HIV pre-exposure prophylaxis and sexually transmitted infections: intersection and opportunity

Abstract

Pre-exposure prophylaxis (PrEP) has revolutionized HIV prevention, but PrEP does not protect against other sexually transmitted infections (STIs). Rates of STIs are rising worldwide, with notably high incidences among PrEP-using men who have sex with men in high-income countries; in low-income and middle-income countries, data are sparse, but results from a limited number of studies among African women initiating and taking PrEP have shown high STI prevalence and incidence. Efforts aimed at markedly reducing HIV in populations worldwide include a major focus on increasing PrEP use, along with improving HIV testing and treatment in order to eliminate HIV transmission. Together, these efforts could augment continued expansion of the global STI epidemic, but they could alternatively create opportunity to improve STI control, including the development of comprehensive sexual health programmes and research to develop new STI prevention strategies. The introduction of PrEP globally has been characterized by challenges and many successes, and its role as part of a range of robust strategies to reduce HIV infections is clear. Looking ahead, understanding rising rates of curable STIs and their relationship to HIV prevention and considering the future directions for synergies in PrEP and STI prevention will be integral to improving sexual health.

Introduction

The use of combination emtricitabine-tenofovir disoproxil fumarate (FTC/TDF) as pre-exposure prophylaxis (PrEP) was approved for adults by the US Food and Drug Administration in 2012 and extended to include adolescents (greater than 35kg) in 2018.^1,2 Recommendations for PrEP for all those at risk for HIV were released by CDC in 2014,³ the World Health Organization in 2015,⁴ and the US Preventive Services Task Force (Grade A recommendation) in 2019;⁵ countries worldwide have followed the USA with regulatory approval.^6,7 PrEP has quickly become a cornerstone of global initiatives to end the HIV pandemic. In October 2019, a second PrEP medication – daily FTC/TAF (tenofovir alafenamide, an alternative tenofovir prodrug that has improved bioavailability and enables a much lower dose) – received approval for use in Canada, Australia, United States, and Taiwan by men who have sex with men (MSM) and other individuals whose HIV risk is not through receptive vaginal sex, based on noninferiority data (IRR of 0.47 (95% CI 0.19-1.15)) in one clinical trial.^8-10

PrEP prevents sexual acquisition of HIV;^11-13 however, PrEP does not protect against curable sexually transmitted infections (STIs). STI rates are growing around the world, with rapid increases in syphilis, gonorrhea, and chlamydia among MSM with multiple sexual partners in high-income countries and an increase in combined bacterial STI incidence (41–72%) has been observed among MSM in Canada and Australia in correlation with initiation of PrEP.^14,15 Data from low-income and middle-income countries are sparse, but suggest high rates of curable STIs, with new Chlamydia trachomatis cases occurring at a rate of more than 20 per 100 person-years among women using PrEP services; in such settings, STI-associated morbidity is commonly high, particularly for women.^16-18

The global rise in availability of PrEP and STI prevalence rates occurring together present potential synergies for comprehensive preventive sexual health. The need for access to PrEP and STI control have both gained attention in the scientific and popular press, signaling urgency.^19,20

In this Review we address the successes and challenges of PrEP to date, its place as part of robust strategies to reduce HIV infections, rising rates of curable STIs and their relationship with HIV prevention, and future directions for synergies in PrEP and STI prevention.

How PrEP works

Use of a combination of antiretroviral agents (e.g., nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors) to inhibit key enzymes needed for viral replication has been the mainstay of treatment of people living with HIV for nearly three decades.²¹ For those who do not have HIV, PrEP uses one or more antiretroviral agents, often similar or identical to those used in HIV treatment,²² and their use as prophylaxis acts so that an HIV exposure does not result in an infection if drug levels are at a therapeutic level at the time of exposure. In essence, by having the antiretroviral agent in the bloodstream or in relevant tissues (such as vaginal tissue, anal tissue and lymph nodes), the virus will be rendered unable to replicate and infection aborted (Figure 1). Notably, although combination antiretroviral therapy (usually with three active agents) is essential for HIV treatment, HIV prevention seems to be successful with only two or even one antiretroviral medication,²³ reducing cost and potential adverse effects. Oral tablets (containing FTC/TDF or FTC/TAF) are currently the only PrEP agents with regulatory approval,²⁴ but multiple other strategies for PrEP delivery, including vaginal rings, injections, and implants are under development to better address individual needs and preferences; all PrEP strategies depend on correct use at the time of exposure and many are aiming for consistency of adherence over longer periods of time (weeks or months) to improve the likelihood of use.

