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HIV pre-exposure prophylaxis and sexually transmitted infections: intersection and opportunity - Nature Reviews Urology
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 an 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. 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. You have full access to this article via your institution. Download PDF Download PDF Introduction . The use of combination emtricitabine–tenofovir disoproxil fumarate (FTC/TDF; a combination of nucleoside reverse transcriptase inhibitors (NRTIs)) as pre-exposure prophylaxis (PrEP) was approved for adults by the FDA in 2012 and extended to include adolescents (weighing more than 35?kg) in 2018 (refs 1 , 2 ). Recommendations for PrEP for all those at risk of HIV were released by the CDC in 2014 (ref. 3 ), the WHO in 2015 (ref. 4 ) and the US Preventive Services Task Force (Grade A recommendation) in 2019 (ref. 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 epidemic. In October 2019, a second PrEP medication — daily FTC/tenofovir alafenamide (FTC/TAF; an alternative tenofovir prodrug that has improved bioavailability and enables a much lower dose) — received approval for use in Canada, Australia, the USA and Taiwan by men who have sex with men (MSM) and other individuals whose HIV risk is not through receptive vaginal sex, based on non-inferiority data (incidence rate ratio of 0.47 (95% CI 0.19–1.15)) in one clinical trial 8 , 9 , 10 . PrEP prevents sexual acquisition of HIV 11 , 12 , 13 ; however, PrEP does not protect against curable sexually transmitted infections (STIs). STI rates are growing around the world, with rapid increases in syphilis, gonorrhoea 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 , 17 , 18 . The global rise in the availability of PrEP and prevalence rates of STIs occurring together presents potential synergies for comprehensive preventive sexual health. The need for access to PrEP and STI control has gained attention in the scientific and popular press, signalling 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 (such as NRTIs (for example, TDF, TAF and FTC) and non-NRTIs) 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 (Fig.? 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 12 , reducing cost and potential adverse effects. Oral tablets (containing FTC/TDF or FTC/TAF) are currently the only PrEP agents with regulatory approval 23 , 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 aimed at consistency of adherence over long periods of time (weeks or months) to improve the likelihood of use. Fig. 1: HIV infection and PrEP mechanism of action. HIV gains entry to target cells via CD4 and either CC-chemokine receptor 5 (CCR5) or CXC-chemokine receptor 4 (CXCR4) by interacting with envelope (Env) glycoprotein (step 1). Fusion and uncoating occur and the viral RNA is then reverse transcribed into DNA (step 2). The resulting pre-integration complex is imported into the host cell nucleus and the viral DNA is integrated into the host genome (step 3). HIV DNA is transcribed to viral mRNAs, which is mediated by host enzymes (step 4). These mRNAs are exported to the cytoplasm where translation occurs (step 5) to make viral proteins and eventually mature virions (step 6). Nucleoside reverse transcriptase inhibitors (NRTIs), such as emtricitabine–tenofovir disoproxil fumarate (FTC/TDF) and FTC/tenofovir alafenamide (TAF) are currently used as pre-exposure prophylaxis (PrEP) and block reverse transcription (step 2) in this cycle, but other agents that target other steps in this process (such as fusion inhibitors, CCR5 or CXCR4 antagonists, integrase strand transfer inhibitors (INSTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), attachment inhibitors, protease inhibitors or maturation inhibitors) could theoretically be used in PrEP in the future. Adapted from ref. 145 and ref. 146 , Springer Nature Limited. Full size image 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 trial 24 , conducted among MSM and transgender women, in which a 44% reduction in HIV incidence (95% CI 15–63; P ?=?0.005) was reported 24 , and the Partners PrEP Study 13 , conducted among heterosexual serodiscordant couples, in which the results showed a 75% reduction in HIV incidence (95% CI 55–87; P ?blood samples after trial completion found that some participants were not adherent to the study medication 25 , 26 . 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 an HIV virus that was resistant to FTC/TDF in the source partner before transmission 27 , 28 . PrEP was first tested in Cameroon, Ghana and Nigeria in 2004 (ref. 29 ) followed by a phase III trial in 2007 in Peru and Ecuador 24 and approved for daily use of FTC/TDF (200?mg/300?mg) 13 , 24 . For daily FTC/TDF use, the WHO implementation tool recommends starting tablets 7 days before sexual exposure to HIV 30 . Limited guidance exists on discontinuation of daily PrEP, ranging from maintained daily dosing for 72?h to 28 days after last sexual exposure 31 , 32 . 