Abstracts 1880–2047

• Book ID: 102850097
• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 999 KB
• Volume: 52
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.23997

✦ Synopsis

Background: Due to high replication rate and poor fidelity of RNA polymerase, preexisting variants resistant to any single direct-acting anti-HCV agent are deemed inevitable. Therefore, therapy with direct antiviral agents will require combination treatment to achieve sustained virologic response. ACH-1625 is an NS3 protease inhibitor that exhibits potent antiviral activity (a 3.81 log 10 mean maximum drop of plasma HCV RNA) after dosing hepatitis C patients at 600 mg QD for 5 days. ACH-2928 is an NS5A inhibitor that displays low picomolar potency against HCV replicons. In this in vitro study, the combinatory effects of two drugs for antiviral activity and for prevention of emergence of resistant variants were investigated in the presence and absence of ribavirin. Methods: Huh-7 cells harboring HCV replicons were utilized for evaluation of combination treatment. These replicons were derived from a laboratory strain or a lab strain within which the inhibitor-targeted region was replaced with a corresponding region of HCV RNA obtained from clinical isolates. For evaluation of antiviral activity, inhibitors were added to cells in serial dilutions of concentrations in a checker board manner. Three days after addition of compounds, the level of HCV RNA replication was quantified with luciferase reporter assay. For evaluation of prevention of emergence of resistant variants, cells were treated with inhibitors either alone or together at several concentrations in the presence of G418 till the cells formed visible colonies. Results: Combination of ACH-1625 and ACH-2928 in the presence or absence of ribavirin yielded an additive to synergistic antiviral effect. Combination of these two agents blocked significantly the emergence of resistant variants and this effect is more pronounced in the presence of ribavirin. More importantly, such an effect in preventing the emergence of resistant variants was also observed with cells harboring a population of chimeric replicons from HCV-infected patients, a system representing the quasispecies nature of HCV virions in patients. Conclusion: Our data showed enhanced antiviral effect and inhibition of emergence of resistant variants when ACH-1625 is combined with ACH-2928 either in presence or absence of ribavirin in vitro. These results warrant clinical investigation of combination of ACH-1625 and ACH-2928 in hepatitis C patients.