Figure 1. HIV infection and PrEP mechanism of action.

a. After an unprotected exposure, HIV integrates into CD4 cells, replicates, and infects other CD4 cells. b. A single pre-exposure prophylaxis (PrEP) tablet, taken daily, stops HIV from replicating and, therefore, prevents acquisition of HIV in the event of an exposure. Current emtricitabine-tenofovir disoproxil fumarate (FTC/TDF) and FTC/tenofovir alafenamide (TAF) PrEP treatments work against reverse transcriptase enzymes but other, future PrEP agents could have antiretroviral activity against other HIV components.

PrEP efficacy and safety for HIV prevention

Data supporting the approval of FTC/TDF as safe and effective PrEP for HIV prevention was derived from gold-standard, large, randomized, double-blind, placebo-controlled trials. The two trials that form the registrational foundation for FTC/TDF PrEP were the iPrEx trial²⁵, conducted among men who have sex with men (MSM) and transgender women, in which a 44% reduction in HIV incidence (95% CI 15-63; p=0.005) was reported,²⁵ and the Partners PrEP Study¹³, conducted among heterosexual serodiscordant couples, in which the results showed a 75% reduction in HIV incidence (95% CI 55-87; p<0.001).¹³ In both trials, testing of blood samples after trial completion found that some participants were not adherent to the study medication.^26,27 For those who were adherent to PrEP, HIV protection is estimated to exceed 95% and few cases of breakthrough infections have been documented worldwide, essentially all seeming to be caused by a HIV virus that was resistant to FTC/TDF in the source partner before transmission.^28,29

PrEP was first tested in Cameroon, Ghana, and Nigeria in 2004³⁰ followed by a phase III trial in 2007 in Peru and Ecuador²⁵ and approved for daily use of FTC/TDF (200mg/300mg).^13,31 For daily FTC/TDF use, the WHO implementation tool recommends starting tablets 7 days before sexual exposure to HIV.³² Limited guidance exists on discontinuation of daily PrEP, ranging from maintained daily dosing for 72 hours to 28 days after last sexual exposure.^33,34 High HIV protection from non-daily use averaging four doses per week is consistent with data from studies including MSM prescribed daily FTC/TDF that showed extremely effective HIV protection, with a 96% reduction in incidence — providing additional evidence that PrEP can be effective in men without daily dosing.³¹ Evidence has been provided for alternatives to daily FTC/TDF in studies limited to MSM and others whose principal risk exposure for HIV is receptive anal sex. A 1:1 randomized, placebo-controlled trial of 400 HIV-negative cisgender men and transgender women who have sex with men in France demonstrated that dosing FTC/TDF in an on-demand strategy (double dose within 2 to 24 hours before sexual exposure to HIV followed by a single dose 24 hours and 48 hours after the initial double dose, also referred to as event-driven dosing or the 2-1-1 schedule), provides high HIV protection, seemingly comparable to daily FTC/TDF with a 97% (95% CI 81-100) reduction in incidence.^35,36 Subsequently, the rapid approval of daily FTC/TAF for use by MSM by the FDA in 2019 was based on strong efficacy evidence for use of TAF in exchange for TDF in HIV treatment regimens in conjunction with robust data on FTC/TDF as PrEP; however, nuanced data on non-daily dosing or efficacy with vaginal receptive intercourse are not yet available.^37,38

