Estradiol Therapy In Transgender Women to Research Interactions With HIV Therapy

Phase 2TerminatedNCT06005610

National Institute of Allergy and Infectious Diseases (NIAID)93 enrolled

Overview

Transgender women (TW) are a key population and priority for HIV treatment. More research is needed to develop evidence-based clinical guidance when it comes to choosing antiretroviral treatment (ART) regimens for TW on feminizing hormonal therapy (FHT). Concerns about ART interacting with FHT and decreasing its effectiveness can lead to decreased ART adherence and increased viral loads. Prior data suggest that access to FHT improves adherence to HIV treatment and decreases treatment interruptions. The Giving Standardized Estradiol Therapy In Transgender Women to Research Interactions with HIV Therapy (GET IT RiGHT) trial aimed to address concerns about drug-drug interactions (DDIs) between ART and FHT while providing access to hormonal therapy to TW living with HIV. This was an open-label, non-randomized, 3-group trial of adult TW and other individuals identifying as female or transfeminine but with male sex assigned at birth living with HIV. Participants were on ART at entry and received study-supplied 17-β estradiol for FHT for up to 48 weeks. The primary objectives of the study were to 1) assess whether TW continue to achieve therapeutic concentrations of ART while receiving FHT for 48 weeks and 2) assess whether serum estradiol concentrations on FHT (across a range of estradiol doses) vary between boosted and un-boosted ART regimens.

A5403 was a phase 2b, 48-week, open-label, non-randomized, 3-group trial, of 90 adult (≥18 years) transgender women and other individuals identifying as female or transfeminine but with male sex assigned at birth (TW) living with HIV on suppressive antiretroviral therapy (ART) and not currently on FHT. The trial aimed to enroll at least 50% participants who identified as non-white or Latine. The trial consisted of three groups, a bictegravir (BIC)-treated group (BIC/TAF/FTC; n=30 accrual target for evaluable participants) (Group 1), a dolutegravir (DTG)-treated group (DTG/TDF/FTC or 3TC; n=30 accrual target for evaluable participants) (Group 2), and a boosted darunavir (DRV)-treated group (DRV/c; n=30 accrual target for evaluable participants) (Group 3), for a total accrual target of 90 participants evaluable for pharmacokinetic (PK) analyses. All participants continued ART (not provided by the trial) and received study-supplied 17-β estradiol for weeks 0-48. At entry, participants were assigned to one of the three analysis groups based on their current ART regimen. Participants on other ART regimens at screening who were willing to switch to one of the regimens above were also eligible to enroll. All participants received study supplied 17-β estradiol for weeks 0-48. Oral 17-β estradiol 2 mg once daily was initiated following study entry. At weeks 4, 12, 24, and 36, study clinicians could titrate 17-β estradiol in 2 mg increments as described in the protocol. Intensive PK subgroup (n=15 per ART group): At entry (week 0), an 8-hour intensive PK sampling assessed ART exposure prior to FHT initiation. At week 24, intensive sampling was repeated to assess 17-β estradiol and ART exposure. A final intensive PK visit occurred at week 48 to assess 17-β estradiol and ART exposure at the maximal FHT dosing achieved during the study period. Sparse PK sampling: all participants not participating in an intensive PK sampling visit on the same day had timed, sparse PK sampling collected at each visit to characterize the trough plasma (BIC, DTG, and DRV) and intracellular ART (Tenofovir diphosphate (TFV-DP), emtricitabine triphosphate (FTC-TP), and lamivudine triphosphate (3TC-TP)), concentrations to evaluate the relationship of ART PK exposure across a range of 17-β estradiol doses. To measure acceptability, participants were asked to self-report the degree to which they found the intervention appropriate and useful using Likert-type agreement scales at three study time points: entry, 24 weeks, and 48 weeks. To measure satisfaction, the 12-question Transgender Congruence Scale (TCS) was used, which assessed associations between gender-affirming treatments, perceived gender congruence, and satisfaction at three study time points: entry, 24 weeks, and 48 weeks. Other assessments during study participation included: anthropometric measurements (including weight, height, minimum waist circumference, and maximum hip circumference), routine chemistry and hematology labs, HIV-1 viral load in plasma, CD4+ and CD8+ T cell counts and percentages, lipids, glucose and insulin, non-estradiol hormone concentrations, stored Peripheral Blood Mononuclear Cells (PBMC), plasma, and serum, and ART and FHT adherence assessments. Planned individual interviews with a subset of participants for further information on intervention satisfaction and acceptability were not conducted. In May 2025, the sponsor, the Division of AIDS (DAIDS) at NIAID, sent notice that the trial was terminated. Participants still in follow-up were contacted to schedule a final, premature discontinuation visit where transition of estradiol management and procurement to local care could be arranged. Additionally, funding to perform batched retrospective lab testing for pharmacokinetics (primary and some secondary outcomes) and insulin testing (secondary outcome) was unavailable.

