CROI 2015 was held last week in Seattle, in the US and the most exciting news to come from the conference concerns pre-exposure prophylaxis (PrEP), the use by HIV-negative people of antiretrovirals to prevent HIV infection.
Two studies of PrEP in gay men and trans women have demonstrated that the availability of PrEP reduced the rate of infection by 86%. This amounts to the highest effectiveness yet seen for PrEP and is superior to most other HIV prevention interventions. Extraordinarily, two separate studies which provided PrEP in very different ways found exactly the same level of effectiveness.
The PROUD study was conducted in England and the IPERGAY study in France and Canada. Both recruited men who have sex with men and trans women who were at elevated risk of acquiring HIV – they had multiple partners, condom use was inconsistent or irregular, rates of sexually transmitted infections (STIs) were high, many participants had needed post-exposure prophylaxis (PEP) before and recreational drug use was common. Participants were generally well-educated and in full-time employment.
Both studies were also designed to be pilot studies, in preparation for larger trials. The fact that each study has demonstrated such a high and statistically significant level of efficacy with a few hundred participants tells us both about how effective PrEP is and how high the rate of infection is in some groups of gay men in western countries.
But there were important differences between the studies. The PROUD study in England, presented by Sheena McCormack, asked participants to take a pill every day (containing tenofovir and emtricitabine, Truvada). Participants randomised to the control group did not receive a placebo, but knew that they would receive the pills after a one-year delay.
PROUD was conducted among 545 gay men, other men who have sex with men (MSM) and transgender women, attending sexual health clinics in England. It was designed to find out whether, if participants knew they were taking PrEP, they would use condoms less and therefore catch more sexually transmitted infections (STIs). It also aimed to see whether PrEP could be provided in a ‘real-life’ setting as close as possible to what clinic attendees already experienced. Because this meant that all participants had to know whether or not they were taking PrEP, it could not be placebo-controlled. Instead, participants were randomised into two groups, half of them given PrEP immediately and the other half given PrEP one year after enrolling. Both the “immediate arm” and the “deferred arm” participants were also provided with safer-sex support, condom provision and testing for STIs. The first participants started in November 2012, with full recruitment by June 2014.
PROUD was unradomised – in other words, all participant were recalled and offered PrEP – in October 2014 when an independent Data and Safety Monitoring Committee realised that the difference in the HIV infection rates between the two study arms had passed a pre-set threshold and was now so large that it would be unethical not to recall all participants and offer them PrEP immediately.
Recall was, ultimately, excellent; while attendance at the quarterly visits was not perfect, and notably lower in the deferred arm, only seven participants in the immediate arm and twelve in the deferred arm have still not been traced. Adding in three participants enrolled but found to have acute HIV at enrolment, this means that 267 men in the immediate arm and 256 in the deferred arm were seen at least twice and tested for HIV.
The study still continues, with everyone taking PrEP, until next year: the results presented here are for the randomised phase that finished in October 2014. These results compare what happened to the men who spent a year on PrEP with what happened to the men who spent a year waiting for it.
The IPERGAY study found that the HIV infection rate in participants taking an intermittent PrEP regime was 86% lower than in people taking an inactive placebo. IPERGAY is a very different study from PROUD, and it is encouraging that two different ways of taking PrEP have both proved effective in gay men, at least in a western-European context.
All trials of oral PrEP so far (other than small safety trials of experimental drugs) have involved taking either Truvada (tenofovir/emtricitabine) or tenofovir alone once a day. The French researchers wanted to see if taking PrEP only around the time participants were actually exposed to HIV would work too. The primary reasons for doing this would be to see if adherence was better, and also to save money, as PrEP’s per-unit cost is far higher than other prevention methods such as condoms. Intermittent dosing could also lower the risk of side-effects. Animal studies had shown that intermittent PrEP might work.
In IPERGAY, gay men and other men and transgender women who have sex with men, and were at high risk of HIV infection, were asked to take two Truvada pills (or a placebo) from one day to two hours before they anticipated having sex. If they actually did have sex, then they were to take another pill 24 hours after having sex and a fourth pill 48 hours after it. The period of taking PrEP would thus cover two to three days. If they continued having sex, they were told to continue taking PrEP until 48 hours after their last experience. As in PROUD, all participants also received risk-reduction counselling, were provided with condoms, had three-monthly tests for HIV and other sexually transmitted infections (STIs), and received hepatitis A and B vaccines if needed.