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 24 . 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?h before sexual exposure to HIV followed by single doses 24?h and 48?h after the initial double dose, also referred to as event-driven dosing or the 2-1-1 schedule), provides high HIV protection, seemingly comparable with daily FTC/TDF with a 97% (95% CI 81–100) reduction in incidence 33 , 34 . Subsequently, the rapid approval of daily FTC/TAF for use by MSM by the FDA in 2019 was based on strong efficacy evidence of the 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 35 , 36 . The paucity of data outside of PrEP use among MSM and transgender women means that 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 37 . Imperfect adherence to daily PrEP has been associated with low drug levels in vaginal mucosa suggesting that daily PrEP dosing might be important for the prevention of HIV in those exposed vaginally 38 , 39 . Importantly, among women who take FTC/TDF PrEP daily, HIV protection is equivalent to that observed in men 25 . In many people taking PrEP, use is for a period, with discontinuation and often resumption, frequently coordinated with changes in sexual behaviour, new partners, or other factors, somewhat analogous to how contraceptives are generally used 40 . PrEP is well tolerated with no major safety concerns 2 , 41 . The most common adverse effect of PrEP in clinical trials was nausea 24 , 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 CDC and WHO guidance recommend PrEP use in people who are pregnant or lactating 4 , 42 , 43 . 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 be similarly safe 44 . 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 45 , 46 . 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 46 , 47 , 48 . Blood biomarkers for FTC/TAF suggest that 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) 23 . PrEP scale-up and effect . The number of people who use PrEP is estimated to be 773,000 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 49 . 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 49 . 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 50 . In Sydney, an intentional PrEP access campaign decreased new HIV diagnoses by 50% over 24 months 51 . 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 52 , 53 , 54 , 55 . Across the USA, 68.7% of PrEP users are white compared with 11.2% who identified as Black 56 . Importantly, despite this reduced uptake 54 , 57 , 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 with 1 in 11 lifetime risk among white MSM 58 . Disparities in HIV incidence and PrEP uptake by race in the USA are not associated with risk behaviour but are associated with sexual networks, geographical distribution of PrEP prescribers and health insurance access 59 . In the USA, 19% of new HIV infections in 2016 were among cisgender women, but only 7% of PrEP use is among cisgender women 60 , 61 . 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 62 , 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) 63 . Many countries in which HIV is endemic have identified all adolescent girls and young women aged 15–24 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 61 , 64 , 65 , 66 , 67 . The WHO sustainable development goals regarding quality health services (3.8) and ensuring access to sexual and reproductive health care (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 health and safety for these communities, large systemic changes will be required to address root causes of these disparities, including addressing structural racism, transphobia and homophobia within health care. Psychosocial factors threaten adherence to medications by many patients, especially in the absence of adherence counselling and support programmes 68 . Barriers to adherence, although common, are driven by many different factors, such as challenges with daily medication in the absence of daily routine, self-perceived risk, belief in efficacy, stigma and costs associated with refills 69 . 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 anti-retroviral pill taken once a day 70 , 71 . 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) 72 , 73 . 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 74 . These important developments in HIV care and prevention coinciding with a new generation of sexually active individuals change perceptions of HIV risk at a population level and reduce risk in sexual networks in which care and prevention are accessible and used 75 , 76 , 77 . At individual and population levels, 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 78 . 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 anti-retroviral therapy 77 , 79 . Communities with high use of treatment and PrEP have been transformed by marked population-level decreases in HIV incidence rates 51 , 80 , 81 . 