Filling in the Gaps: Updates on Doxycycline Prophylaxis for Bacterial Sexually Transmitted Infections

Abstract

Over the past 2 decades, cases of sexually transmitted infections (STIs) from syphilis, gonorrhea, and chlamydia have been rising in the United States, disproportionately among gay, bisexual, and other men who have sex with men, as well as racial and ethnic minorities of all genders. In this review, we address updates about the evidence on doxycycline postexposure prophylaxis for prevention of bacterial STIs, including efficacy, safety, antimicrobial resistance, acceptability, modeling population impact, and evolving guidelines for use. Equitable implementation of doxycycline postexposure prophylaxis will require evaluation of who is offered and initiates it, understanding patterns of use and longer term STI incidence and antimicrobial resistance, provider training, and tailored community education.

Cases of syphilis, gonorrhea, and chlamydia are rising at an accelerating rate in the United States. This epidemic of sexually transmitted infections (STIs) disproportionately occurs among men who have sex with men (MSM), racial and ethnic minorities, and especially those living in urban centers and the Southern United States [1]. To mitigate this trajectory, novel biomedical interventions like doxycycline prophylaxis for bacterial STIs are needed. A previous review of doxycycline prophylaxis highlighted gaps in research and underscored the need for additional studies [2]. In this review, we address updates to its efficacy and safety in larger cohorts, risks of antimicrobial resistance (AMR), modeling impact on priority populations, and current guidelines from public health agencies. Last, we highlight the need for equity-centered implementation of doxycycline postexposure prophylaxis (doxy-PEP).

UPDATED EVIDENCE ON DOXYCYCLINE PROPHYLAXIS

Clinical Efficacy

The first study examining the effect of doxycycline prophylaxis was a small open-label pilot of 30 MSM with human immunodeficiency virus (HIV) that found a 73% reduction (P = .02) in incident cases of syphilis, gonorrhea, or chlamydia among those taking daily doxycycline as STI preexposure prophylaxis (doxy-PrEP) [3]. Subsequently, an open-label extension of the French national HIV research agency (France Recherche Nord & sud Sida-hiv hépatites [ANRS]) Intervention Préventive de l’Exposition aux Risques avec et pour les Gays (IPERGAY) study found significantly lower chlamydia and syphilis incident infections among MSM without HIV who were taking event-driven HIV PrEP and were randomized to doxycycline 200 mg taken within 72 hours of condomless sex, with a relative reduction of 70%–73% in the intention-to-treat analysis [4]. In both studies, the number of sex partners and frequency of condomless sex did not differ between groups [3, 4].

Several additional studies have since been completed or published interim data (Table 1). The Evaluation of Doxycycline Post-exposure Prophylaxis to Reduce Sexually Transmitted Infections in PrEP Users and HIV-infected Men Who Have Sex with Men (DoxyPEP) study was powered to separately assess doxy-PEP effectiveness in MSM and transgender women (TGW) either receiving HIV preexposure prophylaxis (PrEP) or persons with HIV (PWH) in Seattle and San Francisco, USA [5]. In this open-label randomized controlled trial, participants were randomized 2:1 to the doxy-PEP arm in which they took doxycycline 200 mg within 24–72 hours of condomless sex, versus standard of care (SOC) without doxy-PEP. Participants were followed for 12 months with quarterly STI screenings and found no difference in self-reported number of sexual partners between groups. In the PrEP cohort, at least 1 STI was diagnosed in 10.7% of quarterly visits in the doxy-PEP group and 31.9% of visits in the SOC group, with a 0.34 (95% confidence interval [CI], .24–.46; P < .001) relative risk of STI acquisition. In the cohort of PWH, at least 1 STI was diagnosed in 11.8% of quarterly visits in the doxy-PEP group and 30.5% in the SOC group, with a relative risk of 0.38 (95% CI, .24–.60; P < .001). Notably, doxy-PEP was associated was a statistically significant decrease in each STI, with a 55% reduction overall per quarter for gonorrhea and approximately 80% reduction for early syphilis and chlamydia. The number needed to treat (NNT) to prevent an incident STI during a quarterly follow-up period was 4.7 in the PrEP cohort and 5.3 in the PWH cohort.

