Randomized Directly Observed Therapy Study to Interpret Clinical Trials of Doxy-PEP - PROJECT SUMMARY/ ABSTRACT Rates of bacterial sexually transmitted infections (STIs) are rising globally, demanding innovative interventions beyond the scope of current efforts to prevent STIs. While HIV pre-exposure prophylaxis (PrEP) effectively reduces HIV acquisition risk, it does not address the surge in bacterial STIs. The DoxyPEP Study has demonstrated the efficacy of Doxycycline post-exposure prophylaxis (PEP) among men who have sex with men (MSM) and transgender women. However, puzzlingly, doxycycline PEP was found ineffective in cisgender women in the dPEP study, despite doxycycline achieving similar concentrations in the vagina and rectum. Preliminary data from dPEP show low detection of doxycycline among participants, suggesting that low medication adherence may explain the null result. To fully interpret the dPEP study and others, in-depth adherence measurement techniques for doxycycline will need to be developed. As was needed for HIV PrEP to establish the relationship between patterns of pill-taking and drug concentrations, a directly observed therapy (DOT) study, the gold-standard approach to determine the pharmacology of doxy and establish pill-taking cut-offs, is needed (Aim 1). We will enroll 36 participants (12 cisgender men, 12 cisgender women, and 12 transgender women) for a randomized cross-over DOT study, with in-depth pharmacokinetic measurement while dosing and during washout. When combined with sexual behavior data in the trials conducted in MSM/TGW and cisgender women, doxycycline PEP coverage of sexual acts and pharmacodynamic relationships can be established. These data can be used to understand patterns of adherence over time among women in dPEP to interpret the null study, and to understand the relationship between cumulative adherence and STI incidence reduction (Aim 2). We will then examine adherence patterns in the recently completed DoxyPEP study to understand the potential clinical role of a urine or plasma metric amenable to point-of-care test development to identify doxy-PEP adherence challenges (Aim 3). Finally, this work will establish thresholds of doxy levels in hair, urine, and plasma to interpret doxy adherence in roll-out studies in the future. By study end, we will have determined dosing cut-offs for doxy in hair, plasma, and urine, and will use these cut-offs to examine the relationship between adherence patterns and STI reduction in the dPEP study, and adherence predictors and metrics within the DoxyPEP trial. These benchmarks and pharmacodynamic analyses will establish adherence metrics for current and future rollout studies of doxy-PEP.
