Abstract
Doxycycline post-exposure prophylaxis (doxy-PEP) reduced bacterial sexually transmitted infection (STI) incidence in a sexual health clinic over 96 weeks (n=4,592; 2,524 on doxy-PEP), particularly for chlamydia and syphilis, with smaller effects for gonorrhea. Continued surveillance for gonorrhea and antibiotic resistance is essential to evaluate doxy-PEP’s long-term effectiveness.
Keywords: Doxycycline, post-exposure prophylaxis, sexually transmitted infections, sexual health, antibiotic prophylaxis
Rates of sexually transmitted infections (STIs) remain high in the U.S. The DoxyPEP study showed high efficacy of doxycycline post-exposure-prophylaxis (doxy-PEP) against syphilis, chlamydia, and gonorrhea among men who have sex with men (MSM) and transgender women; the DOXYVAX study showed efficacy of this strategy among MSM against syphilis and chlamydia, with efficacy against gonorrhea limited by pre-existing doxycycline resistance [1, 2]. Prior research in San Francisco found decreases in chlamydia and syphilis cases after the release of citywide doxy-PEP guidelines [3]. Similarly, a study of Kaiser Permanente Patients in Northern California found decreases in chlamydia, syphilis, and rectal and urethral gonorrhea in patients receiving doxy-PEP compared to those not on doxy-PEP [4]. We build on this prior research by evaluating the uptake and impact of doxy-PEP after it was offered to all patients attending a large sexual health clinic, including transgender men and cisgender women through shared decision-making [5, 6]. In addition, we control for secular trends in STIs through inclusion of a control group who elected not to take doxy-PEP.
In this analysis, we used controlled interrupted time series methods (ITS), a quasi-experimental observational research design [7], to examine if initial impacts of doxy-PEP against syphilis, chlamydia, and gonorrhea were sustained nearly two years after its implementation (01/2022 – 10/2024).
Methods
Study procedures were approved by the University of California, San Francisco (UCSF) Institutional Review Board, with the study exempted from informed consent as part of local public health and quality improvement efforts. Data were collected as part of routine health care operations between 01/2022–10/2024. All patients receiving PrEP at Magnet, a sexual health clinic were offered doxy-PEP, with at least quarterly STI testing protocolized as part of all PrEP care visits, irrespective of doxy-PEP prescription. Cisgender women and transgender men were offered doxy-PEP using shared decision-making [6]. Patients never prescribed doxy-PEP were included in analyses as a control group. The ITS was fit within a logistic mixed-effects model to account for repeated testing over time. For patients in the doxyPEP group, data consisted of five quarters before and after the introduction of doxy-PEP. For patients in the never doxy-PEP group, data consisted of five quarters before and after the median quarter that doxy-PEP was prescribed in the doxy-PEP group (04/2023) to account for potential cohort/period effects.
Results
Participants (n=4,592) were a median of 33 years-old (range 18 – 85 years); and predominantly cisgender men (89%), followed by nonbinary (6%), transgender women (3%), transgender men (1%), and cisgender women (1%); while 34% were White, 24% Hispanic, 17% Asian, and 4% Black (Table). Overall, 55.0% initiated doxy-PEP over the study period (n=2,524), including 8% of cisgender women and 35% of transgender men (Table). Patients contributed a mean of 4.60 quarters (SD=2.98) to the analysis, which included 67,345 person-quarters of STI testing.
Table.
Patient characteristics of patients who initiated or were never prescribed doxy-PEP.
