PMID- 34041459
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220423
IS  - 2589-5370 (Electronic)
IS  - 2589-5370 (Linking)
VI  - 36
DP  - 2021 Jun
TI  - Safety and Pharmacokinetics of a Tenofovir Alafenamide Fumarate-Emtricitabine 
      based Oral Antiretroviral Regimen for Prevention of HIV Acquisition in Women: A 
      Randomized Controlled Trial.
PG  - 100893
LID - 10.1016/j.eclinm.2021.100893 [doi]
LID - 100893
AB  - BACKGROUND: 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. METHODS: 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. FINDINGS: 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. PLASMA: 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%). INTERPRETATION: 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.
CI  - (c) 2021 The Author(s).
FAU - Thurman, Andrea R
AU  - Thurman AR
AD  - CONRAD, Eastern Virginia Medical School, Norfolk and Arlington, VA, USA.
FAU - Schwartz, Jill L
AU  - Schwartz JL
AD  - CONRAD, Eastern Virginia Medical School, Norfolk and Arlington, VA, USA.
FAU - Cottrell, Mackenzie L
AU  - Cottrell ML
AD  - University of North Carolina at Chapel Hill, NC, USA.
FAU - Brache, Vivian
AU  - Brache V
AD  - Profamilia, Santo Domingo, DR.
FAU - Chen, Beatrice A
AU  - Chen BA
AD  - University of Pittsburgh/Magee-Womens Research Institute, Pittsburgh PA, USA.
FAU - Cochon, Leila
AU  - Cochon L
AD  - Profamilia, Santo Domingo, DR.
FAU - Ju, Susan
AU  - Ju S
AD  - CONRAD, Eastern Virginia Medical School, Norfolk and Arlington, VA, USA.
FAU - McGowan, Ian
AU  - McGowan I
AD  - University of Pittsburgh/Magee-Womens Research Institute, Pittsburgh PA, USA.
FAU - Rooney, James F
AU  - Rooney JF
AD  - Gilead Sciences, Foster City, CA, USA.
FAU - McCallister, Scott
AU  - McCallister S
AD  - Gilead Sciences, Foster City, CA, USA.
FAU - Doncel, Gustavo F
AU  - Doncel GF
AD  - CONRAD, Eastern Virginia Medical School, Norfolk and Arlington, VA, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT02904369
PT  - Journal Article
DEP - 20210523
PL  - England
TA  - EClinicalMedicine
JT  - EClinicalMedicine
JID - 101733727
PMC - PMC8144741
COIS- Dr Schwartz received funding from USAID to support this study. Dr. McCallister 
      and Dr. Rooney are shareholders in Gilead Sciences. Dr. McCallister was a Gilead 
      employee at the time of the study and Dr. Rooney is currently a Gilead Sciences 
      employee. Dr. Chen reports grants from Medicines360, grants from Sebela, personal 
      fees from Merck, outside the submitted work. Dr. McGowan reports grants from 
      CONRAD, during the conduct of the study; other from Orion Biotechnology, outside 
      the submitted work. All the other authors report no conflicts.
EDAT- 2021/05/28 06:00
MHDA- 2021/05/28 06:01
PMCR- 2021/05/23
CRDT- 2021/05/27 06:54
PHST- 2021/03/04 00:00 [received]
PHST- 2021/04/14 00:00 [revised]
PHST- 2021/04/23 00:00 [accepted]
PHST- 2021/05/27 06:54 [entrez]
PHST- 2021/05/28 06:00 [pubmed]
PHST- 2021/05/28 06:01 [medline]
PHST- 2021/05/23 00:00 [pmc-release]
AID - S2589-5370(21)00173-5 [pii]
AID - 100893 [pii]
AID - 10.1016/j.eclinm.2021.100893 [doi]
PST - epublish
SO  - EClinicalMedicine. 2021 May 23;36:100893. doi: 10.1016/j.eclinm.2021.100893. 
      eCollection 2021 Jun.