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5th International Workshop on HIV Drug Resistance & Treatment Strategies4-8 June 2001, Scottsdale, Arizona |
OBJECTIVES: To evaluate the antiviral efficacy and resistance profile of BCH-10618, a new heterosubstituted cytidine analogue, as an anti-HIV-1 drug candidate.
METHODS: The antiviral efficacy of BCH-10618 was tested against various wild-type and drug-resistant laboratory strains and clinical isolates of HIV-1. BCH-10618 was also profiled in the Virco Antivirogram assay. In vitro drug resistance selection was conducted using different T cell lines and HIV-1 strains.
RESULTS: The IC50 values of BCH-10618 against wild-type viruses ranged from 0.02–4.2 µM in T cell lines and peripheral blood mononuclear cells (PBMCs). The CC50 values of BCH-10618 were >270 µM in both primary cells and established cell lines. In vitro drug combination studies in T cell lines or PBMCs showed that BCH-10618 was additive or slightly synergistic with stavudine, nevirapine, didanosine, zidovudine and abacavir, and additive with lamivudine and saquinavir. After repeated passaging in the presence of BCH-10618, K65R, V75I or M184V mutations emerged in reverse transcriptase of the in vitro selected HIV-1 variants. These mutations conferred 1.6- to 4.3-fold resistance to BCH-10618 on the resulting viruses. When tested against recombinant viruses containing K65R or V75I mutations, the sensitivity was reduced 4.6- and 2.8-fold, respectively. Lamivudine-resistant strains of HIV-1 had approximately threefold decreased sensitivity to BCH-10618. The Antivirogram studies have shown that viruses with mutations conferring resistance to zidovudine remain sensitive to BCH-10618, while the sensitivity to this agent of viruses that are resistant to both zidovudine and lamivudine is reduced threefold. The efficacy of BCH-10618 against HIV-1 isolates carrying position 69 insertions was reduced by a factor of 6.9, while viruses carrying the Q151M mutation were approximately 20-fold less sensitive.
CONCLUSION: BCH-10618 is an effective inhibitor of the replication of wild-type and drug-resistant HIV- 1, and low-level resistance to BCH-10618 emerges slowly in vitro. The promising antiviral and safety profile of this compound in vitro support its further development as an anti-HIV-1 agent.
PRESENTING AUTHOR: RC Bethell
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