Results of a phase 1, randomized, placebo-controlled first-in-human trial of griffithsin formulated in a carrageenan vaginal gel.

Autor: Teleshova N; Center for Biomedical Research, Population Council, New York, New York, United States of America., Keller MJ; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America., Fernández Romero JA; Center for Biomedical Research, Population Council, New York, New York, United States of America.; Science Department, Borough of Manhattan Community College, New York, New York, United States of America., Friedland BA; Center for Biomedical Research, Population Council, New York, New York, United States of America., Creasy GW; Center for Biomedical Research, Population Council, New York, New York, United States of America., Plagianos MG; Center for Biomedical Research, Population Council, New York, New York, United States of America., Ray L; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America., Barnable P; Center for Biomedical Research, Population Council, New York, New York, United States of America., Kizima L; Center for Biomedical Research, Population Council, New York, New York, United States of America., Rodriguez A; Center for Biomedical Research, Population Council, New York, New York, United States of America., Cornejal N; Science Department, Borough of Manhattan Community College, New York, New York, United States of America., Melo C; Science Department, Borough of Manhattan Community College, New York, New York, United States of America., Cruz Rodriguez G; Science Department, Borough of Manhattan Community College, New York, New York, United States of America., Mukhopadhyay S; Center for Biomedical Research, Population Council, New York, New York, United States of America., Calenda G; Center for Biomedical Research, Population Council, New York, New York, United States of America., Sinkar SU; Center for Biomedical Research, Population Council, New York, New York, United States of America., Bonnaire T; Center for Biomedical Research, Population Council, New York, New York, United States of America., Wesenberg A; Center for Biomedical Research, Population Council, New York, New York, United States of America., Zhang S; Center for Biomedical Research, Population Council, New York, New York, United States of America., Kleinbeck K; Center for Biomedical Research, Population Council, New York, New York, United States of America., Palmer K; University of Louisville, Louisville, Kentucky, United States of America., Alami M; Center for Biomedical Research, Population Council, New York, New York, United States of America., O'Keefe BR; Division of Cancer Treatment and Diagnosis, Molecular Targets Program, Center for Cancer Research and Natural Products Branch, Developmental Therapeutics Program, National Cancer Institute, Frederick, Maryland, United States of America., Gillevet P; George Mason University, Manassas, Virginia, United States of America., Hur H; Rockefeller University, New York, New York, United States of America., Liang Y; Rockefeller University, New York, New York, United States of America., Santone G; Harvard Medical School, Boston, Massachusetts, United States of America., Fichorova RN; Harvard Medical School, Boston, Massachusetts, United States of America., Kalir T; Icahn School of Medicine at Mount Sinai, New York, New York, United States of America., Zydowsky TM; Center for Biomedical Research, Population Council, New York, New York, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2022 Jan 20; Vol. 17 (1), pp. e0261775. Date of Electronic Publication: 2022 Jan 20 (Print Publication: 2022).
DOI: 10.1371/journal.pone.0261775
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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