Simon Collins, HIV i-Base
PrEP works in the UK. Taking a daily antiretroviral pill dramatically reduced the risk of HIV transmission for gay men and transgender women at high risk. There was little evidence of risk compensation.
Results from the PROUD study were included in one of the opening oral sessions at CROI 2015 looking at HIV prevention, and presented by Professor Sheena McCormack from the UK Medical Research Council Clinical Trials Unit (MRC CTU) at University College London.  Other important PrEP studies followed immediately after.
Four months ago, the PROUD study made news when early and unexpected efficacy results prompted the researchers to change the trial design.  The study was planned to continue for two years after randomising 545 gay men to either immediate PrEP (daily oral tenofovir/FTC) or to PrEP that was deferred for a year. All participants received sexual health advice to reduce their risks for HIV.
In October 2014, the independent data and monitoring committee (IDMC) recommended that all participants should be offered immediate PrEP. This was because significantly more people were becoming HIV positive in the deferred group. Much earlier than expected, PROUD showed that PrEP was highly effective.
Efficacy results at CROI
Detailed results were presented on the numbers of people who became positive in each study group and the relative protection from PrEP, together with information about adherence and risk behaviour on PrEP.
As the PROUD study is still ongoing, results for this analysis were presented up until the January 2015 extract of the data.
Study retention was good, with 523/545 (96%) of participants contributing towards 453 person years of follow up (PYFU). Rates of follow-up time that came from each group were also similar: 92% (239/261 person-years) for the immediate PrEP group and 88% (214/242) for the deferred group.
Overall, 22 participants became HIV positive during the study: 3 in the immediate PrEP group and 19 in the deferred arm. This gave HIV incidence rates of 1.3 vs 8.9 per 100 PYFU in the immediate vs deferred arms, respectively, and a difference in HIV incidence between the two groups of 7.6 per 100 PYFU (90% CI 4.1-11.2). The rate difference is important for calculating the number needed to treat (NNT) for one year to prevent one infection. This is used when calculating cost effectiveness and in PROUD the NNT was only 13 (90%CI: 9-25).
These results were highly significant, with PrEP reducing the risk of HIV by 86% (90% CI 58% to 98%) compared with no-PrEP, (p=0.0002).
Summary details were presented for the three participants who became HIV positive in the immediate PrEP arm that suggested that they were unlikely to be taking PrEP at the time they were infected.
One participant was diagnosed at week 4, raising the possibility that he could either have been seroconverting as he entered the study, or was infected prior to achieving steady state drug levels. Although the participant was HIV negative at enrolment, PCR sampling at study entry was not possible due to a lack of sampling at that time point. As the study was designed to mimic real world use, enrolment was based on negative Ag/Ab testing and PCR samples were not collected.
The two other participants were both HIV negative at enrolment but were not in contact with their clinic for extended periods of time. So they were unable to renew their prescriptions, which were given for the first month, and then three-monthly thereafter. One participant did not return for 14 months, at which point he tested HIV positive. The other was still HIV negative at month 3, but then did not return until month 12 when they presented with seroconversion symptoms indicating a recent infection.
In the deferred arm, six participants were diagnosed at their first test during follow-up, so HIV transmission could have occurred prior to enrolment. The remaining 13 were diagnosed after having had at least one further HIV negative test.
PEP use – before and during the study
At baseline, one third of participants (184/545) had used Post Exposure Prophylaxis (PEP) in the previous year and 17 people had used PEP more than once. PEP involves taking a combination of HIV meds for a month that includes the same drugs (tenofovir/FTC) that are used as PrEP.
During the study, 13/276 (5%) participants in the immediate PrEP group were also prescribed PEP. This was reported as generally being related to a risk of exposure during low/no PrEP adherence.
In the deferred PrEP group, 83/269 (31%) participants used PEP at least once, with a total of 174 prescriptions. Assuming that PEP was taken, this accounts for 14 PYFU when the deferred group was effectively on PrEP via PEP.
It appeared to be rare for people in the deferred arm to access PrEP, but this did occur, including one case that was supported by a drug level test.
Despite the use of PEP and occasional access to PrEP, infection rates were still significantly higher in the deferred arm.
Adherence and risk compensation
Adherence was estimated in several ways, but these are all indirect calculations. Although monthly self-reported questionnaires included both adherence and behaviour risk these were not reported consistently enough to enable overall adherence assessments.
Adherence data is also difficult to interpret because some people adjusted PrEP use to reflect a more real-world setting. If someone’s circumstances and perceived need for PrEP changed, they still remained in the study. For example, if someone stopped being sexually active or their relationship changed, this might involve extended periods when PrEP was not taken.
Based on prescription records, the average adherence in the PrEP arm could not have been higher than 86%. But this is an estimate and the prescription records also show that 14 people (5%) in the immediate group never started PrEP.
Another calculation from prescription records reported that sufficient PrEP was prescribed to only enable 56% of people to be 100% adherence. This is also problematic as 100% adherence is not even needed to provide good protection. Many people on ART are close to 100% adherent and so this is likely to be possible for some people on PrEP. It may nevertheless be helpful for people to understand that missing occasional doses may have little impact on their level of protection.
More importantly, adherence seems to have been high enough in the study not to have caused new HIV infections in the PrEP group.
The difficulty of collecting information from questionnaires meant that information on whether PrEP led to people being at higher risk of HIV through behaviour changes is inferred indirectly from the rates of STIs reported during the study.
