Cidofovir was the first nucleotide analogue approved for clinical use. The drug has been employed almost exclusively to treat cytomegalovirus (CMV) retinitis in patients with the acquired immunodeficiency syndrome (AIDS). However, cidofovir is also used as a therapeutic option against other viral infections. (See "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis".)
MECHANISM OF ACTION
Cidofovir is a monophosphate nucleotide analogue. After undergoing cellular phosphorylation to its diphosphate form, it competitively inhibits the incorporation of deoxycytidine triphosphate into viral DNA by viral DNA polymerase. Incorporation of the drug disrupts further chain elongation . Unlike nucleoside analogues such as acyclovir or ganciclovir, cidofovir is not phosphorylated (and hence activated) by a viral kinase.
SPECTRUM OF ACTIVITY
Cidofovir demonstrates in vitro activity against a number of DNA viruses, including the herpesviruses, adenovirus, polyomavirus, papillomavirus, and poxvirus . Cidofovir also retains activity against thymidine kinase-negative herpes simplex virus (HSV) and UL97 phosphotransferase-negative CMV, which are mutant viruses resistant to acyclovir and ganciclovir. Clinical efficacy has been demonstrated rigorously only against CMV. Its clinical utility in infections caused by other viral pathogens remains to be determined [1,2].
MECHANISM OF RESISTANCE
Reduced susceptibility of CMV to cidofovir has been associated with mutations in the viral DNA polymerase gene [3,4]. Since its mechanism of action does not require phosphorylation, cidofovir is unaffected by mutations in CMV phosphotransferase which confer resistance to ganciclovir. However, prolonged therapy with ganciclovir in patients with CMV retinitis has been associated with the emergence of viral DNA polymerase mutations which confer cross resistance to cidofovir [4-7].
Administration of a single dose of cidofovir (3 to 5 mg/kg IV) yields peak plasma concentrations of 7.3 to 11.5 mg/L. Over 80 percent of the drug is excreted unchanged in the urine within 24 hours, with a half-life of 2.4 to 3.2 hours . However, cidofovir diphosphate, an active metabolite is eliminated more slowly with first and second phase intracellular half-lives of 24 and 65 hours, respectively . This property permits the drug to be dosed every two weeks.