Because of a paucity of data outside of PrEP use among MSM and transgender women, only daily FTC/TDF, not 2-1-1 dosing or FTC/TAF, is currently recommended for cisgender women and transgender men who have receptive vaginal sex.³⁹ Imperfect adherence to daily PrEP has been associated with low drug levels in vaginal mucosa suggesting that daily PrEP dosing might be important for prevention of HIV in those exposed vaginally.^40,41 Importantly, among women who take FTC/TDF PrEP daily, HIV protection is equivalent to that observed in men.²⁶ In many people taking PrEP, use is for a period, with discontinuation and often resumption, often coordinated with changes in sexual behaviour, new partners, or other factors, somewhat analogous to how contraceptives are generally used.⁴²

PrEP is well-tolerated with no major safety concerns.^2,43 The most common adverse effect of PrEP in clinical trials was nausea,³¹ which generally dissipated within the first month. No adverse interactions with contraceptives or fertility (in both women and men) were demonstrated with PrEP use, and USA and WHO guidance recommend PrEP use in women who are pregnant or lactating.^4,44,45 Among those living with HIV, long-term use of FTC/TDF for HIV treatment is also very safe, emphasizing that long-term use of PrEP should similarly be safe.⁴⁶ People living with HIV receiving FTC/TDF treatment demonstrated increased risk of osteopenia and low rates of proximal renal tubulopathy, to some degree probably a synergistic effect between the medication and chronic HIV infection itself.^47,48 However, among HIV-negative people receiving PrEP, safety trials did not show an increase in fractures or renal injuries with FTC/TDF use in the first year of use.^48-50 Blood biomarkers for FTC/TAF suggest this therapeutic might have even better renal and bone safety than FTC/TDF, and FTC/TAF can be used as PrEP in those with some renal compromise (estimated creatinine clearance ≥30 ml/min) unlike FTC/TDF which is not recommended for use in those with renal compromise (estimated creatinine clearance <60 ml/min).²⁴

PrEP scale-up and effect

The number of people who use PrEP is estimated to be773,000 worldwide, a substantial number but many fewer than the 1.7 million who acquire HIV each year and the many more who are at risk.⁵¹ More than half of the worldwide PrEP prescriptions in July 2019 were in four high-income countries: the USA, Australia, France, and England. By October 2020, the USA (200,000) was joined by several low-income and middle-income countries that rapidly scaled up PrEP, including South Africa (88,000), Kenya (72,000), Uganda (47,000), and Zambia (46,000) to make up more than half of PrEP prescriptions.⁵¹ In settings with high PrEP roll-out, such as large urban centres with large populations of MSM (for example, San Francisco), new HIV infections have fallen substantially among white men in the past 5 years.⁵² In Sydney, an intentional PrEP access campaign decreased new HIV diagnoses by 50% over 24 months.⁵³

The USA has the highest number of PrEP prescriptions, but major gaps in PrEP uptake and access persist — only an estimated 35% of those who are at risk of HIV acquisition are being prescribed PrEP, with considerably reduced coverage among racial and gender minorities.^54-57 Across the USA, 68.7% of PrEP users are white compared with 11.2% who identified as Black.⁵⁸ Importantly, despite this reduced uptake,^56,59 epidemiological predictions indicate a much increased risk of HIV acquisition for minority populations, with a 1 in 2 lifetime risk among Black MSM and 1 in 5 among Latino-identifying MSM, compared with1 in 11 lifetime risk among white MSM.⁶⁰ Disparities in HIV incidence and PrEP uptake by race in the USA are not associated with risk behaviour but are associated with sexual networks, geographic distribution of PrEP prescribers, and health insurance access.⁶¹ In the USA, 19% of new HIV infections in 2016 were among cisgender women, but only 7% of PrEP use is among cisgender women.^62,63 In low-income and middle-income countries, incidence rates of HIV infection in adolescent girls are more than three times that of their male peers,⁶⁴ but PrEP access for adolescent girls remains low, in large part owing to limited programmatic roll-out (despite generic drug pricing that results in a year of PrEP medication costing ~$70).⁶⁵ Many countries in which HIV is endemic have identified all adolescent girls and young women aged 15 to 24 years as a key population for PrEP use along with MSM and commercial sex workers; however, this population is much larger than the population currently accessing PrEP.^63,66-69 The WHO sustainable development goals regarding quality health services (3.8), ensuring access to sexual and reproductive healthcare (3.7), are linked with goals needed to improve PrEP service delivery and integrating STI and reproductive care into comprehensive health care. Improving access and use can be achieved through universal health coverage and a variety of financial and psychosocial support programmes that are tailored to meet the needs of individuals and their communities. To truly improve the health and safety for these communities, large systemic changes will be required to address root causes for these disparities, including addressing structural racism, transphobia, and homophobia within health care.