Ipergay started enrolling participants in February 2012. Like PROUD, it was intended to be a pilot study demonstrating the feasibility of its approach and the investigators initially planned to recruit 350 participants.
By November 2014, it had in fact recruited exactly 400 participants who were actually given Truvadaor placebo. Altogether 445 people came forward, but 14 (3.1%) were found to have acute HIV infection when they were screened or on randomisation and 31 others left the study for various reasons. Thus 400 are included in this analysis, though in fact by de-randomisation in November, 47 participants had withdrawn or disappeared, and the number in the study at this point was 353.
The average age of participants was 35, 95% were of white ethnicity, 90% had competed secondary education, only 21% had a primary relationship, and 20% were circumcised – 46% had used methamphetamine, amphetamine, GHB/GBL, cocaine or ecstasy in the last year. At baseline, 25.5% had been diagnosed with gonorrhoea, chlamydia or syphilis in the last year.
The average number of sexual partners participants had had in the previous two months was eight; 70% had had condomless anal sex in the previous two months. A proportion – 28% in the Truvada arm and 37% in the placebo arm – had used post-exposure prophylaxis (PEP) before.
In November 2014, and prompted in part by the PROUD study researchers’ announcement that all participants were to be offered PrEP at once because of high effectiveness, IPERGAY’s Data and Safety Monitoring Board also looked at the HIV incidence data and found high effectiveness too. They announced that IPERGAY would be unradomised and all participants offered Truvada just two weeks after the PROUD announcement. Like PROUD, IPERGAY continues as an un-randomised implementation study.
As with PROUD, HIV incidence in IPERGAY was higher than anticipated, and this meant that the study could prove effectiveness in what is, for a prevention study, a remarkably small number of participants, and in a short space of time. The longest anyone was in the trial before the November de-randomisation was 20 months but the median time was only nine months.
During this time, two participants allocated to Truvada became HIV positive and 14 allocated to placebo (compared to PROUD, where there were three and 19 infections seen in the immediate and deferred arms). HIV incidence – the annual rate of HIV infection seen per 100 participants – was 0.94% in participants taking Truvada and 6.75% in patients on placebo (compared with 1.3% and 8.9% respectively in PROUD).
This translated to an effectiveness of 86% – exactly the same rate as seen in the PROUD study, with 95% confidence intervals of 39.4-98.5%. These are not directly comparable with PROUD, which used 90% confidence intervals.
The two participants in the Truvada arm who acquired HIV did not become infected until late in the study – one 16 and one 21 months after entering the study. Principal investigator Jean-Michel Molina said that the two had pretty certainly stopped taking PrEP by that time – they had even been returning unused pill bottles to the clinic. As with PROUD, there was certainly no evidence that anyone who had been taking Truvada had become infected.
The effectiveness of the study was achieved on an overall pill usage of 14 pills per month, or approximately half the number that would be used if participants had taken them daily, with good adherence – 20% of participants took over 25 pills a month, ie the equivalent of almost daily, and 20% less than four, ie less than one a week.
Participants were also asked if they had taken PrEP the last time they had sex 0 43% reported that they had taken it according to the protocol; 29% had taken some doses; and 28% had not taken any. As principal investigator Jean-Michel Molina said, this did not mean they had necessarily been at risk as participants might vary their PrEP-taking according to whether they perceived themselves as being at risk.
There was no evidence of behaviour change in the study. The proportion of participants reporting at least one episode of condomless anal sex in the previous two months remained at 70%, as did episodes where the participant was the receptive partner, the number of partners remained at just under eight in the last two months, and the number of sexual acts remained completely unchanged at ten in the last month.
During the study, 35% of participants were diagnosed with a sexually transmitted infection including 20% with gonorrhoea and 10% with syphilis; Molina reported two in a hundred participants acquired hepatitis C, equating to eight infections.
There was a higher rate of gastrointestinal side-effects such as nausea, diarrhoea or abdominal pain reported by participants taking Truvada than people taking placebo (13% versus 6%). Two participants (1%) had transient decreases in their kidney function as measured by their creatinine levels but only one person in the entire study discontinued Truvada due to an adverse event – a suspected drug/drug reaction.
Summarising the study, Molina commented that the study showed that gay men were capable of taking PrEP in a way that suited their lifestyle and maximised their safety, if offered the chance to do so.