Efficacy of ganciclovir in combination with zidovudine against cytomegalovirus in vitro and in vivo

Abstract In cultured MRC-5 cells, ganciclovir (GCV) alone had good activity against both the established AD169 strain (IC 50 8 and 9 μM) and a clinical isolate (IC 50 14 μM) of human cytomegalovirus (CMV), while 3′-azido-3′-deoxythymidine (AZT) was relatively inactive [IC 50 508 and >800 (AD169 strain); >800 μ M (clinical isolate)]. When reductions in plaques were compared against reductions in the cellular metabolism of MTT at all GCV and AZT combination concentrations using an improved 3-dimensional linear regression analysis, AZT had an additive effect on the antiviral activity of GCV against the AD169 strain and potentiated the antiviral activity of GCV against the clinical isolate. Calculations showed that, in the presence of 50 μM AZT, the anti-CMV activity of GCV was unchanged for the AD169 strain, whereas the activity of GCV was increased approximately 5–10-fold for the clinical isolate. An increase in GCV efficacy for the AD169 strain first became apparent at 100 μM AZT with an approximately 3-fold increase in activity. In Swiss-Webster mice, the anti-CMV activity of GCV against murine CMV was unaffected when administered in combination with AZT. GCV given alone subcutaneously had an ED 50 of 6 mg/kg which was unaffected by daily intraperitoneal doses of 320 mg/kg AZT. These results suggest that AZT will not adversely affect the efficacy of GCV against CMV in HIV-positive, non-neutropenic patients.