Didanosine, interferon-alfa and ribavirin

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Abstract
Objective: To evaluate the antiviral triple combination didanosine (ddI), interferon-alfa (IFN-α), and ribavirin for potential synergy in inhibition of HIV-1 replication in vitro. Methods: Phytohaemagglutinin-stimulated cord blood mononuclear cells were infected with HIV-1IIIB or the HXB2D molecular clone of HIV-1 then cultured with interleukin-2 with ddI, ribavirin or IFN-α, alone and in combination. Reverse transcriptase activity was measured after 7 days to determine the inhibitory concentration of 50% (IC50) for the various drugs in replicate assays. Analysis of combined effects was performed using both the median effect principle (CalcuSyn, Biosoft®) and three-dimensional modelling (MacSynergy II). Results: The triple combination was highly synergistic against HIV-1 in vitro with combination indices < 1. The mean IC50 was reduced from 6.85 to 0.90 μmol/l (P < 0.001) for ddI and from 6.58 to 1.00 μmol/l (P < 0.001) for IFN-α. No increased cytotoxicity was observed. Results were similar with both viral strains and using both analyses. In the triple combination, increasing concentrations of IFN-α resulted only a slight enhancement of synergy: synergy volumes were 134 [95% confidence limit (CL), 77–191] with 5 U IFN-α and 214.92 (95% CL, 116–314) with 10 U. This supporting the observation that the majority of the synergistic activity was derived from the combination of ddI and ribavirin, with IFN-α providing additional additive suppression. Conclusions: This novel triple combination has the potential to provide simultaneous activity against both HIV and hepatitis C and deserves further study to determine if can be safely administered in the clinical setting.

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