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Documentation of HIV-1 status. 2. On ART for at least 24 weeks prior to study entry. Regimen changes within the 24 weeks prior to study entry are acceptable, but candidates must have been on a stable regimen for at least 28 days prior to study entry. 3. On BIC/FTC/TAF, DTG/TDF/FTC or 3TC, or DRV/c-containing ART for at least 28 days prior to study entry (single tablet regimen not required), and with no plans to change ART regimen over the study duration of 48 weeks. 4. Desire to initiate or restart FHT, regardless of orchiectomy status. 5. HIV-1 RNA \<200 copies/mL at screening. 6. HIV-1 RNA \<400 copies/mL available through routine clinical care between 24 and 96 weeks prior to study entry and while on ART. The HIV-1 RNA must be the most recent value obtained between 24 and 96 weeks prior to study entry. 7. The following laboratory values obtained within 60 days prior to study entry * Hemoglobin ≥9.0 g/dL * Platelet count ≥75,000/mm3 * Estimated Glomerular Filtration Rate (eGFR) ≥30 mL/min/1.73m2 if on or switching to TAF, ≥50 mL/min/1.73m2 if on or switching to TDF without cobicistat, or ≥70 mL/min/1.73m2 if on or switching to TDF in combination with cobicistat, calculated using standardized equation for eGFR * Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) (SGPT), and alkaline phosphatase are within normal range per local laboratory range * Prolactin \<25 ng/dL 8. Serum estradiol level \<75 pg/mL within 60 days prior to study entry. 9. Willingness to avoid the use of prescribed, non-study provided FHT and non-prescribed FHT during the study period, and no planned use of prescribed or non-prescribed anti-androgens for the first 24 weeks of the study. 10. Ability and willingness of participant to provide informed consent and ability and willingness of participant to undergo study procedures. Exclusion Criteria: 1. Known clotting disorders, active deep vein thrombosis (DVT), pulmonary embolism (PE), or history of these conditions, active arterial thromboembolic disease (e.g., stroke, myocardial infarction), or history of these conditions. 2. Known liver impairment or disease. 3. History of chronic hepatitis B virus (HBV) infection or active HBV infection. 4. History of current active hepatitis C virus (HCV) infection. 5. Prohibited medication use (including drugs with known or expected DDIs with FHT or ART) at time of study entry. 6. Receipt of any estrogen therapy within 14 days prior to study entry for persons on oral FHT, or within 30 days prior to entry for persons on injectable FHT. 7. Known HIV-1 resistance mutations that would preclude remaining on current ART or a switch to a study regimen, in the opinion of the site investigator. 8. Personal history of breast cancer. or known personal history of breast cancer (BRCA) gene. 9. Known or a history of testicular cancer. 10. Known or a history of gall bladder disease. 11. Known or suspected pituitary adenoma. 12. Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation. 13. Suicidal ideation in the past 30 days or suicide attempt in the past 90 days, as reported on the Columbia-Suicide Severity Rating Scale (C-SSRS). 14. Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to entry. Stable (in the opinion of the site investigator) treatments for chronic comorbidities are allowed. 15. Presence of any other medical condition that would preclude FHT administration for safety reasons, in the opinion of the site investigator.

Locations (18)

UCSD Antiviral Research Center CRS (701)

San Diego, California, United States

University of California, San Francisco HIV/AIDS CRS (801)

San Francisco, California, United States

University of Colorado Hospital CRS (6101)

Aurora, Colorado, United States

Whitman-Walker Institute, Inc. CRS (31791)

Washington D.C., District of Columbia, United States

The Ponce de Leon Center CRS (5802)

Atlanta, Georgia, United States

Johns Hopkins University CRS (201)

Baltimore, Maryland, United States

Washington University Therapeutics (WT) CRS (2101)

St Louis, Missouri, United States

New Jersey Medical School Clinical Research Center CRS (31786)

Newark, New Jersey, United States

Weill Cornell Uptown CRS (site 7803)

New York, New York, United States

Chapel Hill CRS (3201)

Chapel Hill, North Carolina, United States

...and 8 more locations

Outcomes

Primary Outcomes

Geometric Ratio of Antiretroviral Treatment (ART) Analytes Bictegravir (BIC), Dolutegravir (DTG), and Darunavir (DRV) Trough Concentrations (Ctrough) in Plasma at Each Received Dose of Oral 17-β Estradiol

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.

