IN-VITRO COMPARISON OF SELECTED TRIPLE-DRUG COMBINATIONS FOR SUPPRESSION OF HIV-1 REPLICATION - THE INTER-COMPANY COLLABORATION PROTOCOL

Ten different three-drug combinations have been analyzed for their abi lity to prevent HIV-induced cytopathic effects (CPEs) in a continuous human T-lymphoblastoid cell line. Agents acting at the same as well as at different sites in the HIV-1 replicative cycle were used. Each com pound was analyzed at peak and trough plasma levels achieved in monoth erapy and in the presence of HIV-1 strains 3B and MN at a viral inocul um varying from 1 x TCID50 (50% tissue culture inhibitory dose) to 1,0 00 x TCID50. Using a viral inoculum of 10 x TCID50 HIV-1 3B, it was de termined that triple-drug combinations had greater antiviral activitie s than the corresponding double-drug combinations, which had greater a ntiviral activities than zidovudine (AZT) monotherapy. The most consis tent triple-drug combination, demonstrating superior activity at all c oncentrations of virus, was AZT + dideoxyinosine + lamivudine which re duced the AZT IC95 (95% inhibitory concentration) by 208-, 57-, 133-, and 25-fold at of 1,000, 100, 10, and 1 x TCID50 HIV-1 3B, respectivel y, as compared with the IC95 for AZT monotheraphy. For ail antiviral r egimens tested, higher viral inoculum resulted in less inhibition of v iral replication and a higher IC95 for AZT. This observation argues fo r therapeutic intervention at an earlier stage in HIV infection, when viral burden is lower.