Estradiol Therapy for HIV in Transgender Women

(GET IT RIgHT Trial)

Recruiting at 26 trial locations

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Antiretrovirals

Must not be taking: Estrogen therapy

Disqualifiers: Clotting disorders, Liver disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 48 weeks

93 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications, but you must be on a stable antiretroviral therapy (ART) regimen for at least 28 days before joining and cannot change it during the study. You also need to avoid using any non-study provided feminizing hormonal therapy (FHT) and anti-androgens for the first 24 weeks.

What data supports the effectiveness of the drug Estradiol for HIV in transgender women?

Estradiol is a key component of feminizing hormone therapy, which is important for transgender women. However, concerns about interactions with HIV medications can affect how these drugs are taken, potentially impacting their effectiveness. ^{1 2 3 4 5}

Is estradiol therapy generally safe for transgender women with HIV?

Estradiol therapy is generally considered safe for transgender women, but there can be interactions with HIV medications that may affect how the body processes the hormone. It's important to work closely with healthcare providers to manage these interactions and ensure both treatments are effective. ^{1 2 3 6 7}

How is the drug Estradiol unique for HIV treatment in transgender women?

Estradiol is unique for HIV treatment in transgender women because it is part of feminizing hormone therapy (FHT) that helps align their physical characteristics with their gender identity, which is crucial for their overall well-being. However, it can interact with antiretroviral therapies (ARTs) like efavirenz, affecting its metabolism and potentially complicating HIV treatment. ^{2 3 4 5 8}

What is the purpose of this trial?

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. The GET IT RiGHT trial aims to address concerns about drug-drug interactions (DDIs) between ART and FHT while providing access to hormonal therapy to TW living with HIV. Data suggest that access to FHT improves adherence to HIV treatment and decreases treatment interruptions. This is 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 will be on ART at entry and receive study-supplied 17-β estradiol for FHT for 48 weeks. The primary objectives of the study are 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.

Research Team

Jordan E. Lake, MD, MSc

Principal Investigator

Houston AIDS Research Team CRS

Kimberly K. Scarsi, PharmD, MS, FCCP

Principal Investigator

University of Nebraska

Jorge A. Gallardo-Cartagena, MD

Principal Investigator

Barranco CRS

Eligibility Criteria

This trial is for adult transgender women and transfeminine individuals living with HIV who have been on antiretroviral therapy (ART) for at least 24 weeks. They must have a stable viral load, normal organ function tests, no history of certain cancers or clotting disorders, and not be taking other hormone therapies outside the study.

Inclusion Criteria

I was assigned male at birth and identify as a woman or transfeminine.

I have been on HIV medication for at least 24 weeks and on a stable regimen for the last 28 days.

I have been on the same HIV medication for at least 28 days and don't plan to change it.

Exclusion Criteria

I do not have any health conditions that make it unsafe for me to receive hormone therapy.

I have had breast cancer or carry the BRCA gene mutation.

I have or had hepatitis B or currently have active hepatitis C.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive study-supplied 17-β estradiol for feminizing hormonal therapy (FHT) while continuing their antiretroviral therapy (ART) for 48 weeks.

48 weeks

Visits at weeks 0, 4, 12, 24, 36, and 48

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Intensive PK Sampling

Intensive pharmacokinetic (PK) sampling to assess ART and 17-β estradiol exposure at weeks 0, 24, and 48.

48 weeks

3 intensive PK visits

Treatment Details

Interventions

• Estradiol

Trial Overview The GET IT RiGHT trial studies how well HIV treatment works when taken alongside feminizing hormone therapy (FHT), specifically estradiol. It checks if ART maintains its effectiveness and measures estradiol levels in participants over a period of 48 weeks.

Participant Groups

Group I: Group 3: Boosted DRV-treated Experimental Treatment 1 Intervention

Participants taking any regimen containing darunavir plus cobicistat (DRV/c)

Group II: Group 2: DTG-treated Experimental Treatment 1 Intervention

Participants taking dolutegravir (DTG) once daily + tenofovir disoproxil fumarate (TDF) + (FTC or lamivudine \[3TC\])

Group III: Group 1: BIC-treated Experimental Treatment 1 Intervention

Participants taking bictegravir (BIC) + tenofovir alafenamide (TAF) + emtricitabine (FTC)

Estradiol is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Estradiol for:

• Menopausal symptoms
• Hypoestrogenism
• Osteoporosis prevention
• Breast cancer palliation
• Prostate cancer palliation

Approved in United States as Estradiol for:

• Moderate to severe vasomotor symptoms due to menopause
• Vulvar and vaginal atrophy due to menopause
• Hypoestrogenism due to hypogonadism, castration, or primary ovarian failure
• Prevention of postmenopausal osteoporosis
• Palliative treatment of breast cancer
• Palliative treatment of prostate cancer

Approved in Canada as Estradiol for:

• Menopausal symptoms
• Hypoestrogenism
• Osteoporosis prevention
• Breast cancer palliation
• Prostate cancer palliation

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Findings from Research

In a survey of 87 transgender women in Los Angeles, 54% were living with HIV and 64% were using hormone therapy, highlighting the significant overlap between these two treatments.

Concerns about drug-drug interactions between hormone therapy and antiretroviral therapy led to 40% of participants not adhering to their prescribed treatments, indicating a critical need for better communication and integration of care between providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transgender Women Living with HIV Frequently Take Antiretroviral Therapy and/or Feminizing Hormone Therapy Differently Than Prescribed Due to Drug-Drug Interaction Concerns. Braun, HM., Candelario, J., Hanlon, CL., et al.[2020]

Hormonal therapy for male to female transgender patients aims to maintain estrogen levels within a normal physiological range, which is crucial for managing gender dysphoria.

