title: UC781 microbicide gel retains anti-HIV activity in cervicovaginal lavage fluids collected following twice-daily vaginal application.
abstract: The potent nonnucleoside reverse transcriptase inhibitor UC781 has been safety tested as a vaginal microbicide gel formulation for prevention of HIV-1 sexual transmission. To investigate whether UC781 retained anti-infective activity following exposure to the female genital tract, we conducted an ex vivo analysis of the UC781 levels and antiviral activity in cervicovaginal lavage (CVL) fluids from 25 Thai women enrolled in a 14-day safety trial of twice-daily vaginal application of two concentrations of the UC781 microbicide gel. CVL samples were collected from women in the 0.1% (n = 5), 0.25% (n = 15), and placebo (n = 5) gel arms following the first application of gel (T(15 min)) and 8 to 24 h after the final application (T(8-24 h)) and separated into cell-free (CVL-s) and pelletable (CVL-p) fractions. As UC781 is highly hydrophobic, there were significantly higher levels of UC781 in the CVL-p samples than in the CVL-s samples for the UC781 gel arms. In T(8-24 h) CVL-p samples, 2/5 and 13/15 samples collected from the 0.1% and 0.25% UC781 gel arms, respectively, efficiently blocked infection with ≥ 4 log(10) 50% tissue culture infective dose (TCID(50)) of a CCR5-tropic CRF01_AE HIV-1 virus stock. Independent of the arm, the 11 CVL-p samples with UC781 levels of ≥ 5 μg/CVL sample reduced infectious HIV by ≥ 4 log(10) TCID(50). Our results suggest that the levels and anti-infective activities of UC781 gel formulations are likely to be associated with a cellular or pelletable component in CVL samples. Therefore, cellular and pelletable fractions should be assayed for drug levels and anti-infective activity in preclinical studies of candidate microbicides.
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. hyw9@cdc.gov
authors.forename: Richard E
authors.initials: RE
authors.lastname: Haaland
authors.forename: Tammy
authors.initials: T
authors.lastname: Evans-Strickfaden
authors.forename: Angela
authors.initials: A
authors.lastname: Holder
authors.forename: Chou-Pong
authors.initials: CP
authors.lastname: Pau
authors.forename: Janet M
authors.initials: JM
authors.lastname: McNicholl
authors.forename: Supraporn
authors.initials: S
authors.lastname: Chaikummao
authors.forename: Wannee
authors.initials: W
authors.lastname: Chonwattana
authors.forename: Clyde E
authors.initials: CE
authors.lastname: Hart
mesh_terms: D000293:Adolescent; D000328:Adult; D000813:Anilides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001826:Body Fluids / Q000378:metabolism*; D005260:Female; D005663:Furans / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D008875:Middle Aged; D013854:Thioamides; D014621:Vagina / Q000378:metabolism*; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000813:Anilides; D000890:Anti-Infective Agents; D000998:Antiviral Agents; D005663:Furans; D013854:Thioamides; D014622:Vaginal Creams, Foams, and Jellies; C100668:UC-781