e., fitness) of the variants. Conclusion: Although resistance emerged during monotherapy with BMS-790052, the substantial anti-HCV effect of this compound makes it an excellent candidate for effective combination

therapy. (HEPATOLOGY 2011) The hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a multifunctional protein with key roles in HCV replication. NS5A has also been implicated in the modulation of cellular signaling pathways.1, 2 Because it is required in vivo and in vitro for viral replication and has no known human homologs, NS5A provides an attractive PLX4032 concentration target for therapeutic intervention.3 BMS-790052 is a potent HCV

NS5A replication complex inhibitor, with 50% effective concentration (EC50) values of 9 and 50 pM against genotype 1b and 1a replicons, respectively.4, 5 It is also potent against live virus (genotype 2a, JFH-1), with an EC50 of ∼28 pM.4 BMS-790052 has broad genotype coverage, with EC50 values ranging from pM to low nM for replicons with NS5A sequences derived this website from genotype 2a, 3a, 4a, and 5a.4 Proof of concept for BMS-790052 has been achieved clinically, where its exceptional in vitro potency translated to an in vivo effect in a single-ascending dose study.4 In this study, marked HCV RNA decline (∼2.9 log10) was needed for detection of resistant variants, suggesting that the variants were likely present as preexisting minor quasi species and were uncovered by the efficient suppression of wild-type

virus.4 However, the ability of BMS-790052 to further suppress viral replication with continuous dosing could not be assessed in the single-ascending Paclitaxel manufacturer dose study. In addition, analysis of specimens from the single-ascending dose study did not reveal whether the resistance detected clinically correlates with resistance observed in the in vitro replicon system. In the multiple-ascending dose (MAD) study reported here, a total of 24 chronically infected patients (4 active patients per cohort) were treated with BMS-790052 at 1, 10, 30, 60, and 100 mg once-daily or 30 mg twice-daily for 14 days. The treated patients generally experienced rapid, marked viral load declines. However, HCV RNA remained detectable in all genotype 1a–infected patients, and viral breakthrough was observed during the course of treatment in the majority of these patients. In contrast, viral breakthrough was observed less often in patients infected with HCV genotype 1b, and, in several patients, HCV RNA dropped below the level of quantitation (<25 IU/mL).