PrEP and sexually transmitted infections

Concern has been raised that pre-exposure prophylaxis (PrEP) could lead to, or contribute to, a new epidemic of sexually transmitted infections (STIs) other than HIV.

No other STI combines incurability with near-100% lethality in the absence of treatment as HIV does. But other STIs can have serious health consequences. The bacterial STIs – gonorrhoea, syphilis, chlamydia and chlamydia’s ‘superstrain’, lymphogranuloma venereum (LGV), as well as other infections like Mycoplasma genitalium (MG) and trichomoniasis – are generally easily curable but may have serious health consequences in some people if left untreated. Syphilis may also cause serious symptoms in early disease, and drug resistance in gonorrhoea is of considerable concern.

Viral STIs include herpes, genital warts, hepatitis B and hepatitis C; the latter two can eventually cause fatal liver disease if left untreated. As well as warts, human papillomavirus (HPV) can cause cervical, anal and oral cancer. The rest of this briefing will concentrate mainly on gonorrhoea, chlamydia and syphilis, as these are the infections that have seen large increases in recent years.

The questions we will aim to answer in this briefing are:

• To what extent have cases of STIs increased in recent years?
• Are these increases especially concentrated in gay men, particularly since PrEP became available?
• Are increases in STIs correlated with other changes in behaviour such as reduced condom use, ‘seroadaptive’ behaviours such as serosorting (preference for sexual partners of the same HIV status) or seropositioning (decisions on sex roles dependent on HIV status)?
• Does PrEP directly lead to STI increases? Or are they just happening at the same time?
• Are the observed increases in STIs caused by people taking more tests for them?
• Could increased testing and treatment rates for STIs actually help reduce STIs? Is there any evidence for this already happening and if not, why not?

This briefing will not discuss messaging strategies to deal with STIs in the era of PrEP, or the psychological and social benefits of PrEP.

STI epidemiology – history

There is no doubt that bacterial STI diagnoses, especially in men who have sex with men, have increased since their historic low in the 1990s when condoms were the only effective HIV prevention measure and fear of HIV led to their widespread use. However, it’s important to put recent increases into a historical context. Are STIs now at a historic high in the UK?

Gonorrhoea

Gonorrhoea and syphilis data have been collected in the UK for a century, ever since the Venereal Disease Act of 1917 set up the country’s network of specialist, anonymous STI clinics.

Gonorrhoea cases in the UK reached their lowest-ever point during the early 1990s when the fear of AIDS led to the adoption of condoms and other safer sex strategies. At this point there were about 10,000 cases a year recorded. Cases of gonorrhoea in England increased from 31,177 in 2013 to 71,133 in 2019. Cases fell to 50,678 in 2020, probably due to the COVID pandemic, but increased again to a historic high of 82,592 in 2022.

Diagnoses per 100,000 population rose from 85 in men and 31 in women in 2013 to 207 in men and 73 in women in 2022, meaning that one in 500 male adults in England was diagnosed with gonorrhoea in 2022. This represents a 2.4-fold rise in cases since 2013 for both men and women, though the steepest rises have been in young men aged 16-24.

The annual total now exceeds the previous historic high of about 64,000 cases a year in the mid-1970s. However, as we shall see below, there is probably now more testing and detection of asymptomatic cases, in part due to PrEP.

In the US, gonorrhoea cases have been recorded since 1941, when prevalence was 140 cases per 100,000 population (0.14%). After World War II, there was a peak in cases as soldiers came home from the front, with prevalence at 0.3% in 1946. There was a longer and higher peak in the 1970s reaching 0.5%, then cases fell to a historic low of less than 0.1% per head of population in the 1990s and early 2000s, but since 2011 have more than doubled.

In recent years US diagnoses have continued to increase; there were 555,608 cases in 2017 but 710,151 in 2021, with none of the dip in 2020 coinciding with COVID that was seen in the UK. The 2021 figure represents 0.27% or about one in 370 US adults over 18.

Gonorrhoea is an adaptable organism that retains the capacity to outwit medications. (Resistance is discussed later in this briefing.) In addition, diagnoses are not only sensitive to how many tests are done but also the anatomical sites that are tested; the UK has a better record than most European countries for rectal smear tests but does not always test for pharyngeal (throat) gonorrhoea, which is an important site of infection.

Syphilis

The figures for syphilis are more reliable as the syphilis organism rarely develops antibiotic resistance and is diagnosed via blood tests, which are more consistently performed. A recent review by Public Health England (now the UK Health Security Agency) found that between 1930 and 1945, UK cases ranged between 8000 and 16,000 a year. Cases then fell with the introduction of penicillin to a low of 700-800 cases in the late 1950s, before rising to a peak of about 3000 cases a year in the late 1970s. The ratio of male-to-female cases rose throughout the 1960s and 1970s, suggesting that male-to-male transmission was important in the pre-HIV era. Infections in the US followed the same trends.

Cases then started to fall and in the UK reached a historic low of 280 in 1995, just before the advent of HIV combination therapy, with about a third of male cases being in gay men. There was a sudden doubling of cases in 2001, which was also the first year that cases in gay men formed more than 50% of male cases. Cases only rose by 22% in women between 1997 and 2003 but tripled in heterosexual men and went up 15-fold in gay and bisexual men.

Since then cases have risen over tenfold more, to a historic high of 8692 cases in 2022, with 7428 cases in men and 743 in women. Up to 2018, syphilis was 18 times more common in men than women but is now only tenfold more common.

Chlamydia and LGV

Increases in other STIs have been less marked. Chlamydia is more prevalent in women than men and, as an STI that is asymptomatic in 50% of cases in men and 75% in women, diagnoses may be as much influenced by the number of people testing as actual incidence. In the UK, diagnoses may have been influenced by changes in the focus of the National Chlamydia Screening Programme. Cases decreased between 2013 and 2021, by just 3% in men but 21% in women. This compares with a 224% increase in gonorrhoea and a 183% increase in syphilis, both concentrated in gay men.

Lymphogranuloma venereum (LGV) is caused by a variant of chlamydia which has evolved considerably greater virulence and can cause unpleasant long-term complications, although it is sometimes asymptomatic. The UK has had over 40% of the LGV cases in Europe, and two-thirds of them have been in London. LGV was extremely rare until 2003 when there was an outbreak in the Netherlands, with the first UK cases appearing in 2004. There were 550 cases in 2021, but this increased to 1042 in 2022.

