Estradiol Therapy In Transgender Women to Research Interactions With HIV Therapy

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.