Belgian study asks: is it worth treating asymptomatic STIs?

A study designed to find out whether it is necessary or even desirable to test and treat gay and bisexual male and trans-female PrEP users for the bacterial STIs chlamydia or gonorrhoea every three months has produced an inconclusive result.

The researchers’ hypothesis was that treating asymptomatic STIs found during quarterly STI testing in PrEP users may have little clinical benefit, over-uses antibiotics with consequences for bacterial resistance, and may inflate the importance of the two STIs as a health problem. 

However it found, contrary to the researchers’ hypothesis, that there were fewer STI diagnoses among people who were screened and treated every three months, even for asymptomatic infections, than among people only treated if they had symptoms. So it looks as if regular screening remains beneficial.

Much of this difference may be due to untreated asymptomatic infections persisting from one study visit to the next, and so being double-counted. However there were certainly not fewer infections in people not screened and treated quarterly.

The study was conducted by Dr Thibaut Vanbaelen of the Antwerp Institute of Tropical Medicine and colleagues, and recruited  1011 PrEP users at five clinical centres in Belgium. Half the participants were randomised to have all gonorrhoea and chlamydia infections (including asymptomatic ones) that were detected in routine three-monthly screening treated, while the other participants only had symptomatic infections treated. 

Background

The authors of the study say that although it is generally assumed that three-monthly screening and treatment of the two STIs in PrEP users has a beneficial effect – by driving down the overall levels of the STIs in this population – this is not based on any evidence from randomised controlled trials (RCTs). “Clear evidence of the net benefit of screening” should be obtained before it becomes universal practice, they say in an accompanying commentary. 

It might be assumed that the opportunity to screen more regularly for STIs afforded by PrEP would have a positive effect on the incidence of infection. This is certainly what some modelling studies have predicted.

 A US modelling study found that if STI screening tests took place every six  months instead of every three, then 34% fewer gonorrhoea infections would be detected, 40% fewer chlamydia, and 20% fewer syphilis. And a Dutch modelling study found that if a PrEP programme targeted the 5% most sexually active gay men in the Netherlands and featured three-monthly STI screening, then the incidence of gonorrhoea could fall by as much as 97% in seven years.

These modelling studies formed the basis of the recommendation that STI screening should be conducted at every three-monthly visit by PrEP users in many guidelines. 

In the real world, however, STI diagnoses have not gone down. While chlamydia cases in both Europe and the US have remained relatively stable in the last decade, gonorrhoea cases have increased, especially in Europe. 

Between 2021 and 2022, the last two years for which there’s full data for both the US and Europe, gonorrhoea diagnoses decreased by 9% in the US but increased by 40% in Europe and over 50% in the UK. This has taken gonorrhoea incidence in the UK to the highest ever seen since records began in 1918. “Anyone who thinks we’re in control of this is fooling themselves,” commented  Dr Matt Phillips, president of the UK STI doctors’ organisation BASHH.  

It is not easy, however, to establish whether STI diagnoses have increased because more infections are actually occurring, or on the contrary, whether we’re over-testing and over-treating them. Another possibility is that not enough STIs are being tested and treated to achieve the results predicted in the modelling studies.

On the one hand, a US survey found that most PrEP providers were screening their gay and bisexual male clients for STIs far less often than every three months as recommended by the CDC.

On the other hand, we may be detecting a lot of infections that would never have been detected or treated in the pre-PrEP era.

Both chlamydia and gonorrhoea are often asymptomatic. In gonorrhoea, while at least 85% of urethral infections are symptomatic, the reverse is true for rectal and throat infections, where 85% or more are not symptomatic. With chlamydia at least half of urethral infections, about two-thirds of rectal infections, and nearly all throat infections are not symptomatic. 

In situations where there is no regular screening, only symptomatic infections will involve testing and treatment, and most asymptomatic cases won’t be recorded. So the introduction of three-monthly screening will detect a lot more more infections, and will lead to a lot more antibiotics being used.

This was what was found in a review of self-reported STI results in respondents to the two huge pan-European EMIS surveys of gay and bisexual men and trans women in 2010 and 2017 (a third is underway). 

EMIS found a 79% increase in self-reported diagnoses of gonorrhoea and chlamydia in between the two surveys, and an 82% increase in syphilis. Reasons for more infections apart from an increase in testing – higher partner numbers, less condom use, changes in the age and geographical profile of respondents – almost entirely explained the increase is syphilis. 

But it only explained 33% of the 79% increase in chlamydia and gonorrhoea. When increases in testing were also included, the remaining 46% of the increase disappeared entirely. In other words, most of the apparent increase in chlamydia and gonorrhoea cases was due to more testing, not only in terms of frequency but because more anal and throat swabs were being done as well as urethral ones. (Syphilis, which only needs a blood test, was already being tested for adequately.) Countries with higher rates of screening had larger increases in diagnoses.

It might be argued that even if three-monthly screening is picking up on infections that would not otherwise be diagnosed or treated, it is still useful, because infections may persist and be passed on to others who may develop symptoms – particularly women, who are more vulnerable to the longer-term consequences of chlamydia infection.

However the Belgian authors argue that a lot of gonorrhoea and chlamydia infections are self-limiting. It is an under-appreciated and not fully understood fact that most chlamydia and gonorrhoea infections eventually disappear of their own accord due to immune system activity. In previous studies rectal gonorrhoea infections were found to have resolved within nine weeks on average and rectal chlamydia within 13 weeks. For throat infections gonorrhoea disappeared on average within 16 weeks and chlamydia within nine. This isn’t so much the case with urethral infections, but they are more often symptomatic and so are more likely to be presented for testing and treatment anyway. 