Psychosocial factors threaten the adherence to medications of many patients, especially in the absence of adherence counselling and support programmes.⁷⁰ Barriers to adherence, while common, are driven by many different factors such as challenges with daily medication in absence of daily routine, self-perceived risk, belief in efficacy, stigma, and costs associated with refills.⁷¹ Adherence counselling can be supplemented with a variety of care plans as clinically indicated, such as sexual and reproductive care, mental health counselling, housing access assistance, substance abuse treatment, and gender-affirming care.

A new era for HIV

Innovations in HIV prevention and care in the past decade — including but not limited to PrEP — have ushered in a bold new era of how society and individuals think about HIV. First and foremost among these innovations has been the concept of HIV treatment as prevention. Effective HIV treatment suppresses viral levels to undetectable and results in normal lifespans for those living with HIV, often only requiring a single, combination antiretroviral pill taken once a day.^72,73 People living with HIV who have undetectable viral loads have zero risk of sexually transmitting HIV, a concept commonly referred to as undetectable=untransmittable (U=U).^74,75 U=U messaging on eliminating transmission while on treatment has been an important anti-stigma tool to ease shame and guilt surrounding sexual activity among people living with HIV, which might contribute to high rates of condomless sex and STIs.⁷⁶ These important developments in HIV care and prevention coinciding with a new generation of sexually active individuals changes perceptions of HIV risk at a population level and reduce risk in sexual networks where care and prevention are accessible and utilized.^77-79 At an individual and population level, treatment as prevention can be an important tool for preventing HIV in settings in which people at risk of HIV acquisition have access to health care and timely HIV testing.⁸⁰ At the population level, PrEP and treatment as prevention are complementary, even synergistic, for reducing HIV and HIV stigma. Decreased fear of HIV is informed by knowledge of PrEP efficacy and the decreased risk of transmission from those living with HIV who are adherent to antiretroviral therapy.^79,81

Communities with high use of treatment and PrEP have been transformed by marked population-level decreases in HIV incidence rates.^53,82,83 The psychosocial influence of PrEP, an effective HIV prevention tool that does not require partner participation, has not fully been described; qualitative research among MSM in the USA report important effects of PrEP on increased empowerment, decreased fear during sex, and increased sexual pleasure.^84,85 Prospective studies involving MSM using PrEP in Australia, Netherlands, and the USA revealed an increase in reported condomless anal sex, although as many studies have shown that starting PrEP does not result in reductions in condom use (more accurately, PrEP initiators were generally not using condoms consistently before PrEP).^78,86-88 Changes in rates of condom use have not been reported among cisgender women taking PrEP,⁸⁹ similar to findings of prior research on use of hormonal contraceptives and emergency contraceptives, which did not change rates of condomless sex.^89,90 Importantly, PrEP and ART essentially eliminate HIV acquisition risk, including in the absence of condoms, which has led to calls that their widespread implementation have the potential to end the transmission of HIV.^91,92

Rise of STIs in the era of PrEP

Concurrent with the expansion of PrEP use, as well as a new era of HIV treatment with decreased fear of HIV acquisition, the rates of STIs have substantially risen. In high-income settings, this rise began over a decade ago (preceding PrEP) but has continued steadily upward.⁹³ In the USA, chlamydia, gonorrhea, and syphilis case numbers have grown every year for the last 5 years and data from 2018 indicated an all-time high in case numbers with largest increase in syphilis cases up 13.3% on the previous year.⁹⁴ Globally, more than 1 million new curable STIs are contracted each day.⁹⁵ In many settings, high rates of condomless sex in this new era of HIV are common, which is, in part, the reason for STI rises. Of course, a diagnosis of a new STI often foreshadows HIV acquisition and is, therefore, an indication for considering PrEP initiation, and individuals with STI risks might even seek out PrEP as a strategy to reduce their own risk of HIV infection.^96,97 Untreated STIs increase the biological risk of HIV acquisition and transmission with each sexual act,⁴⁶ and in many cases indicate one or more other HIV risk factors, such as condomless sex within a concurrent partnership.⁹⁸

