Open AccessResults of a phase 1, randomized, placebo-controlled first-in-human trial of griffithsin formulated in a carrageenan vaginal gel
Author(s) -
Natalia Teleshova,
Marla J. Keller,
José A. Fernández Romero,
Barbara Friedland,
G. W. Creasy,
Marlena Plagianos,
Laurie Ray,
Patrick Barnable,
Larisa Kizima,
Aixa Rodríguez,
Nadjet Cornejal,
Claudia Melo,
G. Rodriguez,
Sampurna Mukhopadhyay,
Giulia Calenda,
Shweta U. Sinkar,
Thierry Bonnaire,
Asa Wesenberg,
Shimin Zhang,
Kyle Kleinbeck,
Kenneth E. Palmer,
Mohcine Alami,
Barry R. O’Keefe,
Patrick M. Gillevet,
Hong Hur,
Yupu Liang,
Gabriela Santone,
Rai. Fichorova,
Tamara Kalir,
Thomas M. Zydowsky
Publication year - 2022
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0261775
Subject(s) - medicine , placebo , proinflammatory cytokine , adverse effect , pharmacokinetics , pharmacodynamics , microbicide , pharmacology , immunology , inflammation , human immunodeficiency virus (hiv) , pathology , alternative medicine
HIV pre-exposure prophylaxis (PrEP) is dominated by clinical therapeutic antiretroviral (ARV) drugs. Griffithsin (GRFT) is a non-ARV lectin with potent anti-HIV activity. GRFT’s preclinical safety, lack of systemic absorption after vaginal administration in animal studies, and lack of cross-resistance with existing ARV drugs prompted its development for topical HIV PrEP. We investigated safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of PC-6500 (0.1% GRFT in a carrageenan (CG) gel) in healthy women after vaginal administration. This randomized, placebo-controlled, parallel group, double-blind first-in-human phase 1 study enrolled healthy, HIV-negative, non-pregnant women aged 24–45 years. In the open label period, all participants (n = 7) received single dose of PC-6500. In the randomized period, participants (n = 13) were instructed to self-administer 14 doses of PC-6500 or its matching CG placebo (PC-535) once daily for 14 days. The primary outcomes were safety and PK after single dose, and then after 14 days of dosing. Exploratory outcomes were GRFT concentrations in cervicovaginal fluids, PD, inflammatory mediators and gene expression in ectocervical biopsies. This trial is registered with ClinicalTrials.gov, number NCT02875119. No significant adverse events were recorded in clinical or laboratory results or histopathological evaluations in cervicovaginal mucosa, and no anti-drug (GRFT) antibodies were detected in serum. No cervicovaginal proinflammatory responses and no changes in the ectocervical transcriptome were evident. Decreased levels of proinflammatory chemokines (CXCL8, CCL5 and CCL20) were observed. GRFT was not detected in plasma. GRFT and GRFT/CG in cervicovaginal lavage samples inhibited HIV and HPV, respectively, in vitro in a dose-dependent fashion. These data suggest GRFT formulated in a CG gel is a safe and promising on-demand multipurpose prevention technology product that warrants further investigation.