Clinical trial NCT05663892: Drug-Drug Interaction Study in Trans Women Living With HIV
Official title: Drug-drug Interaction Study Between Bictegravir/Emtricitabine/Tenofovir Alafenamide and Feminizing Hormones in Trans Women Living With HIV
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Hiv
Transgenderism
Keywords: HIV
Feminizing Hormone Therapy
Transgender Women
Antiretroviral Therapy
Drug-Drug Interaction
Lead sponsor: Maple Leaf Research
Sponsor class: OTHER
First posted: 2022-12-23
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: Introduction: Transgender (trans) women have been found to be at higher risk of and to be disproportionally affected by HIV. Trans women with HIV have also been found to have low usage and adherence rates to antiretroviral therapy (ART). Both healthcare providers and trans women, themselves, have expressed concerns of drug-drug interactions (DDIs) between ART drugs and feminizing hormones, which have in turn been shown to contribute to low rates of ART usage amongst trans women with HIV. The objective of this DDI study is to investigate the pharmacokinetic effects of the common feminizing hormone regimens (oral estradiol with an anti-androgen (pharmaceutical and/or surgical and/or medical) on the antiretroviral combination bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) and vice versa.

Methods and Analysis: Participants will be assigned to three groups: group 1 will include 15 trans women with HIV who are taking feminizing hormones and ART (investigational group); group 2 will include 15 premenopausal cis women with HIV taking ART (ART control group); group 3 will include 15 trans women without HIV taking feminizing hormones (hormone control group). Women with HIV will have to be virally suppressed for at least three months and they will have to already be taking B/F/TAF or have their current ART regimen switched to B/F/TAF at baseline. Trans women participants will be required to be on 2 mg oral estradiol or higher and an anti-androgen (pharmaceutical, medical or surgical). Plasma ART drug concentrations will be sampled at the 2-month visit and compared among trans women with HIV on feminizing hormones and premenopausal cis women with HIV. Serum estradiol and total testosterone concentrations will be sampled at the baseline and month 2 visits and compared among trans women with and without HIV. If successful, this trial will serve to provide empirical evidence regarding a lack of, or presence of DDIs between B/F/TAF and feminizing hormones.

Dissemination: The findings will be disseminated through publication in peer-reviewed journals as well as presented at national and international conferences and community groups.

Detailed description: Introduction: Transgender (trans) women have been found to be at higher risk of and to be disproportionally affected by HIV for multiple biologic and social reasons. Trans women living with HIV have also been found to have low usage and adherence rates to antiretroviral therapy (ART). Both healthcare providers and trans women, themselves, have expressed concerns of drug-drug interactions (DDIs) between ART drugs and feminizing hormones, which have in turn been shown to contribute to low rates of ART usage amongst trans women living with HIV. The objective of this DDI study is to investigate the pharmacokinetic effects of the common feminizing hormone regimens (oral estradiol with an anti-androgen (pharmaceutical and/or surgical and/or medical)) on the antiretroviral combination bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) and vice versa.

Methods and analysis: Participants will be assigned to three groups: group 1 will include 15 trans women living with HIV who are taking feminizing hormones and ART (investigational group); group 2 will include 15 premenopausal cis women living with HIV taking ART (ART control group); group 3 will include 15 trans women living without HIV taking feminizing hormones (hormone control group). Women living with HIV will have to be virally suppressed for at least three months and they will have to already be taking B/F/TAF or have their current ART regimen switched to B/F/TAF at baseline. Trans women participants will be required to be on 2 mg oral estradiol or higher and an anti-androgen (pharmaceutical, medical or surgical). Plasma ART drug concentrations will be sampled at the 2-month visit and compared among trans women living with HIV on feminizing hormones and premenopausal cis women living with HIV. Serum estradiol and total testosterone concentrations will be sampled at the baseline and month 2 visits and compared among trans women living with and without HIV. The primary endpoints are B/F/TAF pharmacokinetic parameters (Cmin, Cmax and AUC) between trans and cis women living with HIV at month 2 and the estradiol concentrations (Cmin, C4h, Cmax and AUC) and the proportions of the month 2 C4h that are within target (200 to 735 pmol/L) between trans women living with and without HIV at month 2. Other endpoints will include the mean estradiol and testosterone concentrations at baseline and the difference between baseline and month 2 estradiol pre-dose and C4h, satisfaction with feminizing hormones, HIV viral load, adherence, adverse events, patient-reported outcomes (i.e., symptoms), satisfaction with ART regimen and health status. If successful, this trial will serve to provide empirical evidence regarding a lack of, or presence of DDIs between B/F/TAF and feminizing hormones.

Dissemination: The findings will be disseminated through publication in peer-reviewed journals as well as presented at national and international conferences and community groups.