| Initiated doxy-PEP (N=2524) | Never doxy-PEP (N=2068) | Overall (N=4592) | |
|---|---|---|---|
| Age in years, mean ( SD ) | |||
| Age, median [min, max] | 33 [18,78] | 32 [18, 85] | 33 [18, 85] |
| Race/ethnicity | |||
| Asian | 430 (17%) | 351 (17%) | 781 (17%) |
| Black or African American | 95 (4%) | 103 (5%) | 198 (4%) |
| Hispanic or Latinx | 637 (25%) | 459 (22%) | 1096 (24%) |
| Mixed | 312 (12%) | 263 (13%) | 575 (13%) |
| Other Race | 223 (9%) | 177 (9%) | 400 (9%) |
| White | 827 (33%) | 715 (35%) | 1542 (34%) |
| Gender identity | |||
| Cisgender man | 2273 (90%) | 1832 (89%) | 4105 (89%) |
| Transgender man | 18 (1%) | 33 (2%) | 51 (1%) |
| Cisgender woman | 2 (0%) | 23 (1%) | 25 (1%) |
| Transgender woman | 76 (3%) | 59 (3%) | 135 (3%) |
| Non-binary | 151 (6%) | 120 (6%) | 271 (6%) |
| Other/Missing | 4 (0%) | 1 (0%) | 5 (0%) |
| Sexual orientation | |||
| Gay, lesbian, queer, or same gender loving | 2309 (92%) | 1849 (89%) | 4158 (91%) |
| Bisexual | 159 (6%) | 134 (7%) | 293 (6%) |
| Heterosexual | 24 (1%) | 36 (2%) | 60 (1%) |
| Other/Missing | 32 (1%) | 49 (2%) | 81 (2%) |
| Median condomless sexual partners in the past quarter | |||
| Pre-doxy-PEP initiation, median [IQR] | 5 [2.5, 10] | 3 [2, 6.5] | 4 [2, 10] |
| Post-doxy-PEP initiation, median [IQR] | 7 [3, 15] | 4 [2, 8] | 5.5 [3, 12] |
| PrEP dosing plan | |||
| Daily | 1937 (77%) | 1610 (78%) | 3547 (77%) |
| 2–1-1 | 368 (15%) | 309 (15%) | 677 (15%) |
| Injectable | 68 (3%) | 29 (1%) | 97 (2%) |
| Missing | 151 (6%) | 120 (6%) | 271 (6%) |
Data are presented as No. (%) unless otherwise indicated.
We examined the probability of a positive STI per quarter and compared slopes before and after initiation of doxy-PEP. In the time window before doxy-PEP was initiated, the group that later initiated doxy-PEP had a significantly higher incidence of STIs compared to the group that never initiated (adjusted odds ratio [AOR]= 3.78, 95% CI 3.04, 4.68, p<0.001) but dropped below significance after initiating doxy-PEP (AOR= 0.98, 95% CI 0.64, 1.48, p=0.917; Figure). Older participants had lower incidence of STIs (AOR = 0.73, 95%CI 0.69, 0.77, p<0.001), and Hispanic/Latinx participants had higher incidence of STIs than white participants (AOR = 1.11, 95%CI 1.19, 1.54, p<0.001), therefore all subsequent analyses adjusted for age and race. There was no difference in STI incidence by gender; cisgender men did not differ from cisgender women (OR = 0.44, 95%CI 0.17, 1.19, p = 0.105), non-binary people (OR = 1.04, 95%CI 0.86, 1.27, p = 0.661, transgender men (OR = 0.71, 95%CI 0.40, 1.25, p = 0.229), transgender women (OR = 0.98, 95%CI 0.75, 1.29, p = 0.891), or people who selected ‘other’ for their gender identity (OR = 0.18, 95%CI 0.02, 1.56, p = 0.120). We then fit separate ITS models for the outcomes of chlamydia and syphilis (combined); and gonorrhea. Across models, there was a significant decrease in all individual STIs in the doxy-PEP group, although the impact was less on gonorrhea, (chlamydia and syphilis: AOR=0.17, 95% CI 0.12, 0.25, p<0.001; gonorrhea: AOR = 0.56, 95% CI 0.44, 0.71, p<0.001). For participants who initiated doxy-PEP, after initially declining, gonorrhea rates began to increase by end of analysis (AOR = 1.28, 95% CI 1.03, 1.60, p=0.026), as opposed to syphilis and chlamydia, where the rates were stable after initially falling (AOR = 1.13, 95% CI 0.76, 1.67, p=0.542, Figure).
Figure. Proportion of positive sexually transmitted infection (STI) test per quarter before and after doxycycline post-exposure prophylaxis (doxy-PEP).