The relationship between STI risk and HIV risk is further compounded by changes in sexual behaviour. This association is shown in prospectively obtained data from 114 MSM with mean age 34 years in Australia who had increased STI incidence overall (incidence rate ratio 2.77 (1.52, 5.56)), especially anal detection of Neisseria gonorrhoeae in the first 12 months of PrEP use, with 7.2% prevalence at baseline and 37.8 (per 100 person-years) cumulative incidence at months 3–12, (incidence rate ratio 5.26 (1.33, 45.41)).⁸⁶ Incidence of curable STIs are rising an unprecedented rate among populations with high rates of PrEP uptake, such as MSM in high-income settings, e.g., San Francisco, Seattle, Sydney, Melbourne, where HIV incidence has declined and bacterial STI incidences rate have nearly doubled in the last decade.^14,99-103 Even among populations not yet using PrEP at considerable levels, such as young women in sub-Saharan Africa, or young men in the southern USA, curable STI prevalence rates are high, as high as 29% among both African women and American MSM.^{16,18,65 104} Debate about whether or not the use of PrEP changes sexual risk taking is substantial, largely driven by the high frequency of STI diagnosis, with guidelines calling for an increase from annual screening to biannual or quarterly screening, among PrEP users.^3,105,106 Conversely, concern about sexual liberation has been topic of much debate with each sexual health intervention, such as contraception or condom use.^107,108 Qualitative reports of reduced fear during intercourse were associated with PrEP use as well as some evidence of increased condomless anal sex suggesting increased sexual liberation.¹⁰⁹ Recognizing that PrEP is being used by those with preexisting risk, such as those who have multiple partners of unknown HIV status and low rates of condom use, is important and its protective benefits far outweigh any risk compensation.^81,110,111

Regardless of the causal connection between PrEP and rising rates of STIs, the expansion of STIs globally is notable in general and in people who use PrEP in particular. Escalating N. gonorrhoeae cases are especially concerning as multidrug-resistant organisms become more common.¹¹² Chlamydia trachomatis incidence rates in women in PrEP trials in sub-Saharan Africa approached a notable 50%.¹¹³ N. gonorrhoeae and C. trachomatis are principal aetiologies for severe infections including urethritis, cervicitis, prostatitis, epididymitis, pelvic inflammatory disease, and extragenital disease,^114,115 making their rise alarming. Syphilis incidence rates have been climbing consistently for the last decade in the USA from 14.6 per 100,000 in 2009 to 39.7 per 100,000 in 2019 with a 11.2% increase from 2018 to 2019.^116,117 In 2019, a concerning increase in congenital syphilis was observed in the USA with a total of 1,870 cases, a 279% increase from 2015.^116,117 Interestingly, rates of herpes have decreased,¹¹⁸ and some modest evidence shows that FTC/TDF might reduce herpes acquisition through a dual antiviral effect with a subgroup analysis of a placebo controlled PrEP trial reporting a 0.70 Hazard Ratio (95% CI, 0.49 to 0.99; p=0.047) of HSV-2 acquisition with daily PrEP.¹¹⁹ There are several obstacles to controlling the rise of STI incidence rates and access to aetiologic testing prevents the detection of the majority of infections which are asymptomatic.^18,120 Rising rates of curable STIs demonstrate the importance of frequent testing for public health control of the STI epidemic, to identify patients who could benefit from PrEP, and to improve care of patients taking PrEP.