It is possible, the authors argue, that doctors are giving antibiotics to a lot of people who might not need them.

The study – protocol

The evidence, however, has been tentative so far and hadn’t been tested with a randomised controlled study – so Dr Vanbaelen and colleagues devised one. 

They randomised 1014 HIV-negative gay and bisexual men and trans women who were on PrEP either to receive the recommended three-monthly anal, urethral and throat tests for gonorrhoea and chlamydia (which they called ‘3x3 screening’) and to have every infection treated, or to receive the same tests but only to have symptomatic infections treated (the ‘non-screening’ arm). The study was a year long so there were scheduled appointments at baseline and three, six, nine and 12 months. Screening involved nucleic acid testing on smears taken from throat, rectum and urethra. 

While participants and their physicians knew if they had been allocated to the 3x3 or non-screening arms, neither participants nor their physicians in the non-screening arm were told if asymptomatic infections had been detected, and therefore not treated. 

All participants were able to have extra appointments if they had STI symptoms. 

The aim of the study was firstly to see if not screening or treating asymptomatic infections reduced or increased the overall incidence of infections, and secondly to estimate the total exposure to antibiotics in either arm.

There were 506 participants randomly assigned to 3x3 screening and 508 participants assigned to not-screening. Their average age was 39 and all but three were gay and bisexual men. On average, participants had had two condomless sex partners in the previous three months. 

The study – results

The primary analysis compared the number of chlamydia and gonorrhoea infections, both asymptomatic and symptomatic, in the two arms. 

The idea that three-monthly screening and treatment of all infections, including asymptomatic ones, might inflate the number of diagnoses was not borne out by the study – rather the reverse.

There were a total of 360 gonorrhoea infections and 405 chlamydia infections detected. Out of the gonorrhoea cases, 46% were detected in people in the 3x3 screening arm and 54% in the non-screening arm. This difference failed to reach statistical significance (p=0.138).

In the case of chlamydia, however, 42% happened in the 3x3 screening arm and 58% in the non-screening arm. This difference was highly statistically significant (p=0.008). 

Around two in ten chlamydia cases and three in ten gonorrhoea cases were symptomatic. Symptomatic chlamydia infections were nearly 80% more likely to be diagnosed in the non-screening arm than in the 3x3 arm (p = 0.037). With gonorrhoea there were 16% more symptomatic cases in the non-screening arm, but this was not statistically significant.

In line with previous research findings, it was found that many infections spontaneously resolved without treatment. The average duration of untreated infections (rectal, urethral or throat) in the non-screening arm was 72.5 days (2.5 months) with gonorrhoea, and 90.5 days (three months) with chlamydia.

This could be the main reason diagnoses were higher in the non-screening arm – infections were being double-counted, especially chlamydia, where the chance of an infection resolving between visits was only 50%. In a sensitivity analysis which regarded two consecutive positive tests of asymptomatic infections in the non-screening arm as the same infection, there were no statistically significant differences in incidence between the two study arms. 

This could therefore mean that 3x3 screening makes no difference to the rate of asymptomatic infections – but it certainly doesn’t lead to more of them. Furthermore, there’s a suggestion in the case of chlamydia that, left to themselves, some infections become symptomatic over time.

Incidentally, 24 out of the 405 cases of chlamydia (6%) were of the subtypes of the bacterium that cause lymphogranuloma venereum (LGV). This often causes severe symptoms, but in this study 60% of people with LGV had no symptoms. 

In this study, doxycycline was the primary treatment for chlamydia, and ceftriaxone plus azithromycin for gonorrhoea. In terms of antibiotic exposure, participants in the non-screening arm received 21% less azithromycin, 44% less ceftriaxone and 45% less doxycycline than those in the 3x3 screening arm. 

What do PrEP users think?

As it was recognised that participants might have strong views about leaving STIs untreated, a qualitative substudy involving 12 participants attending three focus groups was conducted. 

Some people were happy with the idea of not screening for asymptomatic STIs:

“Why would you try to detect something if you have no symptoms? And is actually not very dangerous either, even if you pass it on?”

But others were unhappy with not being screened:

“With 5-6 contacts per month, I’d feel safer being tested all the time. If I had a steady partner and, say, one other per month, I would think: OK, let me get tested every six months”.

And still others found it hard to make up their minds:

“I find it difficult to see which carries more weight…the risk of antibiotic resistance, or the risk of having an asymptomatic infection I could spread to others. I find that a difficult balancing act.”

Enough evidence to act on?

The authors conclude that their study found that ‘3x3 screening’ in gay and bisexual men and trans women taking PrEP could lead to a reduction in the incidence of chlamydia infections, but not gonorrhoea infections – “and comes at the cost of higher antimicrobial consumption.”

They call for more evidence, and particularly for more randomised controlled studies, on the benefits and drawbacks of three-monthly screening. Meanwhile their concerns about the spread of antimicrobial resistance among gay and bisexual men have led to the Belgian PrEP guidelines dropping gonorrhoea and chlamydia screening in the absence of symptoms from their recommendations. 

However it may be difficult to reach hard-and-fast conclusions at a time when 3x3 screening of PrEP users, and doxyPEP prophylaxis, are increasingly becoming part of customary STI treatment.