Sensitivity monitoring of clinical isolates of herpes simplex virus to acyclovir

Abstract

Zovirax (acyclovir, ACV) is now widely accepted as a safe and effective treatment for the management of herpes simplex virus (HSV) infections in normal and immunocompromised patients. However, a common concern with regard to the widespread use of any antimicrobial agent is resistance. The virus specific mechanism of action of ACV involves two virus encoded enzymes, thymidine kinase (TK) and DNA polymerase. Any alteration in the genes coding for these two enzymes would therefore be expected to confer resistance. The findings from two extensive resistance monitoring programs have shown that in immunocompetent patients receiving ACV for the management of acute HSV disease, the incidence of resistance is extremely rare. The situation in the immunocompromised is different. In this patient group HSV disease is severe and protracted often requiring prolonged therapy thus increasing the exposure of the virus to drug. As a result HSV isolates resistant to ACV have occasionally been recovered. Biochemical and genetic analysis of the resistant clinical isolates has shown that resistance in the most part is due to an inability of the virus to produce TK which mirrors the findings with cell culture derived resistant virus. Laboratory studies would indicate that TK-deficient virus would have little clinical impact. Significantly, resistance has rarely been attributed to alterations in the substrate specificity of TK or DNA polymerase. The biological significance of these mutants is unclear but to date there has been no evidence of transmission of resistant virus.