Eligibility criteria: Investigational Population (Group 1) - Trans Women Living with HIV

Inclusion Criteria

1. Is a trans woman or person with transfeminine experience (individual assigned male sex at birth who currently identifies as a woman or person with transfeminine experience and is at any stage of medical, social, or legal transition);
2. Is 18 years of age or older;
3. Is living with HIV;
4. Is currently taking combination ART and has been taking these medications for at least 3 months prior to the screening visit;
5. Is willing to adjust their ART dosing to the morning if they are currently taking it at night for at least 28 days before the baseline visit until the completion of the Month 2 visit;
6. Has had an undetectable viral load for at least 3 months on at least two occasions, where most recent (within 12 months including screening) VL\<40 copies/mL and second (within 24 months) VL\<200 copies/mL with no suggestion of relevant ART drug resistance prior to screening;
7. Is willing to switch to or stay on B/F/TAF for the duration of the study (i.e., 6 months);
8. Is currently taking oral estradiol (2 mg or higher) and an anti-androgen (pharmaceutical \[e.g., spironolactone, cyproterone, finasteride, leuprolide, bicalutamide, dutasteride\] and/or surgical \[orchiectomy\] and/or medical \[hypogonadism\]) and has been taking these medications together at the current dose for at least 3 months prior to the screening visit; AND:

   1. Is willing to adjust their oral estradiol dosing to twice a day if they are taking \> 2 mg per day (which is currently recommended as best practice) for at least 28 days before the baseline visit until the completion of the Month 2 visit, with the morning dose set at 2 mg (remaining dose can be taken at night), OR;
   2. If their estradiol dosing is 2 mg per day and they are currently taking their estradiol at night, they must be willing to switch their dosing to the morning for at least 28 days before the baseline visit until the completion of the Month 2 visit;
   3. Is willing to swallow their oral estradiol if they are currently taking it sublingually or crushing it for at least 28 days before the baseline visit and until the completion of the Month 2 visit;
   4. Is willing to keep their anti-androgen (if applicable) medication(s) unchanged until the completion of the Month2 visit;
9. If taking progesterone, is willing to keep the same medication/dose until the completion of the Month 2 visit and must have been taking that dose for at least 3 months prior to the screening visit;
10. Is willing and able to provide full consent for their participation.

Exclusion Criteria

1. Is clinically unable to switch ART to B/F/TAF based on their physician's opinion;
2. Is taking hormonal non-prescription or natural health products in addition to feminizing hormone therapy;
3. Has significant underlying diseases which could worsen due to their participation, or affect their ability to follow the study procedures;
4. Has kidney or liver impairment (ALT \> 5X normal; serum creatinine \[eGFR\] \< 30 mL per minute);
5. Is taking medications known to interact with feminizing hormones, B/F/TAF, or its individual components or has taken such medications within the past 28 days prior to baseline (List of prohibited medications in Appendix B1).
6. Has a known hypersensitivity to bictegravir (BIC), emtricitabine (FTC), tenofovir alafenamide (TAF) or to any ingredient in the formulation.

Comparator Population (Group 2) - Cis Women Living With HIV Inclusion Criteria

1. Is a cis woman (individual assigned female sex at birth who currently identifies as a woman);
2. Is of reproductive age and 18 years of age or older;
3. Is living with HIV;
4. Has a regular period (every 24 - 35 days), or if period is irregular or absent, it is due to the administration of a progesterone only hormone contraceptive (see Appendix B1); or if uterus removed (hysterectomy), ovarie(s) remain functional (FSH level\<27.0 IU/L);
5. Is currently taking combination ART and has been taking these medications for at least 3 months prior to screening;
6. Is willing to adjust their ART dosing to the morning if they are currently taking it at night for at least 28 days before the baseline visit until the completion of the Month 2 visit;
7. Has had an undetectable viral load for at least 3 months on at least two occasions, where most recent (within 12 months including screening) VL\<40 copies/mL and second (within 24 months) VL\<200 copies/mL with no suggestion of relevant ART drug resistance prior to screening;
8. Is willing to switch to or stay on B/F/TAF for the duration of the study (i.e., 6 months);
9. Is willing and able to provide full consent for their participation.

Exclusion Criteria

1. Is clinically unable to switch B/F/TAF based on their physician's opinion;
2. Is pregnant or is planning on getting pregnant for the duration of the study;
3. Has undergone surgery to remove their ovaries (i.e. oophorectomy) or has a condition in which their ovaries produce little or no estrogen (i.e. primary ovarian insufficiency, hypogonadism) or does not have ovaries naturally (i.e. unilateral ovarian absence); total hysterectomy is allowed as long as ovaries are intact and functional;
4. Is taking an estrogen containing or conjugated estrogens hormonal therapies; IUD and progesterone only contraception are allowed (See Appendix B1/2 for list for both prohibited and allowed contraceptives);
5. Has significant underlying diseases which could worsen due to their participation, or affect their ability to follow the study procedures;
6. Has kidney or liver impairment (ALT \> 5X normal; serum creatinine \[eGFR\] \< 30 mL per minute);
7. Has a known hypersensitivity to bictegravir (BIC), emtricitabine (FTC), tenofovir alafenamide (TAF) or to any ingredient in the formulation.
8. Is taking medications known to interact with B/F/TAF, or its individual components or has taken such medications within the past 28 days prior to baseline (List of prohibited medications in Appendix B1/2).