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 reports important effects of PrEP on increased empowerment, decreased fear during sex and increased sexual pleasure 82 , 83 . Prospective studies involving MSM using PrEP in Australia, the Netherlands and the USA revealed an increase in reported condomless anal sex, although 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) 76 , 84 , 85 , 86 . Changes in rates of condom use have not been reported among cisgender women taking PrEP 87 , similar to findings of previous research on the use of hormonal contraceptives and emergency contraceptives, which did not change rates of condomless sex 87 , 88 . Importantly, PrEP and ART essentially eliminate HIV acquisition risk, including in the absence of condoms, which has led to the suggestion that their widespread implementation has the potential to end the transmission of HIV 89 , 90 . 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 upwards 91 . In the USA, chlamydia, gonorrhoea and syphilis case numbers have grown every year for the past 5 years and data from 2018 indicated an all-time high in case numbers, with the largest increase in syphilis cases, up 13.3% on the previous year 92 . Globally, more than 1 million new curable STIs are contracted each day 93 . 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 at risk of STIs might even seek out PrEP as a strategy to reduce their own risk of HIV infection 94 , 95 . Untreated STIs increase the biological risk of HIV acquisition and transmission with each sexual act 44 , and in many cases indicate one or more other HIV risk factors, such as condomless sex within a concurrent partnership 96 . 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 a mean age of 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 during the first 12 months of PrEP use, with a 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)) 84 . The incidence of curable STIs is rising at an unprecedented rate among populations with high rates of PrEP uptake, such as MSM in high-income settings, for example, San Francisco, Seattle, Sydney and Melbourne, where HIV incidence has declined and bacterial STI incidence has nearly doubled in the past decade 14 , 97 , 98 , 99 , 100 , 101 . 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 , 63 , 102 . 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 , 7 , 103 . Conversely, concern about sexual liberation has been a topic of much debate with each sexual health intervention, such as contraception or condom use 104 , 105 . 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 106 . Recognizing that PrEP is being used by those with pre-existing 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 79 , 107 , 108 . Regardless of the causal connection between PrEP and rising rates of STIs, the expansion of STIs globally is notable in general and in PrEP users in particular. Escalating N. gonorrhoeae cases are especially concerning as multidrug-resistant organisms become increasingly common 109 . C. trachomatis incidence rates in women in PrEP trials in sub-Saharan Africa approached a notable 50% 18 . N. gonorrhoeae and C. trachomatis are principal aetiologies for severe infections, including urethritis, cervicitis, prostatitis, epididymitis, pelvic inflammatory disease and extragenital disease 110 , 111 , making their rise alarming. Syphilis incidence rates have been climbing consistently for the past 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 (refs 112 , 113 ). In 2019, a disquieting increase in congenital syphilis was observed in the USA, with a total of 1,870 cases, a 279% increase from 2015 (refs 112 , 113 ). Interestingly, rates of herpes have decreased 114 , and some modest evidence shows that FTC/TDF might reduce herpes acquisition through a dual anti-viral effect with a subgroup analysis of a placebo-controlled PrEP trial showing a hazard ratio of 0.70 (95% CI 0.49–0.99; P ?=?0.047) of herpes simplex virus 2 acquisition with daily PrEP 115 . Several obstacles to controlling the rise of STI incidence rates exist and access to aetiological testing prevents the detection of the majority of infections that are asymptomatic 18 , 116 . 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 61 . 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 117 . 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 pre-existing health-care systems, such as primary care, urology, emergency medicine, gynaecology and other settings 118 . 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 pre-exposure prophylaxis use Full size table 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, for example, I Want PrEP Now in the UK; PrEP Access Now in Australia; and Ready, Set, PrEP in the USA 119 . Decentralized delivery of PrEP relies on new and evolving technology for patient-directed care, such as HIV self-testing kits 120 , 121 , mail-in self-collected STI screening services 122 , and point-of-care STI tests 17 , 123 . 