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Randomized Controlled Trial
. 2023 Apr 6;388(14):1296-1306.
doi: 10.1056/NEJMoa2211934.

Postexposure Doxycycline to Prevent Bacterial Sexually Transmitted Infections

Anne F Luetkemeyer  1 , Deborah Donnell  1 , Julia C Dombrowski  1 , Stephanie Cohen  1 , Cole Grabow  1 , Clare E Brown  1 , Cheryl Malinski  1 , Rodney Perkins  1 , Melody Nasser  1 , Carolina Lopez  1 , Eric Vittinghoff  1 , Susan P Buchbinder  1 , Hyman Scott  1 , Edwin D Charlebois  1 , Diane V Havlir  1 , Olusegun O Soge  1 , Connie Celum  1 ; DoxyPEP Study Team
Collaborators, Affiliations
Randomized Controlled Trial

Postexposure Doxycycline to Prevent Bacterial Sexually Transmitted Infections

Anne F Luetkemeyer et al. N Engl J Med. .

Abstract

Background: Interventions to reduce sexually transmitted infections (STIs) among men who have sex with men (MSM) are needed.

Methods: We conducted an open-label, randomized study involving MSM and transgender women who were taking preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV) infection (PrEP cohort) or living with HIV infection (persons living with HIV infection [PLWH] cohort) and who had had Neisseria gonorrhoeae (gonorrhea), Chlamydia trachomatis (chlamydia), or syphilis in the past year. Participants were randomly assigned in a 2:1 ratio to take 200 mg of doxycycline within 72 hours after condomless sex (doxycycline postexposure prophylaxis) or receive standard care without doxycycline. STI testing was performed quarterly. The primary end point was the incidence of at least one STI per follow-up quarter.

Results: Of 501 participants (327 in the PrEP cohort and 174 in the PLWH cohort), 67% were White, 7% Black, 11% Asian or Pacific Islander, and 30% Hispanic or Latino. In the PrEP cohort, an STI was diagnosed in 61 of 570 quarterly visits (10.7%) in the doxycycline group and 82 of 257 quarterly visits (31.9%) in the standard-care group, for an absolute difference of -21.2 percentage points and a relative risk of 0.34 (95% confidence interval [CI], 0.24 to 0.46; P<0.001). In the PLWH cohort, an STI was diagnosed in 36 of 305 quarterly visits (11.8%) in the doxycycline group and 39 of 128 quarterly visits (30.5%) in the standard-care group, for an absolute difference of -18.7 percentage points and a relative risk of 0.38 (95% CI, 0.24 to 0.60; P<0.001). The incidences of the three evaluated STIs were lower with doxycycline than with standard care; in the PrEP cohort, the relative risks were 0.45 (95% CI, 0.32 to 0.65) for gonorrhea, 0.12 (95% CI, 0.05 to 0.25) for chlamydia, and 0.13 (95% CI, 0.03 to 0.59) for syphilis, and in the PLWH cohort, the relative risks were 0.43 (95% CI, 0.26 to 0.71), 0.26 (95% CI, 0.12 to 0.57), and 0.23 (95% CI, 0.04 to 1.29), respectively. Five grade 3 adverse events and no serious adverse events were attributed to doxycycline. Of the participants with gonorrhea culture available, tetracycline-resistant gonorrhea occurred in 5 of 13 in the doxycycline groups and 2 of 16 in the standard-care groups.

Conclusions: The combined incidence of gonorrhea, chlamydia, and syphilis was lower by two thirds with doxycycline postexposure prophylaxis than with standard care, a finding that supports its use among MSM with recent bacterial STIs. (Funded by the National Institutes of Health; DoxyPEP ClinicalTrials.gov number, NCT03980223.).

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Figures

Figure 1
Figure 1. Enrollment and Follow-up of the Study Participants.
There was no separate screening visit; thus, reasons for screening failure were not collected. The study had two cohorts: those who were taking preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV) infection (PrEP cohort) and persons living with HIV infection (PLWH cohort). Within each cohort, participants in the doxycycline group were assigned to take doxycycline within 72 hours after condomless sex (doxycycline postexposure prophylaxis [doxy-PEP]), and participants in the standard-care group were assigned to receive standard care without doxycycline. Of the 4 participants in the PLWH cohort who underwent randomization but were not enrolled in the study, 3 immediately withdrew consent after receiving their randomization assignment and 1 was withdrawn at the investigator’s discretion. A total of 136 participants were enrolled but had not yet reached the month 3 visit at the time of this analysis. Visit attendance indicates the percentage who had completed visits for which they were eligible at the time that the data and safety monitoring board met. A total of 28 participants remained in follow-up but had not completed a follow-up visit. A total of 473 of 501 participants (94%) in the modified intention-to-treat population contributed follow-up visit data for the primary efficacy analysis. A total of 18 participants discontinued the study early: 5 in the doxycycline groups (1 moved, 1 had a new job, 1 was in a monogamous relationship, and 2 gave no reason) and 13 in the standard-care groups (2 moved, 1 had a new job, 6 wanted doxy-PEP, 1 had a concern about coronavirus disease 2019, and 3 gave no reason).
Figure 2.
Figure 2.. Primary, Secondary, and Subgroup Analyses of Effectiveness against Incident Sexually Transmitted Infections (STIs).
Confidence intervals have not been adjusted for multiple testing.
Figure 3.
Figure 3.. Kaplan–Meier Estimate of Time to First STI Diagnosis.
The cumulative probability of any incident bacterial STI (chlamydia, gonorrhea, or syphilis) is shown according to study group (doxycycline and standard care) and participant cohort (PrEP and PLWH).
Figure 4.
Figure 4.. Antimicrobial Resistance and Culture Positivity in Neisseria gonorrhoeae and Staphylococcus aureus.
In Panel A, the bar height represents N. gonorrhoeae cultures obtained from participants with lab-confirmed gonorrhea at baseline and for adjudicated gonorrhea end points according to study group during follow-up. Of the gonorrhea diagnoses, 44 of 256 N. gonorrhoeae infections (17.2%) had data available for resistance testing. The dark shading represents high-level tetracycline resistance (minimum inhibitory concentration [MIC], ≥2 μg per milliliter). The light shading represents N. gonorrhoeae without high-level tetracycline resistance. Gonorrhea culture was performed through the Centers for Disease Control and Prevention (CDC) Strengthening the United States Response to Resistant Gonorrhea program, and tetracycline-resistance testing was performed by agar dilution through the CDC Antimicrobial Resistance Laboratory Network. With respect to Panel B, all the participants had oronasopharyngeal swabs obtained at enrollment and at months 6 and 12, which were cultured for S. aureus. The bar height represents the percentage culture-positive for S. aureus, and the dark shading represents specimens with doxycycline resistance by ETEST (MIC, ≥16 μg per milliliter).
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