Herpesvirus resistance to antiviral drugs: a review of the mechanisms, clinical importance and therapeutic options.

During the past decade, potent agents against herpes simplex virus (HSV) types 1 and 2, varicella zoster virus (VZV), and cytomegalovirus (CMV) have become available. The increasing clinical use of acyclovir, ganciclovir, and foscarnet has been associated with the emergence of drug-resistant herpesvirus strains. Resistance to acyclovir or ganciclovir most frequently results from deficient intracellular phosphorylation of these agents which is required for drug activation. Resistance to foscarnet is due to viral DNA polymerase mutants that permit viral replication despite the presence of the drug. In immunocompetent patients, herpesvirus resistance is rare and generally does not correlate with clinical outcome. In contrast, in immunocompromised hosts, resistance of HSV, VZV, and CMV is increasingly detected, and may be associated with disease refractory to antiviral therapy. Foscarnet treatment has been used with some clinical benefit in patients with acyclovir-resistant HSV or VZV, or ganciclovir-resistant CMV. For therapy of resistant mucocutaneous HSV disease, topical trifluorothymidine, and topical or intravenous cidofovir (HPMPC) have yielded encouraging results that warrant further investigation. Improved methods for detection of herpesvirus resistance, and validation of alternative therapy for patients with documented resistance are required to reduce the clinical impact of drug-resistant herpesviruses.