Mycoplasma genitalium

First isolated in 1980, Mycoplasma genitalium (MG) is a small bacterium that causes similar symptoms to chlamydia. Like chlamydia, it can cause pelvic inflammatory disease and urethritis in both men and women, but is asymptomatic in over 90% of gay men and 60% of women if it is the only organism present. It may be a ‘commensal’ of chlamydia and gonorrhoea, meaning that it likes to colonise mucous membranes that are already inflamed due to the other two conditions.

In England, 7232 cases were diagnosed in 2022, 65% in men, but the vast majority of infections are probably left undiagnosed, and it may be the second most common STI after chlamydia.

Unlike chlamydia, but like gonorrhoea, MG easily develops resistance to antibiotics; the proportion of patients previously treated for gonorrhoea or chlamydia that had MG with resistance to the second most commonly used antibiotic for gonorrhoea, azithromycin, ranged from 44% in a UK study to 75-100% (depending on infection site) in a US one. A German study also found 7% with resistance to tetracycline antibiotics, one of which, doxycycline, is used for STI prophylaxis.

Because of concerns about resistance, UK doctors were urged in 2021 not to test for MG in gay men without symptoms, especially as the infection is often self-limiting.

Diagnoses are influenced by changes in testing practice as well as by real increases or decreases in prevalence. Testing for MG only started being done widely in 2019; before that symptoms might have been ascribed to other conditions or more likely to a category called ‘non-specific genital infection’ (NSGI).

There were 40,0628 diagnoses of NSGI in 2013 but by 2022 they had fallen to 16,655, a decrease of 23,973. That year there were also 7232 diagnoses of MG; but even if every one would previously have been classed as NSGI, that still leaves 14,436 ‘missing’ NSGI cases, some of which could have been urethral chlamydia or gonorrhoea.

Mpox

A notable event in 2022 was the outbreak of mpox (formerly monkeypox). Mpox is a virus, a member of the herpesvirus family, related to smallpox. Normally it is endemic to central Africa where it circulates as a zoonose (a disease transmitted between humans and animals, hence the previous name). It causes blisters and sores which can appear on any part of the body which usually resolve within a couple of weeks, but which can sometimes develop into a fatal condition.

In May 2022 the first cases were noted of a strain of mpox in the UK which at first appeared in a few people with connections to Africa. Cases soon started to be seen among gay and bisexual men without an African connection. It became clear that the new strain’s main mode of transmission was via intimate, though not necessarily penetrative, sexual contact between gay and bisexual men,

Cases peaked in the summer and then started to decline. By the end of May 2023 the World Health Organization had counted 86,516 cases of the non-endemic strain globally, and the UK saw 3805 cases up to the end of September 2023, though only 73 of these were in 2023, illustrating that the outbreak had declined almost as quickly as it had started.

While most people made a full recovery, a severe, systemic form of the disease was seen in people with HIV and low CD4 counts, with a 27% fatality rate in people with CD4 counts below 100.

A smallpox vaccine was found to be effective against mpox and started to be administered to gay men in the UK in July 2022, after cases had already begun to decline. A modelling study later concluded that the decline in the outbreak was due to “a potentially large (approximately 45%) reduction in sexual partners among gay and bisexual men in mid-2022, and a decrease in the asymptomatic infectious period before isolation from 3.0 days to 2.4 days. Overall, these control interventions, combined with vaccinations prevented 98% of infections that would have occurred with no interventions.”

Viral STIs

Diagnoses of other common viral STIs have not increased, unlike the bacterial ones. There were 34,294 first diagnoses of genital herpes (HSV-2) in 2013 and 24,910 in 2022, with 59% of diagnoses in women.

Diagnoses of genital warts, caused by HPV, decreased by 63% between 2013 and 2022, from 76,987 to 28,477. This decrease, seen in young women and men alike, has been ascribed to widespread vaccination of adolescent girls since 2008 and ‘herd immunity’ among male partners. The decline has not been seen in gay men, who are recommended to ask for HPV vaccination. HPV vaccination was extended to adolescent boys in the UK in July 2018.

Cervical cancer is the most serious consequence of HPV infection in women, and in women with HIV is an AIDS-defining illness. It has not declined to the same extent as genital warts due to the delay between acquisition of HPV and the development of cancer (at the time of writing, only women currently aged below 28 would have been vaccinated against HPV during adolescence). A 2021 paper in The Lancet found that rates in young women vaccinated at the appropriate age (12-13) had declined by 87%.

While 206,000 people in England and Wales or one in 230 members of the adult population may have chronic hepatitis B virus (HBV) infection, most cases are among people who acquired it abroad or many years ago. Widespread HBV vaccination for adults started in the UK in 1986 and has been mandatory for infants since 2017. As a result, new infections are now quite uncommon. There were only 350 acute or suspected acute cases of HBV in 2018 (the latest confirmed figure), representing one per 125,000 people in the general population. This is down from a peak of 1900 in 1984. Incidence is about twice as high in London as the rest of the UK. Fifty-five per cent of new infections were ascribed to heterosexual contact and 15% to male/male sex, with the route of most other infections unknown.

The estimated prevalence of chronic hepatitis C virus (HCV) infection has fallen dramatically in the UK and in many other countries due to treatment and cure using direct-acting antiviral drugs. In 2013 an estimated 130,000 people in UK had chronic hepatitis C infection; in 2020 the figure was 81,000. The decline has been particularly impressive among people living with HIV, as most are in regular contact with health services and have been offered treatment. Between 2015 and 2022, HCV prevalence among gay and bisexual men living with HIV in England declined from 6% to 1%. During the same time, prevalence among people who inject drugs living with HIV declined from 50% to 18%.

While hepatitis C in gay and bisexual men used to be concentrated in those living with HIV, recent studies from several European cities have reported numerous cases of hepatitis C in HIV-negative gay and bisexual men. In Lyon and London, 45% and 40%, respectively, of gay men with new hepatitis infections were HIV negative. Of these, 67% and 81%, respectively, were taking PrEP or had done during the previous year.

