Introduction

The epidemiology of sexually transmitted infections (STI) has changed markedly over the last decade. The increase in syphilis, gonococcal infection, Chlamydia trachomatis infection and lymphogranuloma venereum is now a priority public health problem. In Spain, the latest available data show a sustained upward trend, with more than 93,000 cases of the main notifiable STIs reported in 2024, the highest figures in more than a decade [1]. Since 2015, the mean annual increase has exceeded 20%, particularly after the end of pandemic-related restrictions. This increase reflects a combination of factors: changes in sexual behaviour, a higher number of sexual partners, reduced condom use in certain contexts, chemsex, dating app use, improved access to diagnostic testing and more intensive screening.

At the same time, HIV prevention has undergone a paradigm shift. PrEP has moved from being an innovative intervention to becoming an essential tool in combined prevention. Its implementation has made it possible to substantially reduce the risk of HIV acquisition in people with high-risk sexual exposures, particularly gay, bisexual and other men who have sex with men, trans women and other people with increased vulnerability [2–4]. Nevertheless, PrEP (pre-exposure prophylaxis) programmes have also highlighted a complex clinical reality: people with an indication for PrEP frequently have a high risk of bacterial STIs, meaning that follow-up must go beyond the mere prescription of antiretroviral drugs.

PrEP against HIV: efficacy, implementation and preventive opportunity

PrEP consists of administering antiretroviral drugs to people without HIV infection before possible exposure to the virus. The most widely used oral regimen has been the combination of tenofovir disoproxil fumarate and emtricitabine, taken daily. There is also an on-demand or “2-1-1” regimen, mainly studied in MSM (men who have sex with men) with predictable sexual exposures, as well as long-acting formulations such as injectable cabotegravir, which expand preventive options for people who have difficulties with daily oral treatment or prefer an injectable alternative [2–4].

The efficacy of PrEP has been consistently demonstrated. The iPrEx study showed the ability of tenofovir/ emtricitabine to reduce the risk of HIV acquisition in MSM and trans women [2]. Subsequently, the IPERGAY trial demonstrated the efficacy of the on-demand regimen in MSM at high risk of exposure [3], while the PROUD study confirmed, under pragmatic conditions, a highly significant reduction in HIV incidence with daily oral PrEP [4]. Together, these studies established the scientific basis for PrEP as a highly effective preventive intervention, always conditioned by one central factor: adherence.

In clinical practice, PrEP should not be understood as a simple pharmacological prescription. Its real value lies in its integration into a combined prevention programme that includes individualised risk assessment, regular HIV screening, renal monitoring when tenofovir-based regimens are used, systematic diagnosis of STIs at exposed anatomical sites, vaccination against hepatitis A, hepatitis B, and human papillomavirus where appropriate, risk-reduction counselling, and management of drug use in sexual contexts. This structure makes PrEP programs privileged settings for the early detection of STIs, viral hepatitis, psychosocial needs, and chemsex practices.

In Spain, PrEP was incorporated into the basic services portfolio of the National Health System in 2019. By March 2025, an estimated 34,309 people had received PrEP through national programs, coinciding with a substantial decline (around 70%) in new HIV diagnoses, although this trend cannot be attributed to PrEP alone [1,5]. SIPrEP data show a predominantly male user profile, mostly MSM, with a mean age of 36 years, mostly Spanish nationality, and a high educational level. A significant proportion of users report multiple sexual partners (83.7%), condomless anal sex (78.0%), a history of bacterial STIs (42.2%), and drug use associated with sexual activity (22.2%) [5]. These data show that the strategy is reaching people with high vulnerability to HIV and other STIs.

One of the most frequent debates is whether the expansion of PrEP has contributed to the increase in STIs. The answer requires nuance. Risk compensation may occur in some users, with reduced condom use after starting PrEP. However, it is also clear that PrEP programs substantially increase the screening of asymptomatic infections, which in turn increases reported diagnoses. Therefore, the increase in STIs among PrEP users reflects an interaction between higher exposure, greater detection, and the concentration of programs in populations with a high baseline risk [6]. From a public health perspective, PrEP should be considered an opportunity to strengthen STI control, not an isolated element or a single cause of the problem.

From HIV prevention to the prevention of bacterial STIs

The rise in bacterial STIs in high-incidence sexual networks has encouraged interest in biomedical prevention strategies beyond HIV. The most developed strategy is DoxyPEP, a 200 mg dose of doxycycline taken as soon as possible after condomless sex, ideally within 24 hours and no later than 72 hours, with activity mainly against Chlamydia trachomatis and Treponema pallidum and more variable activity against Neisseria gonorrhoeae.

Clinical evidence for DoxyPEP

The first relevant evidence came from the ANRS IPERGAY substudy, in which 232 MSM using HIV PrEP were randomized to receive post-exposure doxycycline or standard follow-up. The study showed a 70% reduction of episodes of Chlamydia and 73% of syphilis with DoxyPEP but did not show a significant effect against gonorrhea (HR 0.83; 95% CI 0.47-1.47) [7].

Subsequently, the DoxyPEP trial included 501 MSM and trans women with a recent bacterial STI, either living with HIV or using PrEP. STI incidence was lower with DoxyPEP than with standard care in both cohorts (from 29.5% to 9.6% in the PrEP cohort and from 27.8% to 11.7% in people living with HIV) [8].

The ANRS 174 DOXYVAC trial randomized 502 MSM receiving HIV PrEP in France. DoxyPEP was associated with lower risks of Chlamydia (adjusted HR 0.11; 95% CI 0.04-0.30), syphilis (adjusted HR 0.21; 95% CI 0.09-0.47), and a smaller reduction of gonorrhea (33%) [9]. In contrast, the dPEP Kenya trial in 449 cisgender women did not show a significant reduction in bacterial STIs or gonorrhea, probably influenced by low objective adherence and high prevalence of tetracycline resistance [10].

