Estradiol Therapy In Transgender Women to Research Interactions With HIV Therapy

Giving Standardized Estradiol Therapy In Transgender Women to Research Interactions With HIV Therapy

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.

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.