Syphilis and gonorrhoea specifically in gay men

Of the common STIs, it is only syphilis and gonorrhoea (aside from HIV) that have become especially concentrated in gay men. In 2001, NAM aidsmap was already raising concern that hundreds of cases in syphilis in gay men had been reported in the previous two years, compared with a handful in the mid-90s.

In the UK in 2022, 69% of male syphilis cases were in gay and bisexual men – despite the fact that only 11% of STI clinic attendees were gay men. Gay men were 64 times more likely to be diagnosed with syphilis than adult members of the general population.

For gonorrhoea, 47% of diagnoses were in gay and bisexual men, and they were 43.5 times more likely to be diagnosed with gonorrhoea than adult members of the general population.

Even in terms of STI clinic attendees, gay and bisexual men are now 17 times more likely to be diagnosed with syphilis than heterosexual men and nearly six times more likely to be diagnosed with gonorrhoea.

In contrast, while there have been increases in the proportion of other STIs in gay and bisexual men, they still form a minority of cases and increases have been relatively slight. Between 2006 and 2022, the proportion of genital herpes and genital wart diagnoses that were in gay men both increased from 5% to 7%, and the proportion of chlamydia cases from 4% to 10%. But because there are fewer gay and bisexual men, they are still six times more likely to be diagnosed with herpes or genital warts and nine times more likely to be diagnosed with chlamydia than the general population.

In the US the estimated annual incidence of gonorrhoea in gay men was 5% in 2017 – roughly 25 times the general-population incidence, though this varies geographically. On the west coast and in New York there is much more concentration among gay men than in the south. In terms of absolute numbers diagnosed, there were actually slightly fewer cases of gonorrhoea in men than women until 2012, when male cases first outstripped female. In gay men, a slight upward trend in gonorrhoea cases accelerated from 2013 onwards and still continues.

In 2019 the European Centre for Disease Prevention and Control (ECDC) documented 35,039 cases of syphilis in the European Union and European Economic Area (which includes the UK, Norway and Iceland). There were nine times more cases in men than women. Cases in heterosexual men and women have stayed steady at about 3000 since 2021, but cases in gay men accelerated from 3000 in 2010 to 8000 in 2015. The rate of increase since then slackened off and now stands at about 9000 a year; two-thirds of all diagnoses were in gay men in 2019.

A similar pattern was seen in gonorrohea. In 2019 about 120,000 cases of gonorrhoea were diagnosed in the EU/EEA, two-thirds of them in men. Only 13% of clinics reliably documented routes of transmission for gonorrhoea, but among these, cases in heterosexuals increased only slightly, from about 1700 in women and 2200 in heterosexual men in 2010, to about 3000 in either sex in 2019. But cases increased sharply in gay men from 2000 in 2010 to just under 10,000 in 2019, so form about 62% of cases. In contrast to syphilis, gonorrhoea diagnoses show no sign of slackening off.

A note on gonorrhoea resistance

The syphilis and chlamydia organisms seem to find it very hard to acquire resistance to antibiotics. Syphilis is one of the few bacteria still treatable with classic penicillin.

Gonorrhoea resistance, on the other hand, causes significant concern and may be one of the most significant medical risks of increased STI prevalence. The Neisseria gonorrhoeae bacterium easily becomes resistant to antibiotics. Originally treated with sulphonamides and then penicillin in the 1940s, gonorrhoea became progressively resistant to those drugs and then to tetracycline and ciprofloxacin, which replaced them.

As the proportion of gonorrhoea resistant to ciprofloxacin in the UK climbed to 50% in gay men and 20% in heterosexuals, a switch was made to a whole new class of antibiotics – the cephalosporins. A single drug from this class, cefixime, was used for first-line treatment of gonorrhoea starting in 2006.

However, the proportion of gonorrhoea with resistance to cefixime rapidly increased in gay men from about 5% in 2008 to 31% in 2010. As a result, in 2011 the recommended therapy changed, to dual-combination therapy. This combined another cephalosporin, ceftriaxone, with the macrolide drug azithromycin.

Emphasising this as the only approved regimen for gonorrhoea, and guarding against over-treatment, appeared to have positive results both in the US, where rates of resistance to ceftriaxone fell tenfold between 2011 and 2014, and in Europe, where in the UK and Belgium resistance to both drugs halved between 2011 and 2014. No cases of ceftriaxone-resistant gonorrhoea were detected in Europe in 2016, compared with seven in 2013.

Doctors, however, were faced with the dilemma that up to 3% of patients are allergic to ceftriaxone. To preserve the potency of azithromycin, the 2019 British Association for Sexual Health and HIV guidelines reverted back to solo ceftriaxone. At the moment cases of gonorrhoea resistant to ceftriaxone are rare; it persists longer in the body than other cephalosporins and thus makes it difficult for Neisseria gonorrhoeae to complete a cycle of replication. But higher levels of resistance in south and south-east Asia have led to predictions that increases over here are likely; the first cases of multi-drug resistant gonorrhoea seen in the UK were in heterosexual men who had acquired it in south-east Asia.

Conclusion: trends in STI epidemiology

• The truly exceptional period in the epidemiology of STIs both in the UK and globally was the 1990s, when the fear of HIV and the adoption of safer sex led to historic lows in STI diagnoses.
• Diagnoses of most STIs have been increasing since then, beginning well before the advent of PrEP.
• Diagnoses of the bacterial STIs, especially gonorrhoea and syphilis, have now reached the historic highs of the late 1970s to early 1980s. These are particularly concentrated among gay and bisexual men.
• In recent years, there have been declines in the incidence of HPV/genital warts (due to vaccination), hepatitis B (mainly due to vaccination), hepatitis C (due to treatment) and HIV (due to treatment and PrEP), but other STIs continue to rise.
• We will look below at the reasons for the rise in bacterial STIs, and whether PrEP contributes to the increases in the most recent years.

Behaviour change and condom use

It is hard to deny that a gradual, long-term decline in condom use from the high rates of the AIDS era was the first and one of the most important reasons for the rise in STIs in recent years. Surveys have shown increases in condomless sex that started almost as soon as HIV combination therapy started reducing mortality from AIDS in the late 1990s.

Although direct comparisons cannot be made from one survey to another (because the characteristics of respondents changed), the Gay Men’s Sex Surveys (GMSS) in the UK are one of the longest longitudinal data sets investigating gay and bisexual men’s risk behaviour in the world.

