COMBINING INTERFERON + RIBIVARIN with DDI FOR ANTI-HIV & HCV ACTIVITY

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

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-?;) and ribavirin (RIBA), have activity against HIV. As IFN-?;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 IIIBthen cultured in interleukin-2 (IL-2) with ddI, RIBA or IFN-?;, 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.

Comments:
There are concerns about ddI toxicity iof ddI exposure is being increased. On the other hand if this synergy was used to reduce ddI dose to achieve equivalent ddI exposure as if using ddI without RBV that also appears to be an alternate approach.

Conclusions:
The triple combination ddI, RIBA and IFN-?;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.