DOXYVAC was conducted in France as a substudy within the ANRS Prévenir PrEP cohort with a randomized, open-label, factorial design to examine the use of doxy-PEP to prevent chlamydia and syphilis [6]. Participants were randomized 2:1 to receive doxy-PEP 200 mg within 24–72 hours after a condomless sexual encounter or no doxy-PEP. Interim analyses included 332 men randomized to doxy-PEP versus 170 to no doxy-PEP. With a median follow up of 9 months, the time to first chlamydial infection or syphilis showed an adjusted hazard ratio of 0.16 (95% CI, .08–.30; P < .001) in the doxy-PEP group compared with no doxy-PEP. Doxy-PEP lowered the risk of time to first gonococcal infection with an adjusted hazard ratio of 0.49 (95% CI .32–.76, P = .001).

The dPEP study was an open-label randomized trial of doxy-PEP 200 mg taken within 72 hours of sex compared with SOC (quarterly screening and treatment for STIs) among 449 cisgender women ages 18–30 years on HIV PrEP in Kisumu, Kenya [7]. Doxy-PEP was discontinued while women were pregnant. In the intention-to-treat analysis, there was no significant difference in incident STI events between doxy-PEP and SOC (relative risk, 0.88; 95% CI, .60–1.29; P = .51). Among 50 randomly selected participants assigned to doxy-PEP, doxycycline was detected in 58 of 200 hair samples (29%), raising concerns about lack of effectiveness being in part the result of low adherence [7].

A randomized controlled pilot study, Dual Daily HIV and Syphilis PrEP, was conducted in Canada examining concurrent daily HIV PrEP and doxy-PrEP in MSM without HIV who had a syphilis infection in the prior 36 months [8, 9]. Participants (n = 52) were randomized 1:1 to immediate doxy-PrEP 100 mg daily (n = 26) versus delayed initiation after 24 weeks (n = 26). During the first 24 weeks, there were 4 STIs (all gonorrhea) in the immediate doxy-PrEP arm and 19 STIs (1 syphilis, 10 chlamydia, 8 gonorrhea) in the delayed treatment arm. Doxycycline was associated with reduced probability of any STI (odds ratio, 0.18; 95% CI, .05–.68) during follow up [9].

In summary, the current evidence demonstrates consistent efficacy of doxycycline prophylaxis for prevention of STIs in MSM and transgender women, with higher efficacy for syphilis and chlamydia than gonorrhea. More information is needed to understand effectiveness in people assigned female at birth.

Safety and Adverse Events

In the DoxyPEP, DOXYVAC, and Dual Daily HIV and Syphilis PrEP studies, no doxycycline-related serious adverse events were reported [5–8]. Three participants in dPEP reported 4 instances of social harm, which included verbal or physical violence; in total, 1.3% of participants experienced intimate partner violence (IPV) because of doxy-PEP use [7]. A recent systematic review of 67 studies reporting adverse event data with doxycycline use found that longer term use of doxycycline, defined as greater than 8 weeks, was found to be generally safe with minimal side effects [13].

Acceptability & Attitudes Toward Doxycycline Prophylaxis

Multiple studies of community members and clinicians demonstrate high rates of doxy-PEP acceptability, but AMR concerns for some persist and long-term safety data and official guidelines are needed to facilitate adoption [14–16].

