Antiviral Drug Resistance in Herpesviruses

Abstract

The discovery of acyclovir (ACV), a nucleoside analogue, more than 30 years ago, represents a milestone in the management of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. The modest activity of ACV against human cytomegalovirus (HCMV) has prompted the development of another nucleoside analogue, ganciclovir (GCV), for the management of systemic and organ-specific HCMV diseases. Second-line agents such as the pyrophosphate analogue foscarnet (FOS) and the nucleotide analogue cidofovir (CDV) have been approved subsequently. In contrast to ACV and GCV, the latter drugs do not require an initial phosphorylation step by viral protein kinases to be converted into their active forms. Since the introduction of these antivirals, the emergence of drug-resistant mutants has been constantly reported particularly in severely immuno-compromised patients such as bone marrow and solid organ transplant recipients as well as human immunodeficiency virus (HIV)-infected individuals. In this chapter, we review the characteristics of the antiviral agents currently approved for the management of HSV, VZV, and HCMV diseases, the laboratory methods for assessing drug susceptibilities, and the clinical significance of drug-resistant infections and their management.