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

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NATAP

www.natap.org

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8th Retrovirus Conference

Chicago, Feb 4-9

Reported by Jules Levin

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)

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-? 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.

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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.

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