Ganciclovir antagonizes the anti-human immunodeficiency virus type 1 activity of zidovudine and didanosine in vitro

In studies examining potential interactions between ganciclovir (GCV) and either zidovudine (AZT) or didanosine (DDI) in H9 cells, GCV was found to consistently reduce the anti-human immunodeficiency virus type 1 potency of both AZT and DDI. In the presence of GCV, the 50% effective doses of AZT and DDI were increased three- to sixfold, depending on the molar ratio of drugs and the measure of human immunodeficiency virus type 1 replication (p24 antigen, reverse transcriptase activity, or infectious virus yield). Multiple dose-effect analysis revealed strong antagonism between GCV and either AZT or DDI (combination indices, 2.2 to 6.7). This antagonistic effect occurred at drug concentrations that were well below the cytotoxic range. At higher drug concentrations, the combination of GCV and AZT was synergistically cytotoxic (combination indices, <1.0), whereas GCV and DDI were only additively cytotoxic (combination indices, ca. 1.0). Thus, the combination of GCV with AZT or DDI may result in antiviral antagonism and either synergistic (AZT- GCV) or additive (DDI-GCV) cytotoxicity.