The periods before and after individuals initiated doxy-PEP are compared to those who never initiated doxy-PEP, who are centered at the average date of doxy-PEP initiation (April 2023). The impact of doxy-PEP on syphilis and chlamydia combined is compared to gonorrhea.
Across both doxy-PEP users and non-users, there was no difference in the median number of reported condomless sex partners before vs. after doxy-PEP initiation (for doxy-PEP users: 5 vs. 7, p = 0.322; in the same timeframe for never-users: 3 vs. 4, p = 0.399). Before doxy-PEP initiation, there was not a significant difference in number of condomless sex partners between patients who later elected to take doxy-PEP and those who never used doxy-PEP (medianDoxy = 5, medianNeverInitiated = 3, p = 0.135). However, those who had initiated doxyPEP had slightly greater condomless sex partners in the post-doxyPEP period (mediandoxyPEP = 7, medianNeverInitiated = 4, p = 0.021).
Discussion
We found sustained declines in chlamydia and syphilis over 96 weeks after doxy-PEP was implemented in a large sexual health clinic. Those who initiated doxy-PEP had higher STI positivity prior to using doxy-PEP when compared to those who never used it. After starting doxy-PEP, despite a greater number of condomless sex partners than the never-users, STI positivity for chlamydia and syphilis approached rates among the never-users. Although the rate of gonorrhea did decrease initially after starting doxy-PEP, gonorrhea rates began to increase again towards the end of analysis. This could indicate that gonorrhea resistance to doxycycline is increasing [8], or that partially or fully resistant gonorrhea now accounts for a greater proportion of gonorrhea diagnoses among those receiving STI testing [9].
In our clinic, nearly one-third of transgender men elected to start doxy-PEP through shared decision-making, while only 8% of cisgender women elected to start doxy-PEP. Transgender men are disproportionately impacted by the bacterial STI epidemics [10], while cisgender women attending a sexual health clinic are likely also to be at increased risk [11]. Future research should examine the characteristics driving doxy-PEP uptake, as well as the efficacy of doxy-PEP in these populations, ideally through the currently paused Adolescent Trials Network 173 Study (NCT06738407).
Although median number of sexual partners increased over time in the doxy-PEP group, it is unclear if individuals initiated doxy-PEP at a time of increased planned sexual activity, or if knowledge of the protection of doxy-PEP led participants to increase condomless sex [12]. It is reassuring that although the doxy-PEP group had higher partners in the post-doxy-PEP period compared to never-doxy-PEP users, STI positivity was no longer statistically different when compared to those who never initiated doxy-PEP.
Limitations of this analysis include the potential for residual confounding from factors such as secular trends and not having access to gonorrhea resistance data for this sample. Future directions may consider further examining factors that influence the probability of electing to take doxy-PEP beyond number of condomless sex partners, which we examined in the present study. For example, future research may employ quantitative and qualitative research to examine factors that influence decision-making about doxy-PEP, including asking participants whether they participate in group sex activities and their perceived sense of STI risk. In addition, future research may follow-up with participants regarding how they take doxy-PEP, such as whether they take it after each encounter or within three days of unprotected sex following multiple encounters or partners over several days.
As doxy-PEP uptake increases globally, future studies should examine doxy-PEP adherence, effectiveness, and impact on antimicrobial resistance. We present evidence supporting significant decreases in chlamydia and syphilis, and smaller decreases in gonorrhea, for patients taking doxy-PEP over a sustained time period spanning 96 weeks post-dispensation of doxy-PEP.
In conclusion, in examining five quarters before and after doxy-PEP initiation in a large sexual health clinic, patients taking doxy-PEP showed a significant decrease in bacterial STI rates post-doxy-PEP that were similar to the rate of STIs in patients who never took doxy-PEP, despite a greater number of condomless sex partners over the same period. Findings demonstrate significant, sustained reductions in chlamydia and syphilis, with smaller but notable reductions in gonorrhea over 96 weeks.
Acknowledgements:
Data are available upon request from the corresponding author.
Funding
This study was funded by NIH R01AI186641 (MAS).
Footnotes
Conflicts of Interest: The authors report no conflicts of interest.
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