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.

A Comparative Study of the in vitro and in vivo Antiviral Activities of Acyclovir and Penciclovir

“…(Hinuma et al, 1967) were grown as described previously (Arrand et al, 1983;Collins and Ellis, 1993). HSV-1 strain SC16 and HSV-2 strain 186 have been described previously (Rawls et al, 1968;Hill et al, 1975).…”

“…HSV-1 strain SC16 and HSV-2 strain 186 have been described previously (Rawls et al, 1968;Hill et al, 1975). The clinical HSV isolates were obtained during the sensitivity monitoring survey carried out during the clinical development of acyclovir (Collins and Ellis, 1993). Working stocks of cell-free virus were produced in Vero cells.…”

Further Characterization of the Potent and Prolonged Inhibition of Herpes Simplex Virus Replication in Human Cell Lines by Penciclovir

“…However, it seems more likely that an increased viral load within aciclovir-treated cultures itself could favour the selection of resistant variants. Based on clinical experience, the detection of aciclovir-resistant HSV in immunocompetent patients is extremely rare, and is low in severely immunocompromised patients (Collins and Ellis, 1993), but the problem of resistance continues to grow as the immunocompromised population increases (Field and Biron, 1994). It remains to be seen whether the differences in activity observed between penciclovir and aciclovir in cell culture will be reflected in different patterns of virus shedding.…”

Management of multidrug‐resistant viruses in the immunocompromised host

“…The rate of ACV resistance in immunocompetent patients is less that 1% in the UK (Collins & Ellis, 1993). Furthermore, in the immunocompetent patient, ACV-resistant HSV may have limited clinical relevance.…”