Consistent with baseline history, STIs were commonly reported during the study with slightly higher rates in the immediate vs deferred groups (57% vs 50%). But when looking at STIs related to HIV risk from not using a condom (notably rectal gonorrhoea and chlamydia), the difference was not statistically significant (35% vs 32%). However, the number of sexual health screens was also higher in the immediate PrEP group (974 vs 749) because of more frequent clinic visits. Nevertheless, because STI rates were similar in both groups, this can be used as an indirect measure that behaviour might not have been very different in each group.
Safety and drug resistance
There were few reports of side effects. Of the 28 people who stopped treatment because of a medical event, only 13/28 were due to an event considered related to PrEP. Of these, 11/13 restarted PrEP. Two individuals interrupted due reduced markers of kidney function.
Of six participants whose HIV test was positive at the time of starting PrEP, 3/6 developed an M184I or M184V mutation associated with FTC resistance. All three participants were likely to have been seroconverting when they started PrEP.
There were no cases of the K65R mutation associated with tenofovir resistance.
The study recruited gay men in their thirties who were predominantly white, educated and employed. Baseline demographics include median age 36 (IQR: 30-43), ethnicity: white (79%), mixed (4%), Asian (4%), black (3%), Chinese (2%), Irish (2%) and other (5%), ; education level: 60% at university degree level or above, 17% to A-level.
Most men were in full-time (72%) or part-time (9%) employment and 8% were unemployed (11% other or no answer). Almost half (46%) were in an ongoing relationship and 30% were living with a partner. The median number of partners (for anal sex) in the previous three months was 10 (IQR: 4-20) with median of 2 (IQR: 1-5) and 3 (IQR: 1-7) times for receptive and insertive anal sex respectively.
HIV awareness was high with participants having had a median of three HIV tests in the previous year and a third had used post exposure prophylaxis (PEP). Baseline STI history in the previous year highlighted their risk of HIV (rectal gonorrhoea 27%, rectal chlamydia 22% and syphilis 11%). At baseline, approximately 5% of participants tested had each of rectal gonorrhoea, chlamydia and syphilis. These and other baseline data have been previously presented. 
Further details of these results, including a Q&A document from the researchers is on the PROUD website. 
i-Base has also produced a non-technical Q&A resource on these results. 
Simon Collins is involved in the PROUD study as a community representative.
The high HIV incidence in the PROUD study – far higher than the 3.0 per 100 PYFU expected – is important for precisely demonstrating that it is possible to identify people who can benefit from PrEP.
The results – together with those from the French IPERGAY study that were presented immediately afterwards  – do not support widespread access to PrEP, but they do support early access for those at high risk.
The strength of the PROUD results support the growing need for the NHS to rapidly offer PrEP as an option to people at highest risk of HIV infection. Approximately 6000 people are diagnosed with HIV every year. This is equivielent to 500 every month or 16 every day. None of these people currently have access to PrEP.
The preoccupation of some policy professionals with behaviour changes – termed “risk compensation” – was one of the motivations for this pilot study rather than general early access. As with other PrEP studies, PROUD has provided evidence to allay this concern. In contrast to other PrEP studies, this is from randomised data.
Once efficacy is established, “risk compensation” is not used as any additional barrier use to limit access to other medicines. No one deliberately sets out to become HIV positive.
If anything, the very high level of protection against HIV suggests that PrEP can enable people to reduce the need for condoms, when STIs and pregnancy are not a concern.
The HIV Clinical Reference Group (CRG) is developing policy recommendations on the use of antiretroviral for PrEP. These will then be considered by NHS England. Decisions about investment in new services are usually taken on annual basis, but in some cases, in-year decisions can be taken. Unless an emergency case is made for PrEP, investment proposals approved in 2015 are unlikely to be implemented until April 2016.
This will not be soon enough.
Annecdotally, PEP services are already being used to access PrEP. An early access programme for PrEP would protect PEP clinics and provide appropriate monitoring. Use of generics bought online is also likely increase. In Australia, doctors already recommend that patients wanting PrEP buy this online.
The lack of an EU indication for PrEP should not be used to further block access given the wide use of ARVs as PEP without an EU indication.
The PROUD study will continue follow up until 2016, with all participants now having the chance to access PrEP.
- McCormack S et al on behalf of the PROUD Study. Pragmatic open-label randomised trial of preexposure prophylaxis: the PROUD study. 2015 Conference on Retroviruses and Opportunistic Infections (CROI 2015), 23-26 February 2015, Seattle, Washington, USA. Oral late breaker abstract 22LB.
- Collins S. UK PROUD study to provide PrEP to all participants earlier than expected: planned follow-up to continue to two years. HTB November/December 2014.
- Antonucci S et al. The UK PROUD PrEP Pilot Study: a baseline analysis. 20th International AIDS Conference (AIDS 2014), 20-25 July 2014, Melbourne. Poster abstract THPE197.
- PROUD Results Key Messages and Q&A, to be used as a supplement to: PROUD key messages, Q&A and further HIV PrEP trial information.
- HIV i-Base. Q&A on results from the PROUD study (February 2015).
- Molina JM et al. On Demand PrEP With Oral TDF-FTC in MSM: Results of the ANRS Ipergay Trial. CROI 2015. 2015 Conference on Retroviruses and Opportunistic Infections (CROI 2015), 23-26 February 2015, Seattle, Washington, USA. Oral late breaker abstract 23LB.