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 ability 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 compound was analyzed at peak and trough plasma levels achieved in monotherapy and in the presence of HIV-1 strains 3B and MN at a viral inoculum varying from 1 x TCID50 (50% tissue culture inhibitory dose) to 1,000 x TCID50. Using a viral inoculum of 10 x TCID50 HIV-1 3B, it was determined that triple-drug combinations had greater antiviral activities than the corresponding double-drug combinations, which had greater antiviral activities than zidovudine (AZT) monotherapy. The most consistent triple-drug combination, demonstrating superior activity at all concentrations of virus, was AZT + dideoxyinosine + lamivudine which reduced 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, respectively, as compared with the IC95 for AZT monotherapy. For all antiviral regimens tested, higher viral inoculum resulted in less inhibition of viral replication and a higher IC95 for AZT. This observation argues for therapeutic intervention at an earlier stage in HIV infection, when viral burden is lower.
St Clair
M H
MH
Division of Virology, Burroughs Wellcome Co., Research Triangle Park, NC 27709, USA.
Pennington
K N
KN
Rooney
J
J
Barry
D W
DW
D000998:Antiviral Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D016049:Didanosine / Q000494:pharmacology; D004357:Drug Synergism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D019469:Indinavir; D007546:Isoquinolines / Q000494:pharmacology; D019259:Lamivudine; D019829:Nevirapine; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D019258:Saquinavir; D014779:Virus Replication / Q000187:drug effects*; D016047:Zalcitabine / Q000031:analogs & derivatives / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D007546:Isoquinolines; D011725:Pyridines; D011804:Quinolines; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D019469:Indinavir; D016047:Zalcitabine; D019829:Nevirapine; D016049:Didanosine; D019258:Saquinavir