Risks of Antimicrobial Resistance

In DoxyPEP, 56/320 (17.5%) of Neisseria gonorrhoeae detected at baseline or during study follow up had phenotypic tetracycline resistance results available [17]. All available positive N. gonorrhoeae cultures underwent tetracycline susceptibility testing, with 4/15 (27%) N. gonorrhoeae isolates demonstrating tetracycline-resistance at baseline; after enrollment, 6/20 (30%) N. gonorrhoeae isolates in the doxy-PEP group versus 2/19 (10.5%) in the SOC group were found to be tetracycline-resistant (minimum inhibitory concentration [MIC ≥2]). The small number of N. gonorrhoeae isolates limited the power of the study to detect a difference between these 2 groups in doxy-PEP effectiveness against circulating tetracycline resistant N. gonorrhoeae. Larger population-based studies are needed to evaluate doxy-PEP's potential to increase tetracycline and other antibiotic class resistance. Participants had nasal and oropharyngeal cultures for Staphylococcus aureus and commensal Neisseria spp. obtained at baseline and 12 months to assess for doxycycline susceptibility [17]. At baseline, S. aureus was isolated in 46% of participants, with doxycycline resistance in 14% of those with S. aureus colonization. Although oro-nasopharyngeal colonization with S. aureus was lower in the doxy-PEP group at month 12, among those who were colonized, there was a small but statistically significant absolute increase in the percentage of participants with doxycycline resistant S. aureus from baseline (5%) to month 12 (13%). Methicillin-resistant S. aureus (MRSA) with doxycycline resistance was uncommon at baseline (6%) and did not increase with doxy-PEP use. Neisseria spp. were cultured from 87% of participants at baseline, with doxycycline resistance present in 63%. The proportion colonized with commensal Neisseria spp. at month 12 were similar by arm, with a nonstatistically significant increase in observed doxycycline resistance in the doxy-PEP arm and a decrease in doxycycline resistance in the SOC arm.

In DOXYVAC, 65 N. gonorrhoeae isolates were available for resistance testing, representing 15% of all positive polymerase chain reaction tests [6]. At baseline, all N. gonorrhoeae isolates (n = 7) were resistant to tetracycline. Of the 21 N. gonorrhoeae isolates in the doxy-PEP arm, all had tetracycline resistance, of which 33.3% had high-level resistance. In the no PEP arm, all isolates (n = 37) were also tetracycline resistant, of which 18.9% had high-level tetracycline resistance. No tetracycline resistance was detected among Chlamydia trachomatis isolates. At baseline, MRSA was detected from throat swabs in 1.8% in the doxy-PEP arm and 1.2% in the no PEP arm, whereas at month 12, MRSA was detected in 9.9% and 5.1% of swabs, respectively. At baseline, extended spectrum beta-lactamase E. coli was detected from anal swabs in 31.4% in the doxy-PEP arm and 32.1% in the no PEP arm; at month 12, this changed to 40% versus 35.6%, respectively.

The dPEP study reported 100% high-level tetracycline-resistant N. gonorrhoeae, at baseline (n = 16) and at follow up (n = 32) with presence of the tet(M) gene. The tet(C) gene cassette, which may correspond with tetracycline resistance in C. trachomatis, was not detected from any of the C. trachomatis isolates (n = 76) [7].

A systematic review of 7 small, prospective studies found that tetracycline use may increase AMR in subgingival, gastrointestinal, and upper respiratory tract flora [18]. Two studies using whole-genome sequencing data of global N. gonorrhoeae strains demonstrated that isolates with tetracycline resistance are linked to resistance to other antimicrobials, such as ceftriaxone [19, 20]. The authors raise concerns that doxy-PEP use may actively select for these dual resistant strains. Another study analyzing genomic and antimicrobial susceptibility data from a global collection of 5644 N. gonorrhoeae isolates found that the predicted impact of doxy-PEP on N. gonorrhoeae AMR depends on its strength of selection for plasmid- and chromosomally encoded tetracycline resistance [21].

In sum, more studies are needed to fully understand the impact of doxy-PEP on population-level bacterial AMR [22]. Although prevalence of N. gonorrhoeae with tetracycline resistance is high at baseline, particularly among MSM, background resistance rates widely vary in the locations of these studies (20% in the United States vs 56% in France during IPERGAY) [2, 4, 5, 17, 23]. Thus far, data still demonstrate that doxy-PEP significantly reduces incident infections of gonorrhea, chlamydia, and syphilis, including a 50% reduction of gonorrhea in France, despite relatively high population-level tetracycline resistance [5, 6]. Doxy-PEP does not appear to have a significant effect on normal flora, with no significant difference in detection of tetracycline-resistant S. aureus and extended spectrum beta-lactamase E. coli [5, 6, 17, 18]. The potential risks of AMR must be weighed against the reduction of STI incidence with doxy-PEP, which will prevent transmission and result in less antibiotic exposure for treating established infections downstream. These data underscore the importance of appropriate genomic surveillance, potentially leveraging existing programs such as the Gonococcal Isolate Surveillance Project and Strengthening the US Response to Resistant Gonorrhea, as doxy-PEP is implemented. However, these US Centers of Disease Control and Prevention surveillance mechanisms will need to be significantly scaled up to adequately assess the potential AMR impact of doxy-PEP.