Integrating PrEP care with comprehensive care

PrEP prescriptions are becoming increasingly available with PrEP programmes established in 68 countries.⁶³ People who are taking PrEP need HIV testing every 3 months, and many providers and programmes recognize the importance of integrating PrEP care into general care and offering additional services at PrEP follow-up consultations. The monitoring and support recommendations for PrEP prescription are minimal (Table 1), and PrEP prescription is not restricted to HIV care specialists.¹²¹ For individuals and populations, the intersection of PrEP and STIs offers new opportunities for improvements in care, screening, treatment, and prevention. Individuals accessing PrEP have the power to control their own risk of HIV acquisition through diligent adherence to PrEP and reliable access to PrEP is an important component of adherence. PrEP prescriber networks imperatively need to be expanded by integrating PrEP care into preexisting healthcare systems, such as primary care, urology, emergency medicine, gynecology, and other settings.¹²² To maximize the potential of PrEP, decentralized, cost-effective, and comprehensive programmes are needed to close access gaps and support PrEP use.

Table 1.

Recommended monitoring and support for PrEP use.

Timeline	Laboratory tests	Additional care
PrEP initiation
	HIV test	Screen for acute HIV
	Screen for syphilis, chlamydia, and gonorrhea	Document Hepatitis B vaccine
	Serum creatinine	Safer sex counselling and other sexual health services (such as condoms, consideration of other relevant vaccines (for example HPV), and so on)
	**Pregnancy test	**Substance abuse care
Follow-up visits (every *3–6 months)
	HIV test	Adherence counselling
	Screen for syphilis, chlamydia, and gonorrhea	Adverse effect screening
	*Serum creatinine	Repeat safer sex counselling and other sexual health services
	**Pregnancy test	**Substance abuse care

^*Guidelines differ by nation

^**When clinically indicated

With a large unmet need to expand PrEP access, further decentralization of PrEP care outside of clinic appointments could substantially improve access to PrEP. Similar to increasing access to emergency contraceptives, pharmacy-delivered care is an important step in improving access in many parts of the world. Additionally, mail-order PrEP is becoming increasingly popular in high-income countries, e.g., “I Want PrEP Now” in the UK, “PrEP Access Now” in Australia, and “Ready, Set, PrEP” in the U.S.¹²³ Decentralized delivery of PrEP relies on new and evolving technology for patient-directed care, such as HIV self-testing kits,^124,125 mail-in self-collected STI screening services,¹²⁶ and point-of-care STI tests.^17,127

Combining PrEP and STI management

The current syndemic of curable STIs and HIV can readily be observed among people prescribed PrEP and getting STIs and people with a new STI diagnosis leading to a new PrEP prescription. The public health crisis of rising STI rates demands new interventions for populations at risk for HIV and STIs.¹⁹ The current recommendations for STI control continue to rely on presenting for frequent screening and treatment based on physician-identified risk factors.¹²⁸ MSM and transgender women having sex with men, who are already taking PrEP, are identified as at increased risk for STI acquisition, and in guidelines in high-resource settings, where aetiologic testing is accessible, screening all potentially exposed sites (urine, pharynx, and anus) every 3 months is recommended.³ Treatment of existing infections can be augmented by secondary prevention through use of expedited partner therapy; that is, the provision of pathogen-specific treatment to the primary partner of the infected patient.^129,130 In low-income and middle-income countries where testing is not readily available, guidelines rely on empirical treatment in patients presenting with cervicitis or urethritis, or syndromic management.¹²⁸ Syndromic management has low sensitivity (27-61%) and moderate specificity (41-99%), missing ~70% of infections that are asymptomatic, and some patients are exposed to unnecessary antibiotics when treating broadly for nonspecific symptoms and potentially contributing to antimicrobial resistance.^120,131,132 Despite the frequent testing that is recommended for PrEP users in high-income countries, screening programmes for PrEP users in low-income and middle-income countries have not yet expanded beyond syndromic management owing to resource limitations.^32,133 New point-of-care STI testing platforms currently being developed, e.g., binx health,¹³⁴ have the potential to improve access in low-income and middle-income countries if prices are made affordable through collective price negotiations or bulk.^132,135

Frequent testing and treatment of STIs remains the standard for STI control, and the expansion of PrEP services creates an important opportunity for improving STI control. Similarly, a new diagnosis with an STI might be an important cue for detecting an unknown HIV infection or initiation of PrEP given overlapping sexual exposure risk factors.

