Study of Truvada for HIV Pre Exposure Prophylaxis Using Daily Directly Observed Therapy to Look at Potential Interactions Between Truvada and Hormone Therapy
Condition: HIV Prevention; Transgender Health
Study type: Interventional
Phase: Phase 4

Summary: 
      Truvada (Emtricitabine or FTC and tenofovir disoproxil fumarate or TDF) has been approved for
      HIV prevention since 2012. Drug concentrations after receipt of oral Truvada for HIV Pre
      Exposure Prophylaxis (or PrEP) appeared to be lower in transgender women compared to Men who
      Have Sex with Men (MSM) in the iPrEx study, the landmark study of PrEP for HIV prevention.
      Concentrations were especially low among transgender women (TGW) reporting use of feminizing
      hormones. Reasons for the lower drug concentrations may be behavioral or biomedical, or a
      combination of both. While there are no systemic drug-drug interactions between TDF and oral
      contraception, there are known interactions involving these classes of medications with drug
      transporters that could affect drug concentrations in target tissues. Drug-drug interactions
      with natural estrogens and anti-androgenic agents used for gender affirming hormone therapy
      among transgender women have not been studied, neither have interactions between
      emtricitabine and female hormones. Concerns about the impact of PrEP on gender affirming
      hormone therapy is the main barrier for uptake of PrEP among transgender women. In addition,
      very little is known about TDF/FTC pharmacokinetics in transgender men using testosterone
      hormonal therapy. Drug-drug interactions with masculinizing hormones have never been properly
      investigated as trans gender men have not been formally involved in PrEP clinical trials or
      demonstrations projects.This small study will assess pharmacokinetic drug-drug interactions
      between tenofovir disoproxil fumarate/emtricitabine and cross-sex hormone therapy. The
      I-BrEATHe study is a substudy of the Triumph study, a culturally-relevant community-led PrEP
      demonstration project in transgender communities. The I- BrEATHe pharmacokinetic substudy
      will provide Truvada daily using directly observed therapy in 24 transgender women and 24
      transgender men over a one month period, and will measure drug and hormone therapy levels in
      blood collected from participants.
    

Detailed description: 
      BACKGROUND The TRIUMPH study, or trans Research-Informed communities United in the
      Mobilization for the Prevention of HIV, is a new study responding to a pressing need for
      culturally-relevant community-led pre-exposure prophylaxis (PrEP) programs for transgender
      communities, especially for trans women of color who are most affected by the HIV epidemic.
      The TRIUMPH study will strive to identify the most effective PrEP service provision
      strategies which take into account the particular facilitators and barriers that transgender
      communities encounter in the health care system. To date, transgender women included in HIV
      prevention studies have been lumped into the larger aggregate of Men who have sex with Men
      (MSM) without taking into account the unique sociocultural context of transgender women. The
      TRIUMPH study will also include transgender men and other members of various transgender
      communities. The TRIUMPH project's goal is to identify the best methods to deliver PrEP
      safely and effectively to transgender communities while achieving the highest levels of
      adherence possible.

      PrEP is the newest and most promising biomedical HIV prevention intervention yet developed
      and tested. The first clinical trial of PrEP ('iPrEx' or iniciativa Profilaxis
      Pre-Exposición) included MSM and transgender women who were at higher risk for HIV infection,
      and found that daily oral Truvada PrEP reduced the risk of HIV acquisition by 44% on an
      intention to treat basis. However, a sub-analysis of the iPrEx data conducted by Deutsch et
      al , found zero effectiveness on an intention to treat basis among the small subgroup of
      transwomen in the study. Further analyses revealed that the subgroup of trans women in iPrEx
      who were using hormones were less likely to have protective drug levels than those trans
      women not on hormones (OR 0.14, p<0.001). It is unclear if this difference is behavioral
      (less drug uptake) or biomedical (drug-drug interactions) in nature, or due to some
      combination of these factors, given the lack of pharmacokinetic (PK) studies testing for
      interactions between cross-sex hormone therapy (HT) and TDF/FTC, the active ingredients of
      Truvada. While there are studies of systemic drug-drug interactions between oral
      contraceptives and TDF, no such studies have been done with FTC, and no studies have been
      done with gender affirming HT, which differs from hormonal contraception in several respects.
      Drug-drug interactions with bioidentical 17-beta estradiol used for gender affirming hormone
      therapy among transgender women have not been studied.

      The Interactions BEtween Antiretrovirals And Transgender Hormones, or I-BrEATHe study, is a
      sub study of the TRIUMPH study. I-BrEATHe will address one of the secondary aims of the
      TRIUMPH study which is to assess the pharmacokinetic drug-drug interactions between cross-sex
      HT and daily oral FTC/TDF.