Starting in 1993, most of the surveys have either asked all respondents whether they had had condomless anal sex during the year or asked that question solely of men who said they had had anal sex. (GMSS has used quite a strict definition of condomless sex; just one instance during the previous year counts as answering ‘yes’, regardless of the actual or perceived HIV status of partners, their viral load, or their relationship status.)

From 1993 to 1997, roughly 33% of all respondents answered that they had had at least one episode of condomless anal sex during the year. Between 1998 – when antiretroviral therapy became widely available – and 2007, this proportion increased to around 42%. Since then, surveys have been less frequent but in 2008 the figure was 54% and in 2014, 64%.

To put it another way, up until 1997 a third of gay men were not using condoms consistently; by 2014 only a third were using them consistently.

In some years the question has been whether gay men who have anal sex have had condomless sex during the year, which excludes the men who had no anal sex and is therefore a higher figure. This question was first asked in 1998, when the proportion was 47%. The proportion was 59% by 2001 and in surveys up to 2010 the figure hovered around the mid-50s. By the next survey, published in 2014, the figure had increased to 76%.

When discussing condoms and whether the decline in their use has been the root cause of increases seen in STIs other than HIV, it is worth noting that condoms are not as effective against other STIs as they are against HIV.

For instance, a prospective study of self-reported condom use in 929 attendees at five US STI clinics in 2012 found that consistent and correct condom use (i.e. no breaking, slipping, leakage, putting on after first insertion, or taking off before last withdrawal) only reduced bacterial STI diagnoses by 60% – lower than the 70-90% reduction rates seen for HIV in similar analyses.

This is partly because most STIs are not spread exclusively via genital contact. As far back as 2002, studies were already showing that a particularly high proportion of gonorrhoea infections in gay men were in the throat (pharyngeal), often asymptomatic, and spread through oral sex. Subsequent research has reaffirmed this. Similarly, estimates of the proportion of syphilis in gay men spread by oral sex or kissing range from 33 to 50%.

In other words, even if it were possible, making condom use routine again might not have the expected impact against other STIs that it might have in HIV.

Serosorting

Using condoms has never been the only measure taken to avoid HIV infection, especially by gay men. As condom use became less frequent, but before biomedical prevention measures including PrEP and treatment as prevention ('U=U') were adopted or had a significant effect, people with HIV and at risk of it were adopting what were called 'seroadaptive' behaviours that attempted to minimise the risk of sex if it was condomless.

Serosorting (restricting condomless sex to partners of one’s own HIV status) was a major behavioural phenomenon in the 2000s. From 2001 onwards, for instance, in San Francisco, while the amount of condomless sex increased in HIV-positive gay men, and stayed level in HIV-negative men, there was a sharp drop in reported condomless sex between partners of different HIV status. This trend was especially notable in men with HIV, in whom condomless sex 'across the serodivide' fell by two-thirds. Similar trends were seen in other surveys, including in HIV-positive women.

The reason serosorting was led by HIV-positive people was because they could be certain of their status. As a number of studies found, for HIV-negative people it was a much less secure way of ascertaining safety. Many people relied on guessing partners’ HIV status – a process that led to increased stigma towards people with HIV, and against the type of person seen as likely to have HIV.

A meta-analysis of serosorting found that while HIV-negative people who serosorted were half as likely to acquire HIV as people who did not, it was the least effective 'seroadaptive' behaviour. One hundred per cent condom use was more effective, and 'seropositioning' was even more effective than that. Seropositioning involves HIV-negative men adopting the insertive role in anal sex and HIV-positive men the receptive role.

What is clear is that since PrEP came along, there has been a complete reversal in gay men’s ideas of what the safest HIV prevention strategy would be. A study from New York, for instance, found that PrEP was now regarded as by far the safest HIV prevention strategy, ahead of U=U and considerably ahead of seropositioning (they were not asked about serosorting).

This change in perception of the safest way to avoid HIV has been accompanied by a considerable reduction in sexual anxiety among gay men using PrEP and a relaxation of serosorting behaviour.

The importance of networks

The fact that gay men are once more willing to 'cross the serodivide' may significantly contribute to the increases seen in STIs in the last few years.

One of the most convincing explanations of why HIV rates are exceptionally high in certain communities – such as Black gay men in the US or African migrants in Europe – despite similar or lower rates of risk behaviour than in their compatriots, is that racism and cultural isolation means that the population largely has sex only with other members of their minority group. This creates a tightly bound network in which most of the sexually active population is connected closely to other people, including people with HIV – or STIs.

Another example of the power of network effects is the fact that Iceland, of all countries, has one of the highest rates of chlamydia in the world, due to the often-asymptomatic infection recirculating among the country’s small and relatively isolated population.

HIV serosorting had a similar effect on STIs in gay men. The HIV-positive population was only 10% of the size of the negative population but had exceptionally high rates of condomless sex between each other. This led to such a concentration of STIs among HIV-positive gay men that some – such as LGV and sexually transmitted hepatitis C – were almost exclusively seen in HIV-positive men.

However, as soon as serosorting was relaxed, and more HIV-positive and HIV-negative men started having sex with each other, a greater number of infections such as hepatitis C started to occur in HIV-negative men, as has been noted above.

Conclusion: STIs and behaviour change

A rise in STIs following the historic low of the HIV years was therefore probably inevitable, and the reasons for it unsurprising. The rise started just after the millennium, at the time when the availability of antiretroviral therapy first started to reduce people’s fears of the consequences. It has accelerated since 2013-14, when awareness of the efficacy of both PrEP and of treatment as prevention as measures against HIV started to seep into the consciousness of at-risk populations.

The questions to ask at this point are:

• Are these increases all part of an inevitable historic rebound from the days of AIDS?
• Or do PrEP and treatment as prevention have causative roles to play in sustaining, and possibly accelerating, the observed increases in STIs?
• If they do, is this due to phenomena such as the fall in condom use and increased willingness to have serodiscordant sex? Or are other factors at play?
• In particular, do increases in the number and frequency of HIV tests and, alongside them, STI tests, have a part to play? Are we seeing more STIs mainly because we are looking for them more?
• And if so, and if PrEP and awareness of the benefits of immediate HIV treatment lie behind increases in the regularity of STI testing, could they in the longer term have a beneficial effect on STI incidence? Is there any evidence of this happening?