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 of 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 124 . MSM and transgender women having sex with men who are already taking PrEP are identified as at increased risk of STI acquisition, and in guidelines in high-resource settings, where aetiological 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 the use of expedited partner therapy; that is, the provision of pathogen-specific treatment to the primary partner of the infected patient 125 , 126 . 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 124 . 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 treated broadly for non-specific symptoms and potentially contributing to antimicrobial resistance 116 , 127 , 128 . 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 30 , 129 . New point-of-care STI testing platforms currently being developed, such as binx health 130 , have the potential to improve access in low-income and middle-income countries if prices are made affordable through collective price negotiations or bulk 128 , 131 . Frequent testing for 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: the results of two randomized trials, the phase IIb/III trial, HPTN 083 (NCT02720094) 132 and the phase III, double-blind HPTN 084 trial (NCT03164564) 133 of cabotegravir injections every 8 weeks compared with oral TDF/FTC, have been presented. In HPTN 083, HIV incidence was reduced by 66% compared with cabotegravir (HR 0.33, 95% CI 0.18–0.62) in MSM and transgender women (4,566 study participants in total) 134 , and in HPTN 084, HIV incidence was reduced by 89% compared with cabotegravir (HR 0.11, 95% CI 0.04–0.32) in cisgender women (3,223 participants in total) 135 , reflecting the high efficacy of the injection with better adherence than for the daily pills. Ongoing development and roll-out of injectable PrEP along with a dapivirine vaginal ring form of PrEP will provide potential options for selected patients who find taking daily pills challenging 136 . 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 that are widely accessible beyond family planning clinics 137 . 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 138 , 139 . 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; 95% CI 0.07–0.98; P ?=?0.047) with the use of single-dose dPEP following each day that they had had a condomless sexual exposure 140 . Additional trials are ongoing to further investigate the efficacy, safety and acceptability of dPEP 141 , 142 . An epidemiological review in New Zealand noted a substantial (31%; 95% CI 21–39) decrease in gonorrhoea infections among 14,730 patients diagnosed with chlamydia and/or gonorrhoea infection, comparing those who received a full series of conjugate meningococcal vaccine (MeNZB) ( n ?=?7,429) with those who were unvaccinated ( n ?=?6,361), creating renewed hope for the possible creation of a N. gonorrhoeae vaccine 143 . In 2019, a C. trachomatis vaccine entered into a phase III trial, demonstrating that some curable STIs might be vaccine-preventable in the future 144 . 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 an increased risk of acquiring an HIV infection, and STIs are on the rise worldwide. 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Baeten Authors Jenell Stewart View author publications You can also search for this author in PubMed ? Google Scholar Jared M. Baeten View author publications You can also search for this author in PubMed ? Google Scholar Contributions . Both authors researched data for the article, made substantial contributions to discussions of the content, wrote, reviewed and edited the manuscript before submission. Corresponding author . Correspondence to Jenell Stewart . Ethics declarations . Competing interests . J.M.B. has served as an adviser to Gilead Science, Janssen and Merck. J.S. declares no competing interests. Additional information . Peer review information . Nature Reviews Urology thanks C. Blackwell, L. Stranix-Chibanda and L.-G. Bekker for their contribution to the peer review of this work. Publisher’s note . Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Related links . WHO sustainable development goals: https://www.who.int/health-topics/sustainable-development-goals#tab=tab_1 Rights and permissions . Reprints and Permissions About this article . Cite this article . Stewart, J., Baeten, J.M. HIV pre-exposure prophylaxis and sexually transmitted infections: intersection and opportunity. Nat Rev Urol (2021). https://doi.org/10.1038/s41585-021-00527-4 Download citation Accepted : 24 September 2021 Published : 25 October 2021 DOI : https://doi.org/10.1038/s41585-021-00527-4 Share this article . Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative .
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