Evaluation of Cidofovir (HPMPC, GS-504) against adenovirus type 5 infection in vitro and in a New Zealand rabbit ocular model

Purpose. To evaluate Cidofovir in vitro and to determine the efficacy of three different concentrations of Cidofovir against adenovirus type 5 (Ad5) in a New Zealand rabbit ocular model. Methods. The plaque reduction method in A549 cells was utilized to determine the 50% Inhibitory Dose (ID₅₀) of Cidofovir [1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate, HPMPC, GS-0504] against Ad5. The antiviral inhibitory activity of topical Cidofovir against ocular Ad5 infection in the New Zealand rabbit was evaluated. Results. The ID₅₀ of Cidofovir was determined to be 4.7-9.5 μg/ml against four adenoviruses (two Ad5, Ad8 and Ad14). Twenty-four New Zealand rabbits received intrastromal inoculation and topical application of 2×10⁶ plaque-forming units (pfu) per eye of Ad5 McEwen, a clinical isolate. Cidofovir was administered topically at three different concentrations (2x/day), beginning 16 hours postinoculation and continuing for 20 consecutive days. Compared to the placebo group, the Cidofovir treated groups showed markedly reduced Ad5 ocular titers, fewer days of viral shedding, lower humoral antibody titers against adenovirus antigens and less severe subepithelial opacities. Conclusions. Cidofovir proved to have potent antiviral activity against adenovirus replication and may have great promise for the treatment of ocular adenovirus infection.