Trial Outcomes & Findings for Estradiol Therapy In Transgender Women to Research Interactions With HIV Therapy (NCT NCT06005610)

Participants enrolled from 18 sites. Sites were located in the United States and internationally (Mexico, Peru, and Thailand). The first participant enrolled in January 2024, and the last participant enrolled in April 2025.

Participants were assigned to groups based on the anti-retroviral treatment regimen they were receiving at enrollment: Group 1 among those taking bictegravir (BIC) + tenofovir alafenamide (TAF) + emtricitabine (FTC), Group 2 among those taking dolutegravir (DTG) once daily + tenofovir disoproxil fumarate (TDF) + (FTC or lamivudine \[3TC\]), and Group 3 among those taking any anti-retroviral treatment regimen containing darunavir plus cobicistat (DRV/c).

Missing plasma HIV-RNA results from entry visit excluded.

Log-transformed trough concentrations (Ctrough) in ng/mL of the analytes BIC, DTG, and DRV from plasma samples collected 22-26 hours post ART dose, measured over 48 weeks. Geometric ratios will be calculated as the log of Ctrough of the ART analyte at each dose of 17-β estradiol - log of Ctrough of that same ART analyte at baseline. If multiple observations are available at the same estradiol dose, the first sampled qualifying steady-state trough concentration (based on calendar time) taken will be used.

Trough concentration of the analytes BIC, DTG, and DRV in plasma at each received dose of 17-β estradiol summarized at the participant level as indicator of concentration being above drug-specific threshold.

Trough concentrations of Total 17-β estradiol in ng/mL from serum samples collected 22-26 hours post 17-β estradiol dose. Results \< Lower Limit of Quantification (LLoQ) at entry will be imputed as 0 ng/mL at one-half the LLoQ value at visits post-entry. If multiple observations are available at the same estradiol dose, the first qualifying trough concentration (based on time since last dose) taken will be used.

Log-transformed trough concentrations (Ctrough) in ng/mL of the metabolites of the following drugs: TFV-DP, FTC-TP, and 3TC-TP from PBMC samples collected 22-26 hours post antiretroviral treatment (ART) dose, measured over 48 weeks. Geometric ratios will be calculated as the log of Ctrough of the ART analyte at each dose of 17-β estradiol - log of Ctrough of that same ART analyte at entry. If multiple observations are available at the same estradiol dose, the first sampled qualifying steady-state trough concentration (based on calendar time) taken will be used.

Trough concentration of the analytes TFV-DP, FTC-TP, and 3TC-TP in non-viable PBMCs at each received dose of 17-β estradiol summarized at the participant level as indicator of concentration being above drug-specific externally defined threshold.

Reportable Adverse events included the following: all new diagnoses, signs/symptoms and laboratory events of ≥Grade 3; events that led to an interruption or dose reduction of estradiol regardless of grade; all serious adverse events (SAEs) ; ≥ grade 1 lipid and glucose abnormalities; ≥ grade 2 cholecystitis, elevated liver enzymes or hypertension; and all cases of cardiovascular disease (CVD), cancer, diabetes or pre-diabetes and any vascular events were reported. Division of AIDS Adverse Events Grading Table (V2.1) was used. Relatedness to 17-β estradiol determined by local site research personnel.

Targeted adverse events included the following: Serious Adverse Events (SAEs), coronary heart disease or other cardiovascular disease, cancer (exclusive of basal/squamous cell skin cancer), diabetes or pre-diabetes and any vascular events (including arterial events (strokes and myocardial infarctions) or deep venous thrombotic events (venous thromboembolism, deep venous thrombosis, retinal vein thrombosis, and pulmonary embolism).

Results \< lower limit of quantification will be considered to be \<50 ng/dL. If multiple observations are available at the same estradiol dose, the last testosterone concentration (based on calendar time) will be used.

Virologic suppression of HIV is defined as plasma HIV-1 viral load \<50 copies/mL.

The overall transgender congruence score is calculated from participant response to the 12-question Transgender Congruence Scale (TCS). Participants rate each item on a 5-point Likert-type scale (i.e., 1 = strongly disagree, 2 = somewhat disagree, 3 = neither agree nor disagree, 4 = somewhat agree, 5 = strongly agree). Questions 'The way my body currently looks does not represent my gender identity.', 'I do not feel that my appearance reflects my gender identity.', and 'I am not proud of my gender identity.' are reversed scored. The overall score is the average of the response to the 12 questions, with higher scores indicating a higher level of congruence. Positive changes from baseline indicate improvement in transgender congruence.

From pre-dose, 1, 2, 3, 4, 6, and 8 hours post dosing at entry and weeks 24 and 48. The AUC will use the linear up/log down version of the trapezoidal rule in non-compartmental analysis using software called Phoenix WinNonLin (Certara®). This version of the trapezoidal rule uses linear interpolation between untransformed data up to Cmax, and between log-transformed data from Cmax through Clast.

Calculated by dividing weight in kilograms at later time point minus weight at study entry by weight at study entry, and then multiplying by 100.

Calculated by dividing BMI at later time point minus BMI at study entry by BMI at study entry, and then multiplying by 100.

Calculated as waist circumference (centimeters or cm) at later time point minus waist circumference at study entry. Measurements taken on bare skin at the smallest horizontal circumference above the umbilicus and below the xiphoid process. Tape was level and parallel to the floor, and participant's arms were at their sides and their feet and ankles were together. Measurements taken at the end of the participant's normal, relaxed exhalation. Measurements taken in triplicate and averaged. Measurement rounded to nearest tenth of a centimeter. If one value was more than 10% different than the other two values, it was discarded, and the remaining two values were averaged.

Calculated as maximum hip circumference (in centimeters or cm) at later time point minus maximum hip circumference at study entry.

Calculated as waist-hip ratio (WHR) at later time point minus waist-hip ratio at study entry.

Calculated as fasting high-density lipoprotein cholesterol (HDL in milligrams per deciliter or mg/dL) at later time point minus fasting HDL at study entry.

Calculated as fasting glucose result (or FBG in milligrams/deciliter or mg/dL) at later time point minus fasting blood glucose (FBG) at study entry.

Calculated as insulin sensitivity at later time point minus insulin sensitivity at study entry. Insulin will be measured from stored samples. Insulin sensitivity will be calculated as Homeostatic Model Assessment of Insulin Resistance model (HOMA-IR) = (fasting glucose in mmol/L \* fasting insulin in µU/L) /22.5.

Calculated as fasting triglycerides (TRG in milligrams per deciliter or mg/dL) at later time point minus fasting TRG at study entry.

Calculated as fasting total cholesterol (CHOL in milligrams per deciliter or mg/dL) at later time point minus fasting CHOL at study entry.

Calculated as fasting direct low-density lipoprotein cholesterol (LDL in milligrams per deciliter or mg/dL) at later time point minus fasting LDL at study entry.

Calculated as weight in kilograms (kg) at follow-up time minus weight at study entry.

Calculated as BMI (in kg/m\^2) at follow-up time minus BMI at study entry.

Calculated by dividing waist circumference (centimeters or cm) at later time point minus waist circumference by waist circumference study entry, and then multiplying by 100.

Calculated by dividing hip circumference (in centimeters or cm) at later time point minus maximum hip circumference at study entry by hip circumference at entry, and then multiplying by 100.

Calculated by dividing waist-hip ratio (WHR) at later time point minus waist-hip ratio at study entry by waist-hip ratio at entry, and then multiplying by 100.