A study in France that matched new HIV diagnoses in adult men who had been taking PrEP with diagnoses in men at similar risk who had not been taking it, has found that the overall effectiveness of PrEP in stopping infection in this high-risk population was 60%.
This 60% effectiveness figure included some men who discontinued PrEP for at least three months during the study period and who in many cases did not resume it. PrEP effectiveness in men who did not discontinue PrEP was 86%, similar to that found in randomised controlled trials.
Hugo Jourdain and colleagues, from the French National Agency for the Safety of Medicines and Health Products (ANSM), also found that PrEP only had 26% effectiveness in men under 30, compared with 83% in men over 40, and had zero or even negative effectiveness in men on very low incomes, though there were only a few HIV cases in this group. This low effectiveness may be due to difficulties in sticking with PrEP in these groups.
The study covers the first five years of PrEP being freely available through France's public health system. Both daily and event-based PrEP are promoted in France.
The study design
This study was nationwide: it used an anonymised and representative database of all people using the French health system.
Similar nation- or state-wide studies that compare the HIV infection rate among PrEP users and non-users, such as a study from New South Wales in Australia or one from Scotland, have the problem of showing that PrEP users and non-users really are at similar risk of HIV and therefore that it was PrEP that lead to the reduction in infections seen.
To solve this problem, the researchers took a sample of 256 men who became HIV-positive during the study period of January 2016 to June 2020 ('cases') and matched them with a group of men who remained HIV-negative during the same period, but who they deemed to have similarly high risk of HIV ('controls'). This control group contained equal numbers of men who took PrEP and did not take it.
If there were fewer PrEP users in the group that did acquire HIV, the researchers could then calculate the proportion of infections that were prevented by PrEP.
Nonetheless, because the database records prescriptions, diagnoses and procedures, the researchers lacked personal, behavioural data. The criteria for ‘high risk’ they used was therefore based on what is available in anonymised records: tests.
To be in the matched comparison group of men who stayed HIV negative, subjects had to have had at least four HIV screening tests and one STI test within two years during the study period, and at least one more HIV test thereafter. This frequency of tests, the researchers calculated, correlated with the likely ‘background risk’ of HIV in all participants, and was also similar to the minimum testing regime expected of PrEP users.
The figures are as follows: in total, 28,352 men aged 18-65 initiated PrEP and had at least one repeat prescription during the study period. Within the same timespan the researchers found 18,354 ‘high risk’ non-PrEP users with the frequency of HIV and STI tests described above.
In this group of 46,706 men, both PrEP users and non-users, there were 260 who were diagnosed with HIV in the study period.
The two hundred and fifty-six cases were each matched with three to five controls each who were at similarly high risk and who also had other similar characteristics, namely age; geography; HIV prevalence in their area; and whether they were on the French health assistance programme for people on very low incomes. The controls were almost equally split between 591 PrEP users and 622 non-users, but the cases and controls were not matched by PrEP use – only by their other characteristics.
Results
Seventy-three (29%) of the 256 people who acquired HIV during the study period had used PrEP – meaning that 71% had not. This means that PrEP users were only 40% as likely to end up acquiring HIV as non-users – in other words, it was 60% effective.
Of the PrEP users who did acquire HIV, most (78%) used PrEP less than half the time during the study period and only 7% (five men) used it more than 75% of the time. In contrast, among the PrEP-using controls who did not acquire HIV, equal numbers used PrEP less than half the time (40%) and more than three-quarters of the time (again, 40%).
"The study could not distinguish between infrequent but correct use of on-demand PrEP and inadequate adherence to daily PrEP."
Of the PrEP users who tested HIV-positive, 88% (64 of the 73 PrEP users who acquired HIV) discontinued PrEP at some point during the study period. However 34 of them restarted it, and of these, 47% acquired HIV.
If people taking PrEP were excluded from the study after their first discontinuation, then there were only ten people who acquired HIV during their first continuous (though not necessarily fully adherent) period on PrEP. This equated to PrEP being 86% effective, as long as people did not have a period of discontinuation.
As mentioned above, PrEP was only 26% effective in men under 30 (35% of cases of HIV were PrEP users, almost as high a proportion as the 42% of PrEP users who did not catch HIV). It was 66% effective in men in their thirties and 83% effective in men aged 40 and above.
It was 65% effective in people living in large cities (population over 200,000), but only 28% effective in people living in small communities (population under 10,000). And it was only 24% effective in people living in low-prevalence areas of France, compared to 67% in the Paris region and 70% in other high-prevalence areas.
There was actually a higher proportion of new HIV cases in PrEP users who had a low-enough income (defined as 50% of the French poverty level) to be eligible for free state-financed healthcare, as opposed to the insurance-based healthcare most people get. There were nine cases among 38 men who used PrEP in this category (24%) versus 11 cases among 61 men who did not (18%), but the numbers were too low to be statistically significant. It does, however, indicate that people on low incomes – like young people and ones in rural areas – may have difficulty in PrEP continuation.
Conclusions
This study was constructed to include groups of PrEP users and non-users at similar risk of HIV, to rule out differences in risk that could over- or under-estimate the true efficacy of PrEP.
The researchers do acknowledge limitations in their identification of 'high-risk' controls, who were defined by their taking frequent HIV and STI tests. This means they could be missing out a proportion of men who were at high risk of HIV but did not test often, or at all. Since having tests is a part of taking PrEP, a population of ‘invisible’ high risk non-testers would tend to increase the proportion of those acquiring HIV who did not take PrEP. This would tend to increase its apparent effectiveness.
In a commentary, Dr Liza Coyer from the Bavarian Health and Food Safety Authority and Dr Elske Hoornenborg of the Public Health Service of Amsterdam also draw attention to the fact that the 256 HIV cases represent a small proportion of the more than 1000 new cases diagnosed annually in gay men in France, so may possibly not have been representative of all men newly diagnosed with HIV, especially of lower-risk men who nonetheless acquired HIV.
The other limitation of the study was that its measure of PrEP use – which was prescription refills – could not distinguish between infrequent but correct use of on-demand PrEP and inadequate adherence to daily PrEP. However previous studies, including the pivotal French study IPERGAY, appear to show that on-demand PrEP used correctly is as effective as daily PrEP – including in this ‘real-world’ study of which Elske Hoornenborg was a co-author.
The most striking finding, as they comment, is the low effectiveness of PrEP among young men, a finding which has been duplicated in many different studies. Coyer and Hoornenborg urge new structural and personalised interventions to improve accessibility, adherence and continuation of PrEP among young men including more online access, sexual health services integrated into local community initiatives, and access to the new longer-lasting formulations of PrEP.
Jourdain H et al. Real-world effectiveness of pre-exposure prophylaxis in men at high risk of HIV infection in France: a nested case-control study. Lancet Public Health 7, e529-e536, June 2022. See https://doi.org/10.1016/S2468-2667(22)00106-2.
Coyer L and Hoornenborg E. Reaching the full preventive potential of HIV pre-exposure prophylaxis. Lancet Public Health 7, e488-e489. See https://doi.org/10.1016/S2468-2667(22)00116-5.