Foscarnet, also known as phosphonoformate, is a pyrophosphate analog that inhibits viral DNA polymerase by blocking the pyrophosphate-binding site of the viral DNA poly-merase and preventing cleavage of pyrophosphate from deoxyadenosine triphosphate. This action is relatively selective; CMV DNA polymerase is inhibited at concentrations less than 1% of that required to inhibit cellular DNA polymerase. Unlike such nucleosides as acyclovir and ganciclovir, foscarnet does not require phosphorylation to be an active in-hibitor of viral DNA polymerases. This biochemical fact becomes especially important with regard to viral resistance, because the principal mode of viral resistance to nucleoside analogs is a mutation that eliminates phosphorylation of the drug in virus-infected cells. Thus, foscarnet can usually be used to treat patients with ganciclovir-resistant CMV and acyclovir-resistant HSV. Excretion is entirely renal without a hepatic component, and dosage must be decreased in patients with impaired renal function.
Interferons are host cell – encoded proteins synthesized in response to double-stranded RNA that circulate to protect uninfected cells by inhibiting viral protein synthesis. Ironi-cally, interferons harvested in tissue culture were the first antiviral agents, but their clinical activity was disappointing. Recombinant DNA techniques now allow relatively inexpen-sive large-scale production of interferons by bacteria and yeasts.
Interferon alpha is beneficial in the treatment of chronic active hepatitis B and C in-fection, although its efficacy is often transient. Combinations of interferon alpha with 3TC, famciclovir, and other nucleosides are being evaluated for treatment of hepatitis B. Interferon alpha is given for 6 to 12 months to treat chronic hepatitis C disease, and com-bination with ribavirin usually produces improved results. Topical interferon application is beneficial in the treatment of human papilloma virus infections. Interferons cause symptomatic systemic toxicity, (eg, fever, malaise), partly because of their effect on host cell protein synthesis.
Fomivirsen, the first antisense compound to be approved for use in human infection, is a synthetic oligonucleotide, complementary to and presumably inhibiting a coding se-quence in CMV messenger RNA (mRNA). The major immediate early transcriptional unit of CMV encodes several proteins responsible for regulation of viral gene expression. Presumably, fomivirsen inhibits production of these proteins. In this agent, oligonu- cleotide phosphorothioate linkages replace the usual nucleases. Fomivirsen, which ex-hibits greater antiviral activity than ganciclovir on a molar basis, is approved for the local (intravitreal) therapy of CMV retinitis in patients who have failed other therapies.