      Given that there are no PrEP studies to date that have specifically enrolled trans identified
      men, or have looked at the interactions between masculinizing HT and FTC/TDF, I-BrEATHe will
      enroll both transgender women and men. Transgender men report sexual rapport without condoms
      both vaginally and anally (range 26-60%), exhibit patterns of Sexually Transmitted Infections
      (STI) transmission and unwanted pregnancies. Transgender men also report use of sex for
      gender affirmation. Small convenience samples show that HIV prevalence is between 2- 5%. To
      date, there are no programs or PrEP recommendations specific for transgender men.

      Overview of Previous Clinical Studies of PrEP There have been a large number of trials
      conducted with Truvada PrEP, including several demonstration projects. While there is no
      evidence to suggest that TDF/FTC interacts with commonly used feminizing or masculinizing
      hormone regimens, and evidence from studies of Antiretroviral (ARV) interactions with
      hormonal contraceptives have been reassuring, no direct study of these interactions has been
      conducted to date.

      Our team led the only trans-specific sub analysis to date of the iPrEx randomized controlled
      trial (RCT) data as well as the open label extension (OLE) study, which included periodic
      dried blood spot (DBS) drug level monitoring. In iPrEx, gender identity data was not
      collected using current best practices ("two-step" method), making the identification of
      transgender participants in this multinational, multicultural and multilingual trial
      difficult. As all iPrEx participants had been assigned male sex at birth, a transgender
      subgroup of 339/2499 participants (14% of overall sample) was constructed comprised of the 29
      (1%) who identified as women, 296 (12%) who identified as "trans", and 14 (1%) who reported
      use of feminizing hormones. None had undergone gender affirming genital surgery. Compared
      with MSM, transgender women more frequently reported transactional sex, receptive anal
      intercourse without a condom, or more than 5 partners in the past 3 months. Excluding those
      with a male identity who also used feminizing hormones, trans- and woman-identified
      participants were less likely to have TDF levels detected on random testing in the RCT
      (OR=0.39, 95% CI = 0.16 to 0.96, p=0.04). While there was no effectiveness of PrEP for
      transgender women on an intention-to-treat basis, none of the transgender participants who
      seroconverted had detectible drug levels at the time of HIV diagnosis. In comparison to MSM
      in the OLE, transgender participants had less time with protective drug concentrations (17%
      vs 35%, p<0.001) and were less likely to have concentrations indicating > 3 tablets/week (OR
      0.71, 95% CI 0.49 to 1.03, p=0.07). Of the two transgender women who seroconverted during the
      OLE, both had drug levels below 350 fmol/punch in DBS, the level associated use of 2 tablets
      per week at the time of seroconversion. The lower concentrations were more likely if the
      transgender women used feminizing hormones.

      Of the 7 clinical trials of Truvada PrEP for HIV prevention conducted to date, iPrEx is the
      only one with confirmed enrollment of trans women. No clinical studies or demonstration
      projects were conducted with transgender men.

      STUDY RATIONALE The fact that concentrations of FTC/TDF were especially low among transgender
      women reporting use of feminizing hormones in the iPrEx study, which may reflect less PrEP
      use or a drug-drug interaction, is of high interest given that concerns about the impact of
      PrEP on gender affirming hormone therapy is the main barrier for uptake of PrEP among
      transgender women. While transgender men as a group have also been shown to be at elevated
      risk for HIV infection, no information about PrEP use and drug levels is available for
      transgender men since they have never been formally included in PrEP research. Therefore,
      there are no data on the potential effects of testosterone on FTC/TDF drug concentrations.
      FTC/TDF drug concentrations have emerged as strong correlates of protection in PrEP trials,
      accounting for the majority of the variation in PrEP benefits across trials and across
      individual participants in trials. For example, while oral FTC/TDF PrEP had 44% efficacy on
      an intention to treat basis in iPrEx, the protective effect was more than 90% among those
      with detectable drug and negligible among those with no detectable drug in blood.

      The I-BrEATHe pharmacokinetic study of PrEP metabolites concentrations in association with
      feminizing and masculinizing hormones using directly observed therapy (DOT) will allow to
      establish whether interactions exist between these drugs. I-BrEATHe also provides an
      opportunity to include transgender men in PrEP research. Though transgender men are likely to
      be at lower risk for HIV acquisition than transgender women, the lack of available data
      regarding use of PrEP in transgender men must be remediated. I-BrEATHe will recruit equal
      numbers of transgender women who are using estradiol plus spironolactone (the most common HT
      regimen) and transgender men who are using testosterone. The primary aim will be to measure
      the intracellular active metabolites of TDF/FTC, tenofovir diphosphate (TFV-DP) and
      emtricitabine triphosphate (FTC-TP), levels in DBS collected after 1, 2, 3, and 4 weeks of
      video-observed Truvada for PrEP daily dosing, and comparing drug levels in the two groups
      receiving HT to previously acquired DBS drug levels data in MSM.

