Cytomegalovirus (CMV)
infection is the leading cause of congenital
infection, producing both
sensorineural hearing loss and
mental retardation. We evaluated the in vivo efficacy of an orally bioavailable analog of
cidofovir,
hexadecyloxypropyl-cidofovir (
HDP-CDV), against guinea pig CMV (GPCMV) in a guinea pig model of
congenital CMV infection.
HDP-CDV exhibited
antiviral activity against GPCMV with a 50% effective concentration (EC(50)) of 0.004 μM ± 0.001 μM. To evaluate in vivo efficacy, pregnant Hartley guinea pigs were inoculated with GPCMV during the late second/early third trimester of gestation. Animals were administered 20 mg
HDP-CDV/kg
body weight orally at 24 h postinfection (hpi) and again at 7 days postinfection (dpi) or administered 4 mg/kg
HDP-CDV orally each day for 5 days or 9 days. Virus levels in dam and pup tissues were evaluated following delivery, or levels from dam, placenta, and fetal tissues were evaluated following sacrifice of dams
at 10 dpi. All
HDP-CDV regimens significantly improved pup survival, from 50 to 60% in control animals to 93 to 100% in treated animals (P ≤ 0.019). Treatment with 20 mg/kg
HDP-CDV significantly reduced the viral load in pup spleen (P = 0.017) and liver (P = 0.029). Virus levels in the placenta were significantly reduced
at 10 dpi following daily treatment with 4 mg/kg
HDP-CDV for 5 or 9 days. The 9-day treatment also significantly reduced the viral levels in the dam spleen and liver. Although the 4-mg/kg treatment improved pup survival, virus levels in the fetal tissues were similar to those in control tissues. Taken together,
HDP-CDV shows potential as a well-tolerated
antiviral candidate for treatment of congenital human CMV (HCMV)
infection.