Does the use of PrEP lead to more STIs?

Whether PrEP actually leads to further increases in STIs or is instead being adopted by people who would already be likely to get them, is unclear on an epidemiological basis. 

Some randomised and cohort studies of PrEP have found rises in STIs following the initiation of PrEP. Others have found no increase. And in some, high rates of STIs preceded the adoption of PrEP, suggesting the diagnoses may have been motivators for people to start PrEP.

People taking part in PrEP studies have certainly had very high rates of STIs. For example, in the IPERGAY and PROUD studies, the proportions of participants diagnosed with a bacterial STI during follow-up were 43% and 57%, respectively. In the DISCOVER study, the annual incidence of bacterial STIs was almost 100% – this does not mean everyone in the study caught an STI but that the annual number of STI diagnoses nearly equalled the number of participants in the study.

However, only one of these studies, PROUD, was designed to detect whether PrEP influenced sexual risk behaviour, by comparing participants who knew they were taking PrEP with ones who knew they were not. The proportion diagnosed with STIs during follow-up was 57% in participants allocated to start PrEP immediately and 50% in those allocated to start it a year later. This difference was not statistically significant, and there was no significant difference between arms for individual STIs either.

A 2022 German study with just over 1000 gay men with high STI risk compared roughly equal numbers of gay male PrEP users and non-users. It found that STI incidence in PrEP users was not significantly different than in non-users. It was in fact non-significantly lower, and in the case of syphilis was significantly lower. This could be explained by the PrEP users being slightly older than non-users or by other demographic differences, but it certainly did not provide evidence that starting PrEP increased STI risk.

This study was not longitudinal though, meaning it did not follow the participants over time. A French study following the 429 participants in the IPERGAY study found that over a median follow-up period of two years, the incidence of any bacterial STI increased significantly, from 55% to 90% per person per year.

This study, however, collected its data between 2012 and 2016, when the open-label phase of IPERGAY ended. At this point PrEP was a novelty in France, and study subjects are likely to have been in the most at-risk vanguard of gay men who had been waiting for it. It is not surprising if PrEP was seen as allowing less stringency in maintaining ‘safer sex’, especially during the open-label phase.

A study based on data collected in Seattle from 2014 to 2016 found that while chlamydia rates did increase after men started on PrEP, rates of syphilis and gonorrhoea were elevated in the year before men started on PrEP. Rates of gonorrhoea increased no further after starting PrEP, while rates of syphilis declined. This certainly would seem to suggest that PrEP was a response to men’s perception of their high STI risk, not a cause of it.

A more recent Dutch study of 367 men compared daily PrEP with event-driven PrEP, allowing participants to switch PrEP regimen during the study. It found that although the incidence of bacterial STIs was very high at 87% per year, there was no change in the incidence of all STIs and of syphilis over time on PrEP, while there was a slight decrease in chlamydia and gonorrhoea infections in daily PrEP users. Over two years, the median number of sex partners per three-month period decreased from 16 to 12 in men using daily PrEP, and from 12 to 5 in men using event-driven PrEP. The study did not measure STI incidence leading up to PrEP but its findings are in keeping with the idea that gay men may start PrEP at periods of particularly high risk, which may then decline, at least in some men.

However, a study that matched about 200 Dutch PrEP users with 200 non-users between 2015 and 2019 found that before starting PrEP, STI risk factors such as condomless sex with non-regular partners and number of partners, and STIs themselves, were increasing, among both groups. In men who started PrEP, STIs and risk factors continued to increase. But in non-users, risk factors did not further increase and STI diagnoses dramatically decreased.

There are a number of explanations for this curious finding, where the decision not to take PrEP seems to have had more influence over STI risk than the decision to take it. It could be that external influences such as acquiring regular partners may have influenced the decision not to take PrEP, or that a considered decision not to start PrEP may have strengthened subjects’ resolve to reduce their HIV risk another way.

In 2018, a meta-analysis of eight PrEP studies found that the risk of acquiring an STI increased by 25% in the first six months after starting PrEP; the risk of rectal STIs increased by 39% and of rectal chlamydia by 59%. There was also evidence that the increase was greater in more recent studies, with STIs increasing by 47% in the first six months after starting PrEP in studies terminating after 2016.

But meta-analyses average out individual features of studies, and there was actually a wide variation between individual studies. Out of the eight studies, one observed a 60% decrease in STIs, though this was the smallest study and was not statistically significant. Three saw no change, and two saw increases (of 35% and 39%, respectively) that were not by themselves statistically significant. One study found an increase in STIs in the first six months but a decrease, almost to baseline levels, in the following six months.

This meant that only two of the eight studies saw a sustained statistically significant increase in STIs between baseline and follow-up. One was the Kaiser Permanente rollout of PrEP in northern California, which saw a 48% increase in STIs following the start of PrEP.  This was the longest-lasting and the second-largest study, with 972 participants, meaning it had the biggest statistical ‘weight’. The other study was a complete outlier. In this, the Vic-PrEP rollout study in Australia, STI diagnoses tripled (198% increase) after people started PrEP.

A US study was able to measure STI infections in men before, during and after their time on PrEP. The study found that while the number of condomless sex acts men reported tripled during their time on PrEP, the proportion diagnosed with a rectal STI only increased from 7% before to 10% during PrEP use, and fell back to 2% after stopping it. The author commented that his study showed association, but not causation. He said: “[Men] are taking PrEP when they are engaging in high risks and they are stopping PrEP at times when they are no longer at high risk.”

Are STIs concentrated in a minority of PrEP users?

Rises in STIs vary strongly between individuals who start PrEP. An example comes from the PrEPX study in the state of Victoria, Australia, the successor to Vic-PrEP. In people who started PrEP for the first time, the annual incidence of STIs in this study increased by 71%, from 69.5 diagnoses per 100 people a year in the year before starting PrEP to 98.4 diagnoses per 100 people a year in the year after. However, 52% of men did not have an STI during that year: the rise in STIs took place largely in the 25% of men who had two or more STIs, accounting for 76% of infections, including 13% who had three or more infections, accounting for 53%.

