EFFICACY OF GANCICLOVIR IN COMBINATION WITH ZIDOVUDINE AGAINST CYTOMEGALOVIRUS IN-VITRO AND IN-VIVO

In cultured MRC-5 cells, ganciclovir (GCV) alone had good activity aga inst both the established AD169 strain (IC50 8 and 9 muM) and a clinic al isolate (IC50 14 muM) of human cytomegalovirus (CMV), while 3'-azid o-3'-deoxythymidine (AZT) was relatively inactive [IC50 508 and > 800 (AD 1 69 strain); > 800 muM (clinical isolate)]. When reductions in pl aques were compared against reductions in the cellular metabolism of M TT at all GCV and AZT combination concentrations using an improved 3-d imensional linear regression analysis, AZT had an additive effect on t he antiviral activity of GCV against the AD169 strain and potentiated the antiviral activity of GCV against the clinical isolate. Calculatio ns showed that, in the presence of 50 muM AZT, the anti-CMV activity o f GCV was unchanged for the AD169 strain, whereas the activity of GCV was increased approximately 5-10-fold for the clinical isolate. An inc rease in GCV efficacy for the AD169 strain first became apparent at 10 0 muM AZT with an approximately 3-fold increase in activity. In Swiss- Webster mice, the anti-CMV activity of GCV against murine CMV was unaf fected when administered in combination with AZT. GCV given alone subc utaneously had an ED50 of 6 mg/kg which was unaffected by daily intrap eritoneal 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.