THE EFFECTS OF DELAYED-ONSET CHEMOTHERAPY USING FAMCICLOVIR OR VALACICLOVIR IN A MURINE IMMUNOSUPPRESSION MODEL FOR HSV-1

BALB/c mice were immunosuppressed using a dosing regimen of cyclosporin-A previously shown to interfere with T-cell function. HSV-1 was then inoculated into the skin of the ear pinna and the infection allowed to progress for 5 days. In untreated mice, virus replication was observed in both ear tissue and the central nervous system (brainstem). Virus replication continued at high titre in both sites for 15 days, the duration of the experiment. This model was used to investigate the efficacy of famciclovir (FCV) and valaciclovir (VACV), which are the oral prodrugs of penciclovir and acyclovir, respectively, on an established HSV-1 infection. Mice were treated orally with either FCV or VACV at 50 mg kg(-1), from day 5 to day 10 post-infection. Within 2 days of the onset of therapy, virus titres in both skin and neural tissues were reduced significantly, and by day 10 post-infection less than 10(1) p.f.u. per tissue was detectable compared with approximately 10(4) p.f.u. in the untreated control mice. However, when VACV therapy was stopped, there was a recurrence of infectious virus replication within the ear pinna and the brainstem 2 days later. No recurrence of virus replication was observed in mice that had been treated with FCV. In addition, FCV treatment was superior to VACV at reducing the incidence of clinical signs and disease. Furthermore, mice receiving FCV gained weight more quickly than infected controls and reached uninoculated control weights by the end of the study period. In contrast, VACV had no such beneficial effects. These results confirm that VACV and FCV have different effects on the pathogenesis of HSV. The reasons for this appear to result from critical differences in the mechanism of action of the two compounds at a cellular level. We suggest that these data have important implications for the treatment of severe herpesvirus infections in man.