Pre-Exposure Prophylaxis (PrEP)- Gender Affirming Hormone Therapy (GAHT) Interactions in TGW

The PrEP-GAHT Interactions in TGW protocol is a phase 1, open label study to compare the safety, PK and PD of five sequential phases of PrEP administration in the presence or absence of testosterone-reducing therapies or dose-escalated estrogen therapy. Each participant will undergo a Screening Visit to evaluate eligibility. Following Baseline evaluation, eligible participants will receive 300 milligrams (mg) TDF/200 mg FTC (Truvada®) once daily for seven days, using direct observation approaches, to achieve steady state drug PrEP concentrations. After one week of therapy, participants will undergo intensive PK analysis as well as collection of colorectal biopsies for PD testing (PK1). During the PK-intensive day, iohexol will be administered intravenously for the empirical determination of renal function and measured glomerular filtration rate (mGFR). While concurrently on PrEP, participants will then be intramuscularly administered depot leuprolide acetate (11.25 mg Lupron®). Two weeks post-injection, when testosterone concentrations are far below the lower limit of normal of total testosterone in men (typically \< 200 ng/dL, or \< 2 ng/mL), sampling for PK, PD, and renal function will be performed (PK2). Participants will then immediately begin low-dose oral estrogen therapy (1 mg 17β-estradiol) in conjunction with PrEP for one week, at which time samples will be collected for the analyses described above (PK3). While still on PrEP, participants will then transition to high-dose estrogen therapy (6 mg 17β-estradiol) for the remainder of the study. One week post-high dose estrogen therapy in the presence of PrEP, pharmacologic and renal samples will be collected for analysis (PK4). PrEP will then be discontinued, and two weeks later, samples will be collected to assess renal function and hormonal concentrations, and evaluate the presence of any remaining PrEP in plasma, Peripheral Blood Mononuclear Cells (PBMC), or colorectal tissue (though it should be near undetectable levels for most analytes according to the investigators' prior data)(PK5). Safety assessments, including history/physical, chemistry/hematology labs at screening and interim history will be performed at each study-intensive visit. Additionally, periodic assessments of gender dysphoria will be conducted at baseline and a convenient time during PK visits throughout the study. To ensure compliance, participants will undergo direct observation of dosing each day of the week prior to PK visits, using the aforementioned strategies.