Time frame: Study Entry and Weeks 4, 12, 24, 36, and 48

Percentage of Participants With ART Analyte Trough Concentration (Ctrough) Above Drug-specific Threshold

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.

Time frame: Study Entry and Weeks 4, 12, 24, 36, and 48

Trough Serum Total Estradiol Assessed at Each Received Dose of Oral 17-β Estradiol as Quantified Via Batch Testing at Central Lab.

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.

Time frame: Study Entry and Weeks 4, 12, 24, 36, and 48

Secondary Outcomes

Geometric Ratio of Tenofovir Diphosphate (TFV-DP), Emtricitabine Triphosphate (FTC-TP), and Lamivudine Triphosphate (3TC-TP) in Non-viable Peripheral Blood Mononuclear Cells (PBMCs) at Each Received Dose of Oral 17-β Estradiol

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.

Time frame: Study Entry and Weeks 4, 12, 24, 36 and 48

Percentage of Participants With Tenofovir Diphosphate (TFV-DP), Emtricitabine Triphosphate (FTC-TP), and Lamivudine Triphosphate (3TC-TP) Trough Concentration Above Drug-specific Threshold

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.

Time frame: Study Entry and Weeks 4, 12, 24, 36 and 48

Percentage of Participants With an Occurrence of Any Reportable Adverse Event Related to 17-β Estradiol

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.

Time frame: Treatment initiation to Week 48

Percentage of Participants With an Occurrence of Any Targeted Adverse Event

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).

Time frame: Treatment initiation to Week 48

Percentage of Participants With Serum Total Testosterone < 50 ng/dL at Each Received Dose of Oral 17-β Estradiol

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.

Time frame: Study entry to week 48

Percentage of Participants With Virologic Suppression of HIV

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

Time frame: Study entry and weeks 12, 24,36 and 48

Absolute Changes in Overall Transgender Congruence Score (TCS)

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.

Time frame: Study entry to weeks 24, and 48

Area Under the Curve Over 8 Hours (AUC 0-8h) of 17-β Estradiol

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.

Time frame: Study entry and Weeks 24, and 48

Percent Change in Weight

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.

Time frame: Study entry to weeks 4,12, 24, 36, and 48

Percent Change in Body Mass Index (BMI)

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

Time frame: Study entry and weeks 4, 12, 24, 36, and 48

Absolute Change in Minimum Waist Circumference

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.

Time frame: Study entry and weeks 4,12, 24, 36, and 48

Absolute Change in Maximum Hip Circumference

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

Time frame: Study entry and weeks 4, 12, 24, 36, and 48

Absolute Change in Waist-hip Ratio (WHR) Measured

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

Time frame: Study entry and weeks 4,12, 24, 36, and 48

Absolute Changes in Fasting High-density Lipoprotein Cholesterol (HDL)

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.

Time frame: Study entry and weeks 12, 24, and 48

Absolute Changes in Fasting Blood Glucose (FBG)

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.

Time frame: Study entry to weeks 4,12, 24, 36, and 48

Absolute Changes in Insulin Sensitivity

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.

Time frame: Study entry and weeks 12, 24, 36, and 48

Absolute Changes in Fasting Triglycerides (TRG)

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

Time frame: Study entry to weeks 12, 24, and 48

Absolute Changes in Fasting Total Cholesterol (CHOL)

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

Time frame: Study entry to weeks 12, 24, and 48

Absolute Changes in Fasting Direct Low-density Lipoprotein Cholesterol (LDL)

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.

Time frame: Study entry to weeks 12, 24, and 48

Absolute Change in Weight

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

Time frame: Study entry to weeks 4,12, 24, 36, and 48

Absolute Change in Body Mass Index (BMI)

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

Time frame: Study entry to weeks 4, 12, 24, 36, and 48

Percent Change in Minimum Waist Circumference

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.

Time frame: Study entry and weeks 4,12, 24, 36, and 48

Percent Change in Maximum Hip Circumference

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.

Time frame: Study entry and weeks 4, 12, 24, 36, and 48

Percent Change in Waist-hip Ratio (WHR) Measured

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.

Time frame: Study entry and weeks 4,12, 24, 36, and 48

Estradiol Therapy In Transgender Women to Research Interactions With HIV Therapy

Overview

Conditions

Interventions

Eligibility

Locations (18)

Outcomes

Primary Outcomes

Secondary Outcomes