Modeling Population Impact

A study using electronic medical record data included 10 546 MSM, TGW, and nonbinary persons assigned male at birth with ≥ 2 STI tests from 2015 to 2020 at a large lesbian, gay, bisexual, transgender, and queer-focused health center, examining 10 potential doxy-PEP prescribing strategies to minimize use while maximizing impact on STIs [24]. Incidence of any STI was 35.9/100 person-years, with the NNT ranging from 1.3 to 3.9 (median, 1.7) across strategies, and proportion of STIs averted from 8% to 70% (median, 20%). Prescribing doxy-PEP after treatment for a bacterial STI could avert 39% of incident STIs (NNT = 2.4), whereas waiting to prescribe until after concurrent or repeated STIs only averted 11% of STIs. Another modeling study among MSM in Philadelphia found that an uptake scenario of 20% with 80% adherence would reduce cumulative syphilis incidence by 10% over the next decade, whereas 22% of syphilis cases could be prevented in instances where condoms were not used [25].

ONGOING STUDIES AND CURRENT REAL-WORLD USE

Clinical Studies Currently Underway

Several additional studies are in progress (Table 1), which will gather more information on incident STIs, AMR, and sexual activity over time using controlled (daily doxycycline in HIV+ for syphilis PrEP study [DaDHS]) and observational (Syphilaxis Study) study designs [10, 11]. Another study, Doxycycline Intervention for Bacterial STI Chemoprophylaxis, will compare daily (doxy-PrEP) versus event-driven (doxy-PEP) regimens [12].

Current Real-World Use and Guidelines

Since the prior review, several health departments and other agencies have created protocols regarding doxy-PEP use with varying strength of guidance for priority populations (Table 2) [26–40]. These recommendations are critical because recent surveys have estimated up to 10% of MSM in the United States, United Kingdom, Netherlands, and Australia are currently taking antibiotic STI prophylaxis without appropriate guidance [41–44]. The US Centers of Disease Control and Prevention has published considerations on the use of doxy-PEP for bacterial STI prevention [31]. In addition, Australian and German interim position statements also support doxy-PEP, particularly for syphilis prevention [26, 29]. However, other national agencies, such as the British Association of Sexual Health and HIV, do not endorse doxy-PEP for anyone currently [27]. Real-world use of doxy-PEP is expected to grow globally as more organizations endorse this intervention.

EQUITABLE IMPLEMENTATION AND PREVENTING HISTORICAL PITFALLS

Racial and Ethnic Disparities

As a novel biomedical intervention with implications for sexual health promotion, there are valid parallels to HIV PrEP to consider for doxy-PEP. Current disparities in HIV PrEP coverage among groups disproportionately affected by HIV forecast what we can expect from doxy-PEP unless equitable implementation and delivery are prioritized. Notably, only 11% of Black people and 21% of Hispanic/Latinx people for whom HIV PrEP is indicated were prescribed it in 2021 compared with 78% of their White counterparts [45]. The reasons for underutilization of HIV PrEP are related to structural and economic barriers including racism, lack of insurance, higher rates of incarceration, stigma, homophobia, and lack of awareness of HIV PrEP's benefits, medical mistrust, and provider biases [46–48].

These issues also impede access to sexual health services for those most impacted by bacterial STIs, highlighting the syndemic nature of poverty, stigma, HIV, and STIs [49]. Successful implementation and uptake of doxy-PEP will depend on the identification of community-informed delivery strategies that meet the needs of diverse groups. Higher interest in doxy-PEP among key groups most impacted by bacterial STIs, specifically Black and Hispanic/Latinx MSM, is encouraging [50].