Future of PrEP care and STI prevention

PrEP modalities, dosing schedules, and prescription sites are growing in number and diversity and will improve the individualization of the approach to HIV prevention. Long-acting, injectable PrEP has been shown to be effective at preventing acquisition of HIV. Two double-blinded randomized trials of cabotegravir injections every 8 weeks compared with oral TDF/FTC reported 66% (HR 0.33, 95% CI 0.18-0.62, MSM and transgender women) and 89% (HR 0.11, 95% CI 0.04-0.32, cisgender women) reductions in incident HIV infections, reflecting high efficacy for the injection with better adherence than for the daily pills.^136,137 Ongoing development and roll-out of injectable PrEP along with a dapivirine vaginal ring form of PrEP will provide potential options for select patients who find taking daily pills challenging.¹³⁸ As alternatives to daily PrEP use become available, an increased number of patients will be able to find a method that works for them. Additionally, the increased availability of PrEP prescriptions outside of specialty clinics could follow a similar model to the variety of birth control options widely accessible beyond family planning clinics.¹³⁹

Currently, frequent screening for asymptomatic STIs is an important part of STI control but future developments in primary prevention of STIs (such as event-driven doxycycline post-exposure prophylaxis (dPEP) and vaccinations) could theoretically decrease the need for frequent screening.^140,141 A trial in France involving 232 MSM who were taking PrEP found significant reductions in incidence rates of chlamydia (HR 0.30; 95% CI 0.13-0.70; p=0.006) and syphilis (HR 0.27; 0.07-0.98; p=0.047) with use of single-dose dPEP following each day that they had had a condomless sexual exposure.¹⁴² Additional trials are ongoing to further investigate the efficacy, safety, and acceptability of dPEP.^143,144 An epidemiological review in New Zealand noted a substantial (31%; 95% CI 21-39) decrease in gonorrhea infections among 14730 patients diagnosed with chlamydia and/or gonorrhea infection comparing those who received a full series of conjugate meningococcal vaccine, MeNZB, (n=7429) with those who were unvaccinated (n=6361) creating renewed hope for possible creation of a N. gonorrhoeae vaccine.¹⁴⁵ In 2019 a C. trachomatis vaccine entered into a phase III trial, demonstrating that some curable STIs might be vaccine-preventable in the future.¹⁴⁶ Vaccines are frequently the most effective means of infection prevention and could easily be incorporated into HIV prevention care.

Conclusions

PrEP is highly effective and is revolutionizing the prevention of HIV. Individuals presenting with an STI diagnosis are at increased risk of acquiring an HIV infection, and STIs are on the rise worldwide. PrEP and STI care go hand-in-hand: PrEP prescriptions should be considered in patients presenting with an STI diagnosis, and patients who are taking PrEP need frequent screening for STIs. PrEP access needs to be expanded to reach the many individuals who would benefit from biomedical HIV prevention. To maximize the potential of PrEP to help achieve the eradication of HIV, PrEP programmes integrated into other health-care services are needed to close access gaps, support PrEP user adherence, and increase STI prevention. The expansion of PrEP prescribers creates a crucial opportunity to improve comprehensive sexual health care and STI control.

Key points.

• Pre-exposure prophylaxis (PrEP) prevents sexual acquisition of HIV and is a part of comprehensive, evidence-informed primary and specialty care. Expanding access to and initiation of PrEP is a key part of global efforts to reverse the HIV epidemic.

• Sexually transmitted infection (STI) rates are rising worldwide and integration of STI prevention and care with PrEP care is an important opportunity for leveraging resources and synergizing interventions.

• Strategies to simplify PrEP care and STI testing and treatment, including self-care approaches, could increase the number of individuals receiving effective HIV and STI prevention.

• Research into new STI prevention strategies is still needed.