Cidofovir, a New Agent with Potent Anti-Herpesvirus Activity

Abstract

SummaryCidofovir is a potent, broad spectrum antiviral agent with activity in vitro and in vivo against cytomegalovirus and other members of the herpesvirus family, as well as certain other DNA viruses. After uptake into cells it is converted enzymatically to cidofovir diphosphate, a structural analogue of deoxycytidine triphosphate, which selectively inhibits viral DNA polymerases relative to host cell polymerases. Cross-resistance to cidofovir is not usually seen with human cytomegalovirus isolates that are foscarnet-resistant, or isolates that are ganciclovir-resistant due to a deficiency in ganciclovir phosphorylation. Cross-resistance is seen, however, with isolates that are ganciclovir resistant due to polymerase mutations. A prolonged elimination phase seen in vivo, correlates with a long intracellular half-life seen in vitro and allows for efficacy in-animal models of virus infection with infrequent dosing or prophylaxis. Clinical studies of intravenous cidofovir in cytomegalovirus retinitis in patients with AIDS are claimed to show delay of retinitis progression with maintenance doses given once every 2 weeks.

Treatment of BK virus-associated hemorrhagic cystitis and simultaneous CMV reactivation with cidofovir

“…As assessed by electron microscopy and quantitative PCR for BK viruria and by established techniques for CMV viremia, this treatment was effective in our patient. Since antiviral activity of cidofovir against CMV is high in the urine, 19 it is possible that its antiviral activity against BK virus is also maintained, thus contributing to the decrease of BK virus viruria observed in our patient. Interestingly, cidofovir itself caused HC as a side-effect in two of 28 patients treated for CMV disease.…”

Sensitivity of Kaposi's sarcoma-associated herpesvirus replication to antiviral drugs. Implications for potential therapy.

“…In contradistinction to plaque-reduction assays, in which even subtle effects on viral growth can become greatly amplified through multiple rounds of replication and infection, measurements in our assay system reflect the properties of a single cycle of viral growth. As a result, the IC 50 values for the four drugs we examined are not directly comparable with those determined by plaque-reduction assay for the same drugs against other herpesviruses (21,24,25) (they are likely to be higher than those that would arise from a plaque-reduction assay, were one available). Nonetheless, broadly speaking the sensitivity profile of KSHV resembles most closely that found for the ␤ -herpesvirus CMV, which is similarly insensitive to acyclovir, but sensitive to the other three drugs we tested.…”

“…To compare the relative potencies of the antiherpesvirus drugs on KSHV production, we first tested each one at three different concentrations (chosen with reference to the known sensitivities of herpes simplex virus and human cytomegalovirus [CMV]) (21,24,25). The effects of acyclovir, ganciclovir, cidofovir, and foscarnet on KSHV production are compared in Fig.…”

Differences in DNA Packaging Genes and Sensitivity to Benzimidazole Ribonucleosides between Human Cytomegalovirus Strains AD169 and Towne

“…There are currently three nucleoside analogues available in the USA as drugs for the treatment of HCMV infection: ganciclovir (GCV), foscarnet and cidofovir (Crumpacker, 1996;Hitchcock et al, 1996, Chrisp & Clissold, 1991. In addition, the antisense oligonucleotide fomivirsen has been approved for direct treatment of HCMV retinitis (Mulamba et al, 1998;Perry & Balfour, 1999).…”