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Safety and Pharmacokinetics of a Tenofovir Alafenamide Fumarate-Emtricitabine based Oral Antiretroviral Regimen for Prevention of HIV Acquisition in Women: A Randomized Controlled Trial
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May 21, 2021 - Andrea R. Thurman, MD1,*, Jill L. Schwartz, MD1, Mackenzie L. Cottrell, PharmD2, Vivian Brache, Lic3, Beatrice A. Chen, MD, MPH4, Leila Cochon, Lic3, Susan Ju, BA1, Ian McGowan, MD PhD4, James F. Rooney, MD5, Scott McCallister, MD5, Gustavo F. Doncel, MD PhD1
1 CONRAD, Eastern Virginia Medical School, Norfolk and Arlington, VA, USA
2 University of North Carolina at Chapel Hill, NC, USA
3 Profamilia, Santo Domingo, DR
4 University of Pittsburgh/Magee-Womens Research Institute, Pittsburgh PA, USA
5 Gilead Sciences, Foster City, CA, USA

Daily oral emtricitabine (FTC, F)/tenofovir disoproxil fumarate (TDF) combination is approved for HIV pre-exposure prophylaxis (PrEP) in men and women. Tenofovir alafenamide fumarate (TAF) is a newer, more potent prodrug of tenofovir (TFV), and in combination with FTC, has recently been approved for prevention of HIV through rectal transmission.
This Phase I, prospective, interventional, randomized study was conducted in three clinical sites: PROFAMILIA, Santo Domingo, Dominican Republic; University of Pittsburgh and Eastern Virginia Medical School. We assessed the multi-compartmental pharmacokinetics (primary outcome) and safety (secondary outcome) among HIV uninfected women randomized to F/TDF (200mg/300mg) or F/TAF (200mg/25mg; F/TAF25) (n=24) in a single dose phase (SDP) and F/TDF, F/TAF (200mg/10mg; F/TAF10), or F/TAF25 (n=75) in a multiple dose (14 daily doses) phase (MDP). We described PK parameters in plasma, peripheral blood mononuclear cells (PBMCs), and cervicovaginal (CV) and rectal fluids and tissues. ClinicalTrials.gov #NCT02904369, completed.
Recruitment for the study began on 5 October 2016. The first participant was enrolled on 6 October 2016 and the last participant completed the study 21 November 2017.
TFV concentrations area under curve (AUC) were ∼20 fold lower following F/TAF versus F/TDF. TFV-diphosphate (TFV-DP) AUC concentrations in PBMCs were 7-fold higher with F/TAF25 versus F/TDF. Median TFV-DP concentrations in vaginal tissue (4hours post last dose) were approximately 6-fold higher with F/TAF25 versus F/TDF. TFV and TFV-DP were lower with F/TAF versus F/TDF in rectal tissue. Concentrations of FTC and FTC-triphosphate (FTC-TP) were similar across matrices and treatment arms. Gastrointestinal adverse events (AEs) occurred more frequently in F/TDF users (44.0%) than in either F/TAF group (11.5 and 12.0%).
F/TAF was safe and well-tolerated. TFV-DP concentrations were higher in PBMCs and similar or higher (4h post dose) in female genital tract tissues for F/TAF versus F/TDF. High FTC and FTC-TP concentrations in all compartments support the potential of F/TAF as a new PrEP combination for women.
United States Agency for International Development (USAID)/the President's Emergency Plan for AIDS Relief (PEPFAR) through Cooperative Agreement AID-OAA-A-14-00011 with CONRAD/Eastern Virginia Medical School. This publication resulted in part from research supported by the University of North Carolina at Chapel Hill Center for AIDS Research (CFAR).
Oral pre-exposure prophylaxis (PrEP) is recommended as an additional prevention option for HIV uninfected individuals at substantial risk for HIV acquisition.[[1]] Globally, about 40% of new HIV infections are among cis-women (hereafter women), while in sub-Saharan Africa, women account for 59% of new HIV infections among adults.[[2]] HIV disproportionately affects adolescent girls and young women (AGYW) largely because of vulnerabilities created by unequal cultural, social and economic status.[[2]] Although daily oral PrEP has been shown to be safe and effective [3,4,5] in men and women, there are substantial barriers to use, including gastrointestinal (GI) side effects, burdensome daily pill regimen, large pill size, stigma associated with medication use, and lack of partner or family support, which may even result in violence.[[6]] These challenges, among others, have made it difficult for AGYW to uptake and adhere to the limited, approved existing HIV prevention methods.[[7],[8]] Of note, the United States (US) Centers for Disease Control and Prevention (CDC) recommends 20 days of daily oral PrEP use to ensure full protection from HIV exposure for women whose primary exposure is vaginal intercourse.[[9]] After this initial dosing period, pharmacokinetic (PK)/pharmacodynamics (PD) modeling data support that women likely need to take 6 - 7 doses of emtricitabine (F, FTC) combined with tenofovir disoproxil fumarate (TDF) per week in order to achieve optimal mucosal protection against cervicovaginal (CV) acquisition of HIV.[[10]] Safer and more potent oral PrEP regimens that use smaller pill size, lower doses, have fewer side effects, and may be more forgiving, i.e. allowing for missed doses, may help support uptake and adherence, particularly in AGYW.
TDF, in combination with FTC (F/TDF) is approved as Truvada® (Gilead Sciences, Foster City, CA) for both treatment and prevention of HIV acquisition.[3,4,5] Tenofovir alafenamide fumarate (TAF) is another antiretroviral (ARV) prodrug of tenofovir (TFV) with improved safety and PK properties over TDF.[11,12,13,14] TAF 25 mg, in combination with FTC 200 mg (F/TAF 25), has also been approved by the US Food and Drug Administration (FDA) as Descovy® (Gilead Sciences, Foster City, CA) for the treatment of HIV infection and for HIV prevention in individuals who are at-risk for sexually acquired HIV other than through vaginal intercourse.[[15]] Unlike F/TDF, there is no current approval of F/TAF 25 for the prevention of vaginal acquisition of HIV-1 among healthy women. TAF is more potent than TDF,[[16]] which results in significantly higher active metabolite concentrations in lymphoid cells and tissues, and demonstrates higher antiviral activity in target cells with less long-term toxicity in tissues, particularly kidney and bone.[17,18,19,2021] Therefore, an oral PrEP regimen based on TAF may be safer and potentially more forgiving of imperfect adherence for HIV prevention.[[15],[22]] The active metabolites of TFV and FTC, TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP), compete with endogenous deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate (dCTP) for incorporation into the proviral DNA of HIV resulting in strand termination and determining the activity of the two drugs.[[23],[24]]
The current study evaluated the short term safety and systemic and genital tract PK of two oral forms of daily F/TAF based regimens compared to F/TDF in women for up to 2 weeks of dosing. Two doses of F/TAF [F/TAF 200 mg/10mg (F/TAF10) and F/TAF 200 mg/25mg (F/TAF25)] were compared with the current dose of F/TDF (200mg/300 mg). Our hypothesis was that F/TAF would result in lower TFV systemic exposure and higher systemic and local intracellular and mucosal levels of the active metabolite (TFV-DP), thus maintaining or enhancing antiviral efficacy, while also improving the safety profile.

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