Understanding obstacles to scaling up doxy-PEP through implementation science studies using theoretical frameworks will be important to adapt programs to assure equity. Large-scale community engagement with leadership from Black and Hispanic/Latinx healthcare workers, community workers, peers, advocates, and potential patients both inside and outside of the lesbian, gay, bisexual, transgender, and queer community must be enlisted to devise strategies to achieve equitable access to doxy-PEP, prioritizing those who may benefit the most [51]. Of equal importance, clinicians and other healthcare providers must improve capacity for delivering culturally competent, inclusive, affirming care that is centered on pleasure and sexual wellness [52].

Gender Disparities

Cisgender women, transgender men, and nonbinary persons assigned female at birth find themselves in an unsatisfactory and unfortunately familiar position where their needs for effective sexual health interventions remain unmet. The results of dPEP are reminiscent of early HIV PrEP trials among cisgender women that demonstrated significantly lower observed effectiveness compared with cisgender men [53, 54]. However, a recent real-world analysis of HIV PrEP in cisgender women now supports high effectiveness of PrEP in women, relatively equivalent to that in men, with consistent adherence [55]. Objective measures of doxycycline use in dPEP suggests that adherence to doxy-PEP was low, possibly impacting its observed effectiveness; we ultimately require more doxy-PEP efficacy trials that include cisgender women and people assigned female at birth regardless of gender. Bacterial STIs have potentially severe, devastating consequences involving the female genital tract in addition to perinatal complications as evidenced by the sharp increase in congenital syphilis cases over the past decade [1]; these issues underscore the urgent need for accessible and effective STI prevention measures for all persons assigned female at birth. Concerns regarding the theoretical teratogenicity risk of doxycycline must be weighed against data supporting its use in pregnancy [56, 57] and, most importantly, the agency of people with potential for pregnancy to make informed decisions regarding doxy-PEP use for themselves. Instances of IPV among participants in dPEP demonstrate the role that gendered power dynamics may have in health-seeking and adherence behaviors. Further data on IPV and other social harms associated with this intervention should be captured in future studies across all populations. Finally, as with HIV PrEP [58, 59], we must have gender equity in doxy-PEP clinical trials to develop solutions that protect all populations across their sexually active lifespan.

Global Disparities

Inequities in STI incidence and outcomes span every region of the globe. In low- and middle-income countries, access to sexual health resources mirrors what is experienced by Black and Hispanic/Latinx people in the United States [60]. As doxy-PEP is implemented across the world, policy and service delivery must consider the impacts of systems and structures related to poverty and human/civil rights. Key to these global disparities is the lack of access to STI testing. In the absence of asymptomatic STI screening, implementing doxy-PEP would require additional evaluation of risks of intermittent antibiotic use in the setting of potentially untreated infections and the benefits of introducing access to prevention tools in high prevalence settings.

CONCLUSION

Doxy-PEP is a well-tolerated and inexpensive intervention with the potential to significantly decrease bacterial STIs among high burden populations. Multiple studies have demonstrated an efficacy of almost two-thirds overall reduction in bacterial STIs with doxy-PEP among MSM and TGW, regardless of HIV status (Table 1). Multiple public health agencies have recognized the role doxy-PEP can play in STI prevention (Table 2). Although this intervention could significantly reduce incident STIs, its implementation has the potential to perpetuate existing inequities. Community-led, equity-centered approaches to implementation of doxy-PEP are critical to ensure those disproportionately impacted by syndemic STI epidemics have unencumbered access to this intervention.

Notes

Acknowledgments. The authors acknowledge the participants and staff of these trials for their invaluable contributions to science. They also recognize the countless community leaders and advocates who have been working tirelessly to implement doxy-PEP.

Financial support. This work was supported by in part through the National Center on Minority Health and Health Disparities (R21MD018707) as well as support from the AIDS Research Institute at UCSF and the UCSF Center for AIDS Research.

References

Author notes