The mechanism for the increases in STIs that have been seen does not appear to be a reduction in condom use, at least in people using PrEP, but rather an increase in partner numbers. In the PrEPX study, there was not a statistically significant difference in STI rates according to the frequency of condom use, either with casual or regular partners. The relative lack of significance of condom-use frequency may be due to the fact that condom use was already very low in study participants even before starting PrEP.

The number of partners with whom participants had receptive anal sex was much more significant than condom use. Compared to people who had had one to five such partners in the last six months, people with between 11 and 20 partners were 91% more likely to have an STI, and people with 21 to 50 partners, 117% more likely.

The PrEPX study was not the only one to find wide variations between gay men in terms of STI risk and incidence. A study of PrEP trial participants in the Netherlands used a technique called latent class analysis to find that they fell into three groups:

• One group started PrEP with an already low risk of STIs and stayed at a low risk throughout. Their STI incidence was a steady 0.4 STIs per year. They formed 52% of the study cohort but had only 13% of the STI diagnoses.
• Another group entered the study with a moderate to high risk of 1.6 STIs per year and stayed at the same risk throughout. They had the majority of the STI diagnoses in the study – 64%.
• The third and smallest group entered the study with a very high risk of STIs – 2.8 per year. Even though they only formed 5% of the study population, they had 23% of the STI diagnoses. After starting PrEP their risk peaked two years into the study at four STIs per year, but then started to fall and by the 45th month of the study period was actually lower than the moderate-to-high group at 1.2 STIs per year.

Other studies that have tried to get ‘under the bonnet’ of gay men’s HIV and STI risk behaviour have also used latent class analysis and found contradictory attitudes in different groups. One analysis of the Australian PrEPX study found that the majority (78%) of participants fell into two classes called 'high concern and higher risk' and 'low concern and highest risk'. These were distinguished by highly disparate attitudes towards STIs, but with a similar proportion of participants diagnosed with a bacterial STI in the last 12 months (48% and 57%, respectively). This would suggest two very different types of behavioural intervention, one concentrating on reducing anxiety and increasing self-efficacy, and the other concentrating much more on education and providing more testing opportunities.

Most other studies of risk behaviour in gay men initiating PrEP have found little change in risk behaviour. Those who rarely used condoms before PrEP continued not using them, while a minority who had been concerned about STIs before PrEP continued using them. In a Belgian study, 10.7% of men starting PrEP continued to use condoms to avoid STIs after PrEP, though there were signs of a falling off in condom use after 6-12 months on PrEP.   

Similarly, a study from Buffalo in the US that sorted PrEP initiators into ‘condom continuers’,  ‘condomless sex continuers’, ‘condomless sex increasers’ and ‘condomless sex decreasers’ in terms of their behaviour before and after PrEP found very few people in the last two classes. However, it did find that some people made decisions on individual occasions, both before and after PrEP, based on their perception of whether partners were ‘STI risks’.

Overall, therefore, the preponderance of evidence suggests that PrEP, in itself, is not a trigger for more sex that risks STIs. It is more often a response to reducing the risk of pre-existing patterns of behaviour. Over the very long term, of course, condom use has decreased considerably in gay and bisexual men and STI rates risen equally considerably. The evidence would seem to suggest that this is more to do with the lifting of the fear of HIV than with a reduction in concern about STIs.

Are more STIs due to more STI testing?

One significant confounder of the observed rise in sexually transmitted infections is that there has also been a significant increase in testing for them. This applies to people receiving PrEP as well as the wider population.

It is an increase not only in the overall number of tests but in the appropriate testing of all anatomical sites and in screening of people who do not report symptoms. Apart from programmes like chlamydia screening in the UK, STI testing in the main used only to be conducted if people had symptoms, and even gay men attending clinics regularly tended to do so only every six months. In contrast, many PrEP programmes in high-income countries have required testing every three months.

More testing, especially of asymptomatic STIs, will at least temporarily inflate the number of diagnoses. So it is important to establish the extent to which the rises in STI diagnoses are rises in incidence: are we finding more STIs primarily because we are testing more often for them?

Gonorrhoea and chlamydia are often both asymptomatic and self-limiting; the immune system can eventually get rid of the infection (though not always, which is what can give rise to serious consequences). In one Dutch study of people who were not treated immediately for diagnosed gonorrhoea and chlamydia, but came for a second visit to start treatment, the average gap between initial and second tests was only ten days. Even so during this time, 12.7% of cases of rectal chlamydia and 20% of cases of rectal gonorrhoea in men spontaneously cleared, without the need for treatment. Other studies suggest that gonorrhoea, at 20% spontaneous clearance within 10 days of diagnosis, clears even faster than chlamydia, which according to a meta-analysis of 10 studies, clears at a rate of 11-44% within several weeks to several months.  

Syphilis is not self-limiting and can have serious acute symptoms as well as chronic ones, but its early stages can often be missed.

In the UK, the number of STI tests performed at sexual health clinics increased by 17.5% between 2013 and 2017, with the largest increases in women (20%) and gay men (44%). By 2019, a total of 8,296,764 tests for chlamydia, gonorrhoea, syphilis or HIV were performed, including 1,176,157 for HIV. After declining during COVID, testing nearly recovered to 7,234,502 tests in 2022, but the number for HIV was still notably lower than in 2019, at 654,007.

In gay men especially, part of the long-term increase may be due to the demand for testing brought on by PrEP. Central London clinics began offering medical support for people buying PrEP online in spring 2016 and saw the first significant decline in HIV incidence that year. The IMPACT demonstration study, which began in October 2017, would in itself be expected to increase the number of HIV and STI tests performed by gay men by an additional 20 to 25% if all its participants test quarterly and had not done with the same frequency before.

Furthermore, the UK is one of the few countries in Europe which has tested appropriately in the past for rectal, urethral and pharyngeal (throat) infections. For instance, the first EMIS – a large pan-European survey of gay men – asked its participants if they had had an STI test in the last year, and only 30% had. However, many 'STI tests' consisted solely of a blood test, which cannot detect chlamydia or gonorrhoea. Fewer than 50% of EMIS’s gay and bisexual male respondents had had a urethral swab and only 16% a rectal swab, indicating that about one in 20 of EMIS’s 180,000 respondents had had a test in the previous year that could detect two of the most common STIs in gay men in every site.

