title: Vaginally delivered tenofovir disoproxil fumarate provides greater protection than tenofovir against genital herpes in a murine model of efficacy and safety.
abstract: Increased susceptibility to genital herpes in medroxyprogesterone-treated mice may provide a surrogate of increased HIV risk and a preclinical biomarker of topical preexposure prophylaxis safety. We evaluated tenofovir disoproxil fumarate (TDF) in this murine model because an intravaginal ring eluting this drug is being advanced into clinical trials. To avoid the complications of surgically inserting a ring, hydroxyethylcellulose (HEC)-stable formulations of TDF were prepared. One week of twice-daily 0.3% TDF gel was well tolerated and did not result in any increase in HSV-2 susceptibility but protected mice from herpes simplex virus 2 (HSV-2) disease compared to mice treated with the HEC placebo gel. No significant increase in inflammatory cytokines or chemokines in vaginal washes or change in cytokine, chemokine, or mitochondrial gene expression in RNA extracted from genital tract tissue was detected. To further evaluate efficacy, mice were treated with gel once daily beginning 12 h prior to high-dose HSV-2 challenge or 2 h before and after viral challenge (BAT24 dosing). The 0.3% TDF gel provided significant protection compared to the HEC gel following either daily (in 9/10 versus 1/10 mice, P < 0.01) or BAT24 (in 14/20 versus 4/20 mice, P < 0.01) dosing. In contrast, 1% tenofovir (TFV) gel protected only 4/10 mice treated with either regimen. Significant protection was also observed with daily 0.03% TDF compared to HEC. Protection was associated with greater murine cellular permeability of radiolabeled TDF than of TFV. Together, these findings suggest that TDF is safe, may provide substantially greater protection against HSV than TFV, and support the further clinical development of a TDF ring.
authors: Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors: Briana
authors: B
authors: Nixon
authors: Thomas
authors: T
authors: Jandl
authors: Ryan S
authors: RS
authors: Teller
authors: Ekaterina
authors: E
authors: Taneva
authors: Yanhua
authors: Y
authors: Wang
authors: Umadevi
authors: U
authors: Nagaraja
authors: Patrick F
authors: PF
authors: Kiser
authors: Betsy C
authors: BC
authors: Herold
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000282:Administration, Intravaginal; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D003274:Contraceptive Devices, Female; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D006558:Herpes Genitalis / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000821:virology; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D063065:Organophosphonates / Q000008:administration & dosage*; D016019:Survival Analysis; D000068698:Tenofovir; D014621:Vagina / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D014622:Vaginal Creams, Foams, and Jellies
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D014622:Vaginal Creams, Foams, and Jellies; D000068698:Tenofovir; D000225:Adenine