title: Cidofovir and brincidofovir reduce the pathology caused by systemic infection with human type 5 adenovirus in immunosuppressed Syrian hamsters, while ribavirin is largely ineffective in this model.
abstract: There are no drugs approved specifically to treat disseminated adenovirus (Ad) infections in humans. Cidofovir is active against Ad in cell culture, and it is used frequently in the clinic with disseminated infection in pediatric transplant patients; however, controlled clinical studies have not been conducted to prove the anti-Ad efficacy of cidofovir. Brincidofovir, a lipid-linked derivative of cidofovir, which has strong activity against Ad in cell culture and in animal models, is a promising new drug currently in clinical trials. Ribavirin, which has modest activity against some Ad types in cell culture, has been used in the clinic against disseminated Ad, but the efficacy of ribavirin is unknown. In the current study, we have examined the activity of cidofovir, brincidofovir, and ribavirin against disseminated Ad5 infection in the immunosuppressed Syrian hamster model. Hamsters are immunosuppressed by treatment with cyclophosphamide, then infected intravenously with Ad5, leading to disseminated Ad5 infection, especially in the liver. We found that cidofovir and brincidofovir have excellent activity against Ad5 pathology and replication in the liver, even when administered therapeutically starting at 3 days post-challenge with Ad5. Ribavirin did not have anti-Ad5 activity in our model. Our data support the use of cidofovir and brincidofovir in humans for the treatment of disseminated Ad infections in humans.
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Tollefson
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Spencer
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA.
authors.forename: Baoling
authors.initials: B
authors.lastname: Ying
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA.
authors.forename: R Mark L
authors.initials: RM
authors.lastname: Buller
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA.
authors.forename: William S M
authors.initials: WS
authors.lastname: Wold
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA. Electronic address: toth@slu.edu.
authors.forename: Karoly
authors.initials: K
authors.lastname: Toth
mesh_terms: D000257:Adenoviridae Infections / Q000188:drug therapy* / Q000473:pathology* / Q000821:virology; D000260:Adenoviruses, Human / Q000254:growth & development*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001835:Body Weight; D002460:Cell Line; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008099:Liver / Q000473:pathology / Q000821:virology; D008647:Mesocricetus; D063065:Organophosphonates / Q000627:therapeutic use*; D012254:Ribavirin / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D063065:Organophosphonates; D012254:Ribavirin; C525733:brincidofovir; D003596:Cytosine; D000410:Alanine Transaminase; D000077404:Cidofovir
keywords: Adenovirus; Antiviral; Brincidofovir; Cidofovir; Hamster; Ribavirin