A PrEP demonstration project in New York City found evidence that increased testing rates were contributing to at least some of the rise in STI diagnoses in gay men on PrEP. In this study, from 68 to 83% of the STIs diagnosed were asymptomatic, and the researchers estimated that 24% of STIs would have been missed even if participants had screened for STIs every six months, as US guidelines recommend, instead of every three months as in the study.

In other words, an increase in testing, and especially frequency of testing, often diagnoses STIs that would simply have remained undiagnosed before, especially as chlamydia and gonorrhoea infections are often self-limiting.

Going back to the PrEPX study in Australia, the observed, large, increases in STI diagnoses became much smaller when testing frequency was controlled for. Among those starting PrEP, the number of clinic visits increased from 3.2 in the year before PrEP to 4.7 in the year after, and tests for individual STIs increased from 8.5 to 12.9. In multivariate analysis, controlling for testing frequency turned the 71% increase in STI diagnoses to a 21% increase in incidence.

Similarly, an observed increase of 84% in chlamydia turned into an increase in incidence of 38%. After controlling for testing, increases in gonorrhoea (at any site) were no longer significant, and there was no increase in syphilis even before controlling for testing.

While confirming, therefore, that some of the rises in STI incidence seen in Victoria’s PrEP users were real, it also confirms that most of the rises were caused by more testing.

Might frequent testing and treatment reduce STIs?

It is clear that high rates of testing and treatment for HIV are starting to produce substantial falls in HIV incidence in some countries and communities, as the proportion of people with HIV who are infectious shrinks. Might the same apply to STIs?

A couple of mathematical models suggest that, if large numbers of the gay and bisexual men and trans people most at risk of both HIV and STIs are enrolled in PrEP programmes, then the frequent STI testing that should result might lead to substantial drops in STI incidence.

A modelling study presented in 2017 found that if PrEP became widespread among gay men in the US, diagnoses of STIs would rise in the first year, but would fall thereafter.

If the testing interval was once every six months, for instance, the annual incidence of all STIs in all gay men would fall from about 5.4% a year after starting a PrEP programme to 4% after three years, and to less than 2% after 10 years.

This was based on an assumption that 40% of all sexually active gay men take PrEP, but also that condom use in gay men on PrEP would fall by 40%. Incidence would decrease further if condom use did not fall.

There was no support for the hypothesis that PrEP and reduced condom use would lead to rises in STIs in the general population at risk of STIs. In this model, even zero condom use under PrEP could not transform the STI rates seen in the general gay population into the rates seen in PrEP seekers.

A second modelling study based on Dutch data was published in 2019. This found that if 75% of the gay and bisexual men in the Netherlands who met the criteria for PrEP started taking it, and therefore tested for HIV and STIs every three months, this would not only cause a 70% drop in HIV incidence – in both PrEP users and other gay men­ – but would lead to even greater reductions in gonorrhoea.

In the ‘base case’ of the model, gonorrhoea would almost be eliminated, with a 97% fall in gonorrhoea cases relative to 2018, the year the model assumed the PrEP programme was started.

That would be if condom use did not change. But even if the PrEP programme resulted in a 75% rise in the likelihood of condomless anal sex in gay men, it would nonetheless lead to a 73% drop in gonorrhoea cases. PrEP would not lead to a rise in gonorrhoea unless condom use fell almost to zero.

There is already evidence that higher testing rates can achieve falls in some STIs, notably hepatitis C. One study found that new cases of hepatitis C among HIV-positive gay and bisexual men seen at three clinics in London had declined by nearly 70% since 2015, which was attributed to regular hepatitis C screening and a treatment-as-prevention effect resulting from wider use of direct-acting antiviral (DAA) therapy. A previous study in the Netherlands found the same thing. In Australia, a study among a different population, people who inject drugs, found that testing and DAA treatment had reduced the community prevalence of hepatitis C viraemia (a detectable viral load) from 43% in 2015 to 25% in 2017. The British HIV Association declared that hepatitis C could be eliminated in the UK by 2021 if these trends continued.

Achieving this with the more contagious and often asymptomatic bacterial STIs is more difficult. England has had a national chlamydia screening programme for young people under 25 since 2003. Modelling showed that between 26 and 43% of 16-24 year olds would have to be tested and treated for chlamydia yearly to have an effect in infections. A 2009 report by the National Audit Office found that only 50% of primary care trusts were achieving 26% coverage, and since then coverage has declined and the proportion of young people testing positive for chlamydia has increased, from 7.5% in 2013 to 9% now.

However, it is arguable that high rates of testing and treatment might have a more positive effect in smaller, more targeted populations with very high background incidence. At London’s 56 Dean St, the largest sexual health clinic in Europe, there was a huge increase in gonorrhoea testing from 3000 in the fourth quarter of 2013 to 11,000 in the third quarter of 2015. This was followed by a decline from 1600 gonorrhoea diagnoses during that quarter to 1100 per quarter for the next seven quarters, up until June 2016, despite testing rates staying at the same level. This apparent decline in gonorrhoea infections was to some extent reflected in a national decline in gonorrhoea diagnoses from 22,000 to 17,000 in 2016.

However, this decrease was not sustained. Gonorrhoea diagnoses started increasing again, both at Dean St and nationally, in the second half of 2017. Although resistant infections may have had a part to play, this was most likely because clinics found it hard to cope with a surge in demand for appointments coupled with NHS cuts that reduced the number available.

If 'test and treat' against STIs is not a complete answer, how about adding in 'STI PrEP'? This is now more often called ‘doxyPEP’, because it was found that taking a single dose of the antibiotic doxycycline (chosen because it is not in a class currently used to treat gonorrhoea) soon after a possible exposure to the bacterial STIs was in the region of 80% effective in preventing syphilis and chlamydia. Its efficacy against gonorrhoea was more variable, from zero to 56%, and depended on the amount of resistance to doxycycline in local strains of the gonorrhoea bacterium. DoxyPEP studies are ongoing, some including other prevention measures such as a vaccine for gonorrohea, and are summarised separately on aidsmap. 

How often should PrEP users be tested for STIs?

One analysis of gay and bisexual men and trans women in the Dutch AmPrEP study looked at how many STIs would have been left undiagnosed if the study had required testing every six months instead of every three.

