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Antimicrob. Agents Chemother. doi:10.1128/AAC.01004-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Evolution of Resistant Mutant M414T in HCV Replicon Cells Treated with Polymerase Inhibitor A-782759

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois; Gilead Sciences, Foster City, California

^* To whom correspondence should be addressed. Email: liangjun.lu{at}abbott.com.

	Abstract

Treatment of HCV replicon cells with any single specific anti-HCV inhibitor in vitro leads to a rapid selection of resistant mutants. However, the source and the kinetic evolution of these resistant mutants during treatment are poorly understood. In this study we developed allele-specific real-time PCR assays for quantitative detection of the M414T mutant that was selected by a number of benzothiadiazine HCV polymerase inhibitors. Low levels of preexisting M414T mutants were detected in both 1b-con1 (0.22%) and 1b-N (0.18%) subgenomic replicon cell lines, as well as in HCV isolated out of the sera from six of fifteen treatment-naïve HCV-infected patients at 0.11% and 0.60%. The proportion of M414T mutants in replicon rapidly increased in a dose-dependent manner upon treatment with benzothiadiazine inhibitor A-782759. After 4 days of treatment, 2.5%, 26% or 60% of the replicon population contained M414T mutants with the use of A-782759 at 1x, 10x or 100x above its EC₅₀, respectively. In addition, the short four-day treatment resulted in significant changes in inhibitor susceptibility in the replicon cells. Our results indicated that the resistant mutant preexisted as a minor population in replicon cells and the mutant was selected within days of treatment with the inhibitor. The findings from this study suggested that early application of combination therapy of an HCV specific inhibitor with IFN-based regimens or other classes of available inhibitors will be necessary to avoid quick viral rebound or treatment failure.

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