Didanosine, interferon-alfa and ribavirin: a highly synergistic combination with potential activity against HIV-1 and hepatitis C virus.
OBJECTIVE
To evaluate the antiviral triple combination didanosine (ddI), interferon-alfa (IFN-alpha), and ribavirin for potential synergy in inhibition of HIV-1 replication in vitro.


METHODS
Phytohaemagglutinin-stimulated cord blood mononuclear cells were infected with HIV-1(IIIB) or the HXB2D molecular clone of HIV-1 then cultured with interleukin-2 with ddI, ribavirin or IFN-alpha, alone and in combination. Reverse transcriptase activity was measured after 7 days to determine the inhibitory concentration of 50% (IC(50)) 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 IC(50) was reduced from 6.85 to 0.90 micromol/l (P < 0.001) for ddI and from 6.58 to 1.00 micromol/l (P < 0.001) for IFN-alpha. No increased cytotoxicity was observed. Results were similar with both viral strains and using both analyses. In the triple combination, increasing concentrations of IFN-alpha resulted only a slight enhancement of synergy: synergy volumes were 134 [95% confidence limit (CL), 77-191] with 5 U IFN-alpha 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-alpha 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.
Klein
Marina B
MB
Immunodeficiency Service, Montreal Chest Institute, Department of Medicine, McGill University Health Centre, Montreal, Quebec Canada.
Campeol
Nadia
N
Lalonde
Richard G
RG
Brenner
Bluma
B
Wainberg
Mark A
MA
D019380:Anti-HIV Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D016049:Didanosine / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D020128:Inhibitory Concentration 50; D016898:Interferon-alpha / Q000627:therapeutic use*; D012254:Ribavirin / Q000627:therapeutic use*; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D004338:Drug Combinations; D016898:Interferon-alpha; D012254:Ribavirin; D016049:Didanosine