Comparator Population (Group 3) - Trans Women Living Without HIV Inclusion Criteria

1. Is a trans woman or person with transfeminine experience (defined as individual assigned male sex at birth who currently identifies as a woman or person with transfeminine experience irrespective of medical, social, or legal transition);
2. Is 18 years of age or older;
3. Is HIV negative at screening;
4. Is currently taking oral estradiol (2mg or higher) and an anti-androgen (pharmaceutical \[i.e., spironolactone, cyproterone, finasteride, leuprolide, bicalutamide, dutasteride\] and/or surgical \[orchiectomy\] and/or medical \[hypogonadism\]) and has been taking these medications at the current dose for at least 3 months prior to the screening visit, AND:

   1. Is willing to adjust their oral estradiol dosing to twice a day if they are taking \> 2 mg per day (which is currently recommended as best practice) for at least 28 days before the baseline visit until the completion of the Month 2 visit, with the morning dose set at 2 mg (remaining dose can be taken at night) OR;
   2. If their estradiol dosing is 2 mg per day and they are currently taking their estradiol at night, they must be willing to switch their dosing to the morning for at least 28 days before the baseline visit until the completion of the Month 2 visit;
   3. Is willing to swallow their oral estradiol if they are currently taking it sublingually or crushing it for at least 28 days before the baseline visit until the completion of the Month 2 visit;
   4. Is willing to keep their anti-androgen (if applicable) medication(s) unchanged until the completion of the Month2 visit;
5. If taking progesterone, is willing to keep their dose the same until the Month 2 visit and must have been taking that dose for at least 3 months prior to the screening visit;
6. Is willing and able to provide full consent for their participation.

Exclusion Criteria

1. Is taking hormonal non-prescription or natural health products in addition to feminizing hormone therapy;
2. Has taken HIV pre-exposure prophylaxis (PrEP) (i.e, TDF/FTC or TAF/FTC) or HIV post-exposure prophylaxis (PEP) in the prior 28 days from baseline and plans to continue during the study;
3. Has significant underlying diseases which could worsen due to their participation, or affect their ability to follow the study procedures;
4. Has kidney or liver impairment (ALT \> 5X normal; serum creatinine \[eGFR\] \< 30 mL per minute);
5. Is taking medications known to interact with feminizing hormones or has taken such medications within the past 28 days prior to baseline (List of prohibited medications in Appendix B1).

Primary outcomes:
measure: BIC, FTC, and TAF minimum plasma concentrations.
timeFrame: Month 2
measure: BIC, FTC, and TAF maximum plasma concentrations.
timeFrame: Month 2
measure: BIC, FTC, and TAF area under the curve (AUC) plasma concentrations.
timeFrame: Month 2
measure: 2h PBMC and DBS TFV-DP and FTC-TP concentrations.
timeFrame: Month 2
measure: Minimum serum concentrations (Cmin) of estradiol.
timeFrame: Month 2
measure: 4 hour serum concentration (C4h) of estradiol
timeFrame: Month 2
measure: Maximum serum concentrations (Cmax) of estradiol
timeFrame: Month 2
measure: Estradiol serum concentration area under the curve (AUC)
timeFrame: Month 2
Secondary outcomes:
measure: Baseline estradiol pre-dose serum concentration (Cmin) and comparison to month 2
timeFrame: Months 0 & 2
measure: Baseline estradiol C4h serum concentration and comparison to month 2
timeFrame: Months 0 & 2
measure: Baseline total testosterone serum concentration and comparison to month 2
timeFrame: Months 0 & 2
measure: FEM-SQ questionnaire score
timeFrame: Months 0, 2 & 6
measure: Proportion of patient with an undetectable HIV-RNA.
timeFrame: Months 0, 2 & 6
measure: ART adherence using theMedication Adherence Self-Reported Inventory (MASRI)
timeFrame: Months 0, 1, 2 & 6
measure: Frequency of BIC, FTC, and TAF related adverse events
timeFrame: Months 1, 2 & 6
measure: Patient reported outcomes (PROs) using the HIV Symptom Index Distress Module (HSIDM)
timeFrame: Months 0, 1, 2 & 6
measure: Satisfaction with ART Regimens using the HIVTSQ
timeFrame: Months 0, 2 & 6
measure: Participant health status using the SF-36
timeFrame: Months 0, 2 & 6
Other outcomes:
measure: Basic sociodemographic variables
timeFrame: Month 0
measure: Clinical variables
timeFrame: Months 0 & 2
measure: FHT regimens
timeFrame: Month 0
measure: HIV clinical history
timeFrame: Month 0
measure: Menstrual history
timeFrame: Month 0, 2 & 6
Locations:
city: Toronto
country: Canada
facility: Maple Leaf Research
state: Ontario
Study officials:
affiliation: Maple Leaf Research
name: Mona Loutfy, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: