participants who became newly infected in the deferred group, six had received a total of 12 courses of PEP. Of the three participants who became infected in the immediate group, one had a positive HIV test at week 4 of the study and is thought to have been infected before enrolment. The other two participants developed positive HIV tests much later in the study and are thought to have been non-compliant as they had not been issued sufficient PrEP prescriptions to cover the period in which infection likely occurred. These results suggest that HIV infection does not occur in people who take PrEP.
Sexual behaviour questionnaires at year one of the study revealed that 21% of participants randomised to the immediate group reported receptive anal sex without a condom with 10 or more partners versus 12% in the deferred group (p = 0.03). Regardless of this, diagnoses of bacterial STIs occurred in 152 (57%) of 265 participants in the immediate group and 124 (50%) of 247 participants in the deferred group. After adjustment for the number of study screens in each group, no significant difference was found between the groups for incidence of bacterial STIs. Importantly the incidence of rectal gonorrhoea or chlamydia, indicators of receptive anal intercourse without condoms, were similar in both groups.
None of the participants of either group who became HIV-infected, had resistance mutations to either emtricitabine or tenofovir, apart from the participant who tested positive at week 4 and was suspected to have been infected before enrolment. This person had resistance to emtricitabine at codon 184 of reverse transcriptase.
These results demonstrate that PrEP is highly effective in a real-life setting and importantly is not associated with increased risk-taking in this group. Cost effectiveness is a major concern for cash-strapped national health services. Economic modelling based on the UK epidemic in MSM suggests that PrEP would be cost effective at current drug pricing if it is targeted to this group . Without high-risk group targeting, that study found that PrEP would be cost effective if the price of Truvada was dropped by 50%. Further cost reductions may be made by on-demand adminsitration of PrEP, in which HIV negative individuals take PrEP in a regimen designed for use when they expect to have an exposure. The French IPERGAY trial reported that this approach is equally as effective as continuous PrEP .
1) 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. Sept 9 2015.
2) Cambiano V et al. Is pre-exposure prophylaxis for HIV prevention cost-effective in men who have sex with men who engage in condomless sex in the UK? BASHH Spring Conference 2015; June 1–3, 2015; Glasgow, UK. Abstract O1.
3) Molina J-M et al. On demand PrEP with oral TDF-FTC in MSM: results of the ANRS IPERGAY trial. Conference on Retroviruses and Opportunistic Infections; Feb 23–26, 2015; Seattle, WA, USA. Abstract 23LB.
This article was first published in HIV Treatment Bulletin October 2015 (http://i-base.info/htb/29040)