In three cases of transgender HIV-positive women, the antiretroviral drug efavirenz was found to significantly affect the metabolism of estradiol, potentially impacting the effectiveness of hormone therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Efavirenz on Estradiol Metabolism in Transgender Women. Leinung, MC., Miller, CH., Tehrani, B., et al.[2020]

Transgender women (TGW) face significant barriers to effective HIV treatment, leading to lower rates of virologic suppression and higher mortality, with an HIV prevalence of 19.1% among TGW worldwide.

There is a lack of comprehensive studies on drug-drug interactions (DDIs) between feminizing hormone regimens and antiretroviral therapy (ART), particularly concerning the effects of different types and doses of estrogens, highlighting the need for further research to ensure safe and effective treatment for HIV-positive TGW.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transgender women, hormonal therapy and HIV treatment: a comprehensive review of the literature and recommendations for best practices. Radix, A., Sevelius, J., Deutsch, MB.[2022]

Transgender populations in the USA have a high HIV prevalence of 13.7%, highlighting the urgent need for effective HIV prevention and treatment strategies tailored to their unique needs.

Current HIV prevention methods, like topical microbicides and PrEP, have not been adequately tested in transgender individuals, and concerns about drug-hormone interactions may affect their adherence to treatment, indicating a critical gap in research and healthcare provision.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HIV Antiretroviral Treatment and Pre-exposure Prophylaxis in Transgender Individuals. Poteat, TC., Radix, A.[2021]

Interviews with 9 HIV-positive trans women and 15 HIV providers in Manila revealed that provider communication styles significantly impact the integration of feminizing hormone therapy (FHT) and antiretroviral therapy (ART), with non-affirmative rhetoric potentially hindering treatment decisions.

The study highlights the need for a gender-affirmative HIV care framework, as misalignment between provider concerns and patient goals can lead to mixed regimens and beliefs about FHT and ART among trans women, emphasizing the importance of training providers in gender-affirmative practices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gender affirmative HIV care framework: Decisions on feminizing hormone therapy (FHT) and antiretroviral therapy (ART) among transgender women. Restar, AJ., Santamaria, EK., Adia, A., et al.[2023]

In a study of 20 transgender women with newly diagnosed HIV, the pharmacokinetics of estradiol (E2) were significantly reduced when combined with antiretroviral therapy (ART), indicating potential drug-drug interactions that could affect hormone therapy effectiveness.

Some pharmacokinetic parameters of tenofovir (TFV) and efavirenz (EFV) were also lower when feminizing hormone therapy (FHT) was present, suggesting that both therapies may influence each other's effectiveness, warranting further investigation into their clinical significance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug-drug Interactions Among Thai Transgender Women Living with Human Immunodeficiency Undergoing Feminizing Hormone Therapy and Antiretroviral Therapy: The iFACT Study. Hiransuthikul, A., Himmad, L., Kerr, SJ., et al.[2021]

In a study of 1495 trans women, only 71.8% of those with HIV were prescribed feminizing hormone therapy (FHT), compared to 88.4% of those without HIV, indicating a potential gap in treatment for trans women living with HIV.

Despite concerns about drug-drug interactions, serum estradiol and testosterone levels were similar among trans women on FHT regardless of their HIV status, suggesting that FHT can be safely administered alongside antiretroviral therapy (ART).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feminizing hormone therapy in a Canadian cohort of transgender women with and without HIV. Armstrong, I., Lacombe-Duncan, A., Shokoohi, M., et al.[2023]

In a study of 15 HIV-negative transwomen taking PrEP, plasma levels of tenofovir and emtricitabine were found to be lower compared to historical data from cisgender adults, which may affect the effectiveness of PrEP in this population.

Despite lower plasma concentrations, the active forms of the drugs, tenofovir-diphosphate and emtricitabine-triphosphate, were found to be higher in transwomen's cells than previously reported, suggesting that intracellular drug levels may still provide protective effects against HIV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma and intracellular pharmacokinetics of tenofovir disoproxil fumarate and emtricitabine in transgender women receiving feminizing hormone therapy. Cirrincione, LR., Podany, AT., Havens, JP., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Transgender Women Living with HIV Frequently Take Antiretroviral Therapy and/or Feminizing Hormone Therapy Differently Than Prescribed Due to Drug-Drug Interaction Concerns. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

The Effect of Efavirenz on Estradiol Metabolism in Transgender Women. [2020]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Transgender women, hormonal therapy and HIV treatment: a comprehensive review of the literature and recommendations for best practices. [2022]

4. New Zealand pubmed.ncbi.nlm.nih.gov

HIV Antiretroviral Treatment and Pre-exposure Prophylaxis in Transgender Individuals. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Gender affirmative HIV care framework: Decisions on feminizing hormone therapy (FHT) and antiretroviral therapy (ART) among transgender women. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Drug-drug Interactions Among Thai Transgender Women Living with Human Immunodeficiency Undergoing Feminizing Hormone Therapy and Antiretroviral Therapy: The iFACT Study. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Feminizing hormone therapy in a Canadian cohort of transgender women with and without HIV. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Plasma and intracellular pharmacokinetics of tenofovir disoproxil fumarate and emtricitabine in transgender women receiving feminizing hormone therapy. [2022]