42. Antiviral therapy
In 1990, there were only five licensed antiviral drugs; in 2009 there were over 40, but mostly for the treatment of HIV and herpesviruses. This is a rapidly growing area but fundamentally the drugs mostly target the replication cycle of viruses.
The replication of viruses depends on utilizing the biochemical machinery of the host cell. Drug selectivity is, therefore, harder to achieve than with antibacterial drugs. There are, however, several aspects of the virus replication cycle that can be targeted (Fig. 3.42.1). Optimal therapy depends on rapid diagnosis, and this is particularly difficult when the virus has a long incubation period or prodrome. Latent viruses also prove relatively resistant to antiviral therapy.
Treatment of herpesviruses
Aciclovir (acycloguanosine) and its derivatives are the mainstay of treatment of herpes simplex virus infections. Aciclovir is a nucleoside analogue that requires conversion to a triphosphate to be active. The first phosphate group is added by herpesvirus-coded thymidine kinase, which ensures selectivity for virally infected cells. The two further phosphates are added by host cellular kinases to produce an inhibitor of DNA polymerase. The phosphylated drug is also a substrate of the enzyme, being incorporated in place of guanosine triphosphate; however, as it lacks an essential hydroxyl group, it causes termination of elongation of the DNA chain. Two newer derivatives of aciclovir, penciclovir and valaciclovir, have additional clinical activity against varicella zoster virus. There are a number of agents that are clinically active against cytomegalovirus and useful in patients who are immunocompromised: ganciclovir, valganciclovir, foscarnet, cidofovir and fomivirsen (the last of these is given by intraviteal injection for eye infections).
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