Danish study finds that STI rates in gay men increase before they start PrEP, not after

A Danish study which was able to chart the annual incidence of the three bacterial STIs, chlamydia, gonorrhoea and syphilis, in people attending sexual health clinics both before and after they started PrEP has found that they had more than twice as many (115% more) STI diagnoses while on PrEP than they had some time before starting it.

However it also found that much of this increase in diagnoses was due to increased testing. While the average STI testing rate in people some time before starting PrEP was in the region of 50 tests per 100 person years (i.e. a test every two years), it was three to four tests per year in people on PrEP, with tests peaking each three months due to PrEP checkups.

When this was taken into account, the diagnosis rate of any of the bacterial STIs in people on PrEP was only 35% higher than it was before PrEP, and in the case of syphilis there was no significant increase.

The investigators also found, however, that the increase in tests started some 10-20 weeks before people actually started PrEP, increasing in this period from about 200 to 500 tests per 100 person-years in that period, even when the large spike in tests at PrEP initiation was discounted.

Dr Sebastian von Schreeb and colleagues at Copenhagen University Hospital say that their study is evidence against the idea that PrEP leads directly to “risk compensation”. This is the theory put forward by some behavioural scientists that if people feel less anxious because they adopt one protective behaviour, they will tend to increase a related risky behaviour – driving faster because they wear a seat belt, for instance. In the early days of PrEP and U=U some researchers were concerned that this would lead to condom use dropping by such an extent that it might wipe out some or all of the benefits of biomedical prevention.

The authors say that their study shows that this is not the case with PrEP and STIs: “If risk compensation was valid, we would expect STI incidence to increase when people feel protected against HIV [and that it] could occur immediately following the initiation of PrEP or gradually over time, as they became more assured.

“As no such increase was seen, an alternative explanation is that…changes in sexual risk-taking lead people to PrEP.”

More about the study

Demonstrating whether PrEP leads to risk compensation requires data about people’s STI incidence before they start PrEP, and this can be difficult to establish. This is because researchers often only have access to STI diagnosis data in PrEP users, and also because PrEP use usually involves more STI tests, which will diagnose more infections – especially asymptomatic ones (it is estimated that 85% of rectal chlamydia and gonorrhoea infections in gay men are asymptomatic).

A couple of other studies have found that STI diagnoses or STI risk behaviour increased before, rather than after, gay and bisexual men started PrEP, but others have found higher rates after the start of PrEP –  as described in aidsmap’s evidence brief on PrEP and STIs.

Find out more: PrEP and sexually transmitted infections

The new study’s data are particularly robust because of Denmark’s thorough healthcare surveillance. Each citizen is given a unique civil registration number which can be linked to comprehensive databases of microbiological test results. Results are thus less likely to get lost in the system.

PrEP became available through the Danish public health system in 2018 and all people starting PrEP are enrolled in a nationwide prospective cohort study, DanPrEPD, and continue as participants even if they stop PrEP. All cisgender gay men and trans men and women who initiated PrEP between January 2019 and June 2022 and who lived in the Capital Region of Denmark, which includes 30% of the country’s population, were included.

The total number of participants was 1326, of which 10 were transgender. Their average age was 35 (range: 16 to 78). All but eight participants started on a daily PrEP regimen. One hundred and forty-seven participants (11%) were already on PrEP before January 2019 and were excluded from the before/during PrEP comparison, as were 237 people who stopped PrEP during the study (this doesn’t mean 384 exclusions, as some could belong to both groups).

The rest of the participants, who started PrEP during the study and were still on it at the end, were observed for roughly equal times before and after PrEP: there were 2155 person-years of data available before the start of PrEP and 2351 after it. The average gap between entering the study and starting PrEP was 22 months in a 42-month study, so roughly halfway through.

There were 708 STI diagnoses in people before they started PrEP and 1849 after it. This implies an unadjusted annual incidence rate of 35 per 100 person-years before PrEP and 81 per 100 afterwards (as other studies have shown, this does not mean that all participants had an 81% chance of acquiring an STI while on PrEP: some may have had no STIs and others may have had repeated episodes.)

This means that the frequency of STI diagnoses (the Incidence Rate Ratio or IRR) was 2.15 times greater after PrEP than before, both for all STIs and for each individual STI.

However, people took three times as many STI tests after starting PrEP than before: in total, 7936 before PrEP but 23,654 after it. In terms of individual STIs people took 2.6 times more tests for gonorrhoea and chlamydia after PrEP than before, but 4.4 times more tests for syphilis; this appears to reflect the test for syphilis, which is an antibody test done on blood, becoming as routine as the swab tests done for the other two diseases, whereas it was only done half the time before PrEP.

When the IRR of post- compared to pre-PrEP STI diagnoses was adjusted to take account of greater test frequency, the IRR for all STIs fell from 2.15 to 1.35, or in other words from more than doubling to a 35% increase. In chlamydia it fell from 2.25 to 1.23, for gonorrhoea from 2.21 to 1.24, and in syphilis from 2.46 to 1.15, which was no longer statistically significant, meaning that the increase seen in syphilis cases on PrEP might have been due to chance.

Chlamydia in the throat or urethra is less likely to be symptomatic than rectal chlamydia; conversely, in gonorrhoea, while 85% or rectal and throat infections are asymptomatic, only 10% of urethral symptoms are. This implies that if more asymptomatic infections are being diagnosed on PrEP, the IRR of post- compared to pre-PrEP rectal chlamydia should be higher than that seen for throat or genital chlamydia, and the IRR for urethral gonorrhoea should be considerably lower than for throat or rectal.

This is exactly what was seen. The test-adjusted IRR for rectal chlamydia was 1.26 while the rates for oral and genital were 1.19 and 1.14, and lost statistical significance. With gonorrhoea, the adjusted IRRs for rectal and oral gonorrhoea were 1.12 and 1.16 and were not statistically significant; but the tested-adjusted IRR for urethral gonorrhoea was 0.66 and was statistically significant. This means that, adjusting for test frequency, urethral gonorrhoea was actually 34% less likely to be diagnosed while on PrEP than before it (compared with an unadjusted IRR of 1.66). The researchers point out that this does not mean that actual infections decreased on PrEP, merely that in this one case, because most urethral gonorrhoea infections were likely to be detected even before the test increase on and just before PrEP, the unadjusted IRFR of 1.66 may more closely reflect reality.

So one reason more STIs were diagnosed in people starting PrEP was because prior to PrEP, people might only have come for tests if they had symptoms. Because the testing rate in the 10-20 weeks before PrEP was the same as after PrEP, in a sensitivity analysis the researchers excluded the tests taken in the 26 weeks before PrEP initiation. This raised the IRR of post- compared to pre-PrEP STI diagnoses from 1.35 to 1.91, showing that a large proportion of the STI diagnoses after starting PrEP probably were of asymptomatic infections.

If pre-PrEP testing had picked up all asymptomatic infections, the true increase in the rate of all STIs, symptomatic and otherwise, during and immediately before PrEP, might be nearer 90% than 35%. Whether this matters, with two conditions that may not only be asymptomatic but also self-limiting (as a previous Dutch modelling study has explored) is a matter of public health debate.

The study “does not imply that PrEP causes risk compensation,” say the authors. “Rather, it indicates that PrEP is being given when the risk of STIs is increased, i.e. when it is most needed.” They add that “this makes PrEP programmes a critical point of intervention [in which] it is crucial so provide a safe and supportive environment that includes comprehensive sexual health consultation.”