A 2024 meta-analysis of randomized trials found a clear overall reduction in bacterial STIs with DoxyPEP, with the greatest effects for Chlamydia (81%) and syphilis (77%) and a more modest and heterogeneous effect for gonorrhea (45). These findings support DoxyPEP as a targeted intervention in populations similar to those included in the trials, rather than as a universal population-level strategy [11].

Based on these trials, several international recommendations have proposed the selective use of DoxyPEP. The most cautious approach is to consider it in MSM and trans women with a recent bacterial STI or frequent reinfections, always through shared decision-making and within comprehensive sexual health programs. There is currently insufficient evidence to recommend its generalized use in heterosexual populations, cisgender women, or people with vaginal exposures, and its use should be individualized when applied outside the groups best studied [12].

Real-world data are beginning to define how DoxyPEP performs outside trials. In PRIDOX, a PrEP cohort study conducted between March 2023 and August 2024, 197 of 876 PrEP users (22.4%) initiated DoxyPEP; 98.4% were MSM, and the mean follow-up was 14.0 months. Chlamydia and syphilis incidence fell markedly after DoxyPEP initiation, while the reduction in gonorrhea was smaller and not statistically significant. All cultured gonococcal isolates were susceptible to ceftriaxone, and tetracycline resistance did not differ significantly between DoxyPEP and non- DoxyPEP users (42.7% versus 46.3%; P = 0.23) [13].

Safety, resistance, and the limits of DoxyPEP

Doxycycline is a well-known, generally well-tolerated, inexpensive, and widely available antibiotic. The main limitation of DoxyPEP is not individual tolerability but its potential ecological impact. Repeated antibiotic use for preventive purposes may exert selective pressure on pathogens and commensal microbiota. This point is particularly relevant for Gonococcus, where tetracycline resistance is already common, and for other microorganisms such as Staphylococcus aureus or intestinal bacteria carrying resistance genes. Recent studies on the microbiome and resistome suggest that exposure to DoxyPEP may increase the presence or expression of tetracycline resistance genes, although the long-term clinical implications are not yet fully defined [14].

A further potential limitation is diagnostic: intermittent doxycycline exposure may partially suppress early syphilis without reliably eradicating infection, potentially delaying symptoms or modifying non-treponemal titres. Clinicians should therefore interpret low or unexpectedly negative RPR results cautiously when recent exposure or compatible lesions are present. Evidence from doxycycline-treated syphilis cohorts shows that serological response varies by disease stage, reinforcing the need for careful follow-up when syphilis is suspected [15].

For these reasons, DoxyPEP should not be presented as a “universal pill” against STIs. Its potential role is in people at very high risk and with recurrent bacterial STIs, in whom the individual and community benefit of preventing new infections may outweigh the theoretical risk of selecting resistance. The key is to select candidates appropriately, review the indication periodically, maintain microbiological surveillance and avoid trivialising its use outside clinical pathways.

Integrating PrEP and DoxyPEP into clinical practice

The parallel between PrEP and DoxyPEP is useful, but the two strategies should not be confused. HIV PrEP is a consolidated intervention, with very high efficacy and a central role in combined prevention. DoxyPEP, by contrast, is an emerging and promising strategy, but one that requires caution because of its relationship with antibiotic use and antimicrobial resistance.

In clinical practice, potential candidates for DoxyPEP can often be identified within PrEP clinics themselves: people with repeated bacterial STIs, multiple sexual partners, condomless sex, participation in highincidence sexual networks or chemsex practices. In these cases, the PrEP follow-up visit provides an opportunity to assess STI risk in a structured way, review previous diagnoses, explain the benefits and limitations of DoxyPEP, rule out contraindications and agree on a follow-up plan.

This plan should include STI screening every three to six months, sampling from all exposed anatomical sites, symptom surveillance, partner notification and treatment, vaccination, health education and periodic review of the need to continue DoxyPEP. The intervention must be accompanied by clear messages: DoxyPEP does not protect against all STIs, does not replace condoms, does not prevent viral infections such as HIV, HBV, HCV, HPV or herpes, and should not be used as treatment for symptoms without clinical assessment.

Conclusions

PrEP has represented one of the most important advances in HIV prevention. Its efficacy, safety and ability to be incorporated into structured programmes make it an essential intervention in populations at increased risk. At the same time, the high burden of bacterial STIs observed in many PrEP users underlines the need to broaden the approach towards comprehensive sexual health.

DoxyPEP represents a new preventive tool with demonstrated efficacy against Chlamydia and syphilis in selected populations, and a more limited effect against gonorrhoea. Its implementation should be cautious, targeted at people with a high risk of recurrent STIs and always accompanied by clinical follow-up, regular screening and resistance surveillance. The future of these strategies does not lie in replacing one measure with another, but in integrating them rationally into individualised, evidence-based models of combined prevention.

Funding

The authors declare that no funding was received for the research, authorship and/or publication of this article.

Author contributions

Conceptualisation: M.V.-A.; Methodology: M.V.-A.; Investigation: M.V.-A.; Formal analysis: J.G.S.-C., D.J.M.-G., M.V.-A.; Writing – original draft: J.G.S.-C., D.J.M.-G., M.V.-A.; Writing – review & editing: J.G.S.-C., D.J.M.-G., M.V.-A. All authors have read and approved the final version of the manuscript.

Conflicts of interest

The authors declare that there is no commercial or financial conflict of interest for this research.

AI statement

The authors declare that no artificial intelligence tools (such as ChatGPT, Copilot, Gemini, or others) have been used in the writing, analysis, or review of this article.

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