      Risk / Benefit Assessment Oral Truvada for PrEP has been FDA approved since 2012. At this
      time, there is plentiful evidence to support the use of daily oral FTC/TDF in
      HIV-1-uninfected heterosexual biological men and women, and men who have sex with men for HIV
      prevention. The toxicity and tolerability of daily oral FTC/TDF in HIV-uninfected individuals
      have been established. Side effects that may arise in the first weeks of PrEP use -- nausea,
      abdominal cramping, vomiting, dizziness, headache, and fatigue usually go away without
      treatment interruption (see Truvada Prescribing information for more details). Known
      potential risks can be effectively managed by experienced PrEP providers. Participants
      enrolled in this study will be provided Truvada for PrEP within the confines of an
      established PrEP clinic, and will benefit from the expertise of trained staff. Individuals
      who may be susceptible to the possible nephrotoxic effect of FTC/TDF as determined by the
      measure of creatinine clearance (see exclusion criteria) will not be enrolled in the study.
      Long term effect of Truvada use (such as bone density loss or kidney dysfunction) are
      unlikely to occur over the course of this short study in otherwise healthy participants.
      Participants will be seen weekly by a clinician, and any adverse event immediately addressed,
      in addition participants will be interacting daily with study staff via phone, providing an
      opportunity to address any questions or concerns. Moreover, the daily interactions with study
      staff will provide support for adherence. Concerns about risks of combining gender-affirming
      hormone therapy and PrEP will be alleviated by trained providers with expertise in the
      management of both antiretroviral and hormone therapy. Guidelines for these matters will be
      provided by the University of California San Francisco Center of Excellence for Transgender
      Health.

      STUDY OBJECTIVES Primary Objective To assess pharmacokinetics for daily oral FTC/TDF in
      transgender women and transgender men, and to determine if FTC/TDF drug concentrations are
      lower among transgender women who are using hormone therapy and in transgender men who use
      testosterone compared to historical controls in non-transgender MSM.

      Secondary Objectives To determine if daily oral FTC/TDF is associated with comparable rates
      of adverse events (AEs) in transgender women and in transgender men compared to historical
      controls in non-transgender MSM.

      STUDY DESIGN Study Overview This is a single center pharmacokinetic study of daily oral
      Truvada at the following FDA approved dose of one tablet containing 200 mg of emtricitabine
      (FTC) and 300 mg of tenofovir disoproxil fumarate (TDF) for PrEP using daily directly
      observed therapy (DOT).

      The study will include 48 participants will be divided into two groups: one group will
      include 24 participants who currently describe their gender identity as "woman" or
      "transgender women", or other transfeminine spectrum identity, and the second group will
      enroll 24 participants who identify as "man" or "transgender man", or other transmasculine
      spectrum identity.

      Each participant will be taking a single daily dose of study drug in DOT performed either via
      video calling, or at study visit, for a total study duration of 28 to 30 days (4 weeks).

      Laboratory evaluations for HT (including testosterone, or estradiol) drug levels will be
      performed at enrolment, and after 4 weeks on study drug. Study drug levels will be monitored
      weekly in DBS while participants are on study.

      Screening data will be reviewed to determine participant eligibility. Participants who meet
      all inclusion criteria and none of the exclusion criteria will be entered into the study.

      The treatment regimen that will be used:

      Truvada at the following FDA approved dose of one tablet containing 200 mg of emtricitabine
      and 300 mg of tenofovir disoproxil fumarate

      Total duration of participant participation will be up to 4 weeks, plus the 28 days of
      screening window period between screening visit and on study daily observed therapy. Total
      duration of the study is expected to be 9 -10 months.

      Pharmacogenetic testing Pharmacogenetics (PGx) studies the variability in drug response due
      to hereditary factors in populations. There is increasing evidence that individual's genetic
      background may impact the pharmacokinetics (absorption, distribution, metabolism and
      elimination) of drugs. The goal of the PGx analyses is to investigate a relationship between
      genetic factors and PK measures in I-BrEATHe, for example if there is potential unexpected or
      unexplained variation in drug levels. Blood samples collected for drug levels on DBS may be
      used for DNA extraction and PGx assessments. Participants will be specifically asked if they
      wish to participate in the genetic testing in the informed consent form.
    

Intervention name(s): 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate
Intervention type(s): Drug
Intervention description(s): All study participants received daily observed therapy with FTC/TDF.
Other intervention name(s): Truvada
Intervention MeSH terms: Tenofovir; Emtricitabine
Intervention model: Single Group Assignment
Intervention model description: All participants will receive Truvada for study duration and will take pills using daily observed therapy.
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Pre Exposure Prophylaxis; HIV prevention; Emtricitabine, Tenofovir Disoproxil Fumarate; transgender health; transgender persons; drug combination; androgens; estrogens; drug combinations; transmen; non binary; Truvada; daily observed therapy