In this study among 366 PrEP users paying a total of 4974 three-monthly visits, a total of 1183 STIs were diagnosed. To the researchers’ surprise, 79% of STIs diagnosed at the three-monthly test visits were asymptomatic. Additional ad-hoc check-ups were provided if study participants did experience symptoms, but even with these added, two-thirds of diagnosed STIs were asymptomatic.

This faced the researchers with a dilemma. Out of the 364 participants with an STI whose diagnosis would have been delayed if they only had six-monthly tests, 53% had condomless sex and could have transmitted it. So frequent testing and treatment may be justified on public health grounds. On the other hand, if gonorrhoea and chlamydia often spontaneously resolve, is treating people frequently with antibiotics for asymptomatic infections justified on individual health grounds? In the case of gonorrhoea, might it give rise to more antibiotic resistance? And is it justified on cost grounds?

In a cost-benefit analysis, the researchers found that testing every three months instead of every six months, would avert 18,250 further chlamydia and gonorrhoea infections. This would cost €47 million more than six-monthly testing – but at a cost of €430,000 per quality-adjusted life-year (QALY) saved, which is far in excess of the normal European threshold for cost-effectiveness, which is around €25,000 per QALY saved. 

A meta-analysis of 38 studies of the frequency of STI screening provided more evidence that many STIs, especially asymptomatic ones, spontaneously resolve. In studies of STI screening conducted every 2-3 months, the positivity rate was 20% for chlamydia, 17% for gonorrhoea and 7% for syphilis. In studies of screening every 4-6 months, the positivity rate was unchanged for syphilis, but was 10% for gonorrhoea and only 4% for gonorrhoea.

To summarise the last two sections: modelling studies, whose initial premises may be on the optimistic side (as in the Dutch study, which hypothesised that 75% of at-risk gay men be on PrEP and therefore testing every three months for STIs), forecast that after an initial rise, increased STI testing might bring down infection rates. Studies of the actual effectiveness and cost-effectiveness of STI testing, however, tend to moderate this optimism with questions of necessity, cost and drug resistance.

This is not the first time that studies have exposed a tension between the aims of public health and of benefit to the individual. To quote one of the researchers in the Dutch cost-effectiveness study: “Why are we treating an STI in a client on PrEP? To eliminate symptoms? Or to contain an epidemic?”   

These studies have been conducted in settings with good sexual health provision that already had adequate STI testing and screening – it is no coincidence that researchers in the Netherlands have conducted many of these studies. 

In other countries, STI testing is less frequent and regular. In the US, PrEP is now provided in many settings ranging from sexual health clinics which have thousands of PrEP users, to primary care physicians who only have one patient on PrEP. In one study, 40% of 4200 healthcare providers did not file any reimbursement claims for STI testing at both PrEP initiation and follow-up visits and, disturbingly, more than half did not claim for HIV testing at PrEP initiation.

This is not just a problem in the US. An earlier study by the same researchers of 61 PrEP programmes worldwide found that 30% were not testing for STIs at PrEP initiation and only 43% of PrEP projects provided triple site (anal, genital, throat) STI screening.

In high-income countries, only 8%, 8% and 13% of programmes did not test for gonorrhoea, chlamydia and syphilis, respectively, but in lower-income settings 29%, 36% and 25%, respectively, did not. While 72% of of programmes in higher-income countries provided regular repeat STI tests, only 45% in lower-income settings did. Screening for hepatitis A (38%), hepatitis B (53%) and hepatitis C (36%) was less common in all settings.

To summarise

• There is no doubt that there has been a considerable increase in STIs since the historic lows of the 1990s. The exceptions are in HIV and hepatitis C (largely due to treatment) and in HPV and hepatitis B (largely due to vaccination).
• Gonorrhoea and syphilis, as well as some less common conditions such as LGV, have become proportionally more common in gay and bisexual men, in the UK, the US and in western Europe.
• A number of influences have contributed to the rises in STIs and may have done so sequentially. Fewer gay men employed 100% condom use as their primary HIV prevention method. ‘Seroadaptive’ methods such as serosorting and seropositioning became more popular. These may have had some efficacy against HIV but less against STIs.
• While there has been an upward inflection in the already steady increase in STI diagnoses in gay men since 2010-2013, it is hard to ascribe this to PrEP having an impact on risk behaviour.
• A combination of factors ranging from falls in condom use to a relaxation of sexual segregation between HIV-positive and HIV-negative gay men is more likely to have been the cause, as these trends have been around for longer. The majority of studies find that STI risk behaviour prior to PrEP remains unchanged after initiating it.
• There is some evidence, however, that a proportion of gay men starting PrEP do experience an additional rise in STI infections, especially of syphilis and gonorrhoea. One study has found that this was associated with a rise in the number of partners with whom they have receptive anal sex.
• However, only a minority of gay men experience this increased incidence of STIs and it is difficult to disentangle cause and effect. Does PrEP have a disinhibitory effect on risk behaviour, or is it sought because the person knows that their risk behaviour has risen, or will rise?
• Another complicating factor is that STI testing rates have increased in all populations and especially in gay men. The PrEPX study found that most – though not all – of the increase in STI diagnoses after men started PrEP was due to more STI testing.
• The potential exists for more testing and treatment of STIs to lead to falls in new STIs, as more people get treated sooner after infection. This has already been observed with hepatitis C.
• As PrEP use requires engagement with sexual health services, PrEP might facilitate this happening.
• On the other hand, some studies suggest that testing for STIs every three months may not benefit individual health, as the majority of asymptomatic chlamydia and gonorrhoea infections self-resolve, and is also not cost-effective. Testing less frequently – for example, every six-months – and for symptomatic infections may be better.
• Although condoms are not as fully effective against most STIs as they are for HIV, they remain the most effective preventative strategy, at least for rectal and vaginal infections, but doxyPEP is available.

Two final thoughts. PrEP’s role in reducing sexual anxiety has been cited as a significant positive effect by PrEP users, especially gay men, in a number of studies. Another aidsmap research briefing reviews studies of the benefits to gay men’s mental health provided by PrEP and its role in reducing HIV anxiety.

And PrEP continues to perform the task it was designed for – preventing HIV. Cases of HIV infection are rare in PrEP users. Bacterial and other STIs only rarely have life-threatening results, and even more rarely require lifelong treatment to prevent those results. HIV still does, which is why avoiding having to take lifelong HIV treatment is PrEP’s most significant benefit.