Effect upon the anti-HIV Activity of 3′-Azido-3′-Deoxythymidine and 3′-Fluoro-3′-Deoxythymidine of Combination with anti-Herpes Nucleoside Analogues

Abstract

The treatment of the severe and often life-threatening herpesvirus infections which commonly occur in AIDS patients is complicated by the need to treat simultaneously with drugs directed against the human immunodeficiency virus (HIV). Combining together different drugs in this way can lead to effects upon the activities of the individual drugs, such as synergism or antagonism. The effect upon the anti-HIV activity of 3′-azido-3′-deoxythymidine (AZT) and 3′-fluoro-3′-deoxythymidine (FLT) of combination with the anti-herpesvirus drugs 9-(1,3-dihydroxy-2-propoxymethyl-)guanine (DHPG; ganciclovir) and (-)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine ([-]-2HM-HBG) was investigated. Neither DHPG nor (-)-2HM-HBG showed antiviral activity against HIV-1 up to 50 [AM. When combined with AZT or FLT at ratios of antiherpes:anti-HIV drug of 10:1 or greater, both DHPG and (-)-2HM-HBG antagonized the anti-HIV activity of AZT and FLT. When combined at a lower ratio (1:1), there was no effect upon the anti-HIV activity of either AZT or FLT. The phosphorylation of FLT was found to be unchanged in the presence of DHPG or (-)-2HM-HBG, indicating that the mechanism of the antagonism was not owing to an effect of DHPG or (-)-2HM-HBG upon the metabolism of the anti-HIV drugs. The results suggest that combination chemotherapy with the anti-herpes drugs DHPG/(-)-2HM-HBG and AZT/FLT should be used cautiously. The possibility of such antagonistic interactions should be borne in mind when considering the choice of drug and ratio for treatment of herpesvirus infections in AIDS patients on anti-HIV therapy.