308   A Highly Synergistic Tripe Antiviral Combination with Potential Activity against Both HIV and Hepatitis C Viruses.

M. B. Klein*¹, N. Campeol¹, R. G. Lalonde¹, and M. A. Wainberg².
¹McGill Univ. Hlth. Ctr. and²McGill AIDS Ctr., Montreal, Quebec, Canada.

Background:The increase in HIV and HCV co-infection is presenting new therapeutic challenges. HIV therapy has no impact on HCV and may even exacerbate liver disease. In contrast, both drugs used to treat HCV, interferon alpha (IFN-α;) and ribavirin (RIBA), have activity against HIV. As IFN-α;and RIBA individually are synergistic with purine analogs such as didanosine (ddI), we investigated the anti-HIV activity of the 3 drugs in combination.

Methods:PHA-stimulated cord blood mononuclear cells were infected with HIV III_Bthen cultured in interleukin-2 (IL-2) with ddI, RIBA or IFN-α;, alone and in combination. Reverse transcriptase activity was measured after 7 days to determine the IC₅₀s for the various drugs in triplicate assays. Analysis of combined effects was performed using the median effect principle (CalcuSyn, Biosoft).

Results:Mean IC₅₀s of drugs alone and in combination are presented below. Combination indices (CI) of <1 are synergistic with smaller values of CI representing greater degrees of synergy.

Conclusions:The triple combination ddI, RIBA and IFN-α;was highly synergistic against HIV in vitro, raising the prospect of a new clinical strategy for the treatment of dual infection. Of note, the activity of ddI in the combination exceeded 80 times the IC₅₀of wild-type HIV and thus may be sufficient to inhibit resistant viral strains. This novel triple combination has the potential to provide simultaneous activity against both HIV and hepatitis C and deserves further study in clinical trials.