9 ng/mL or 150 nM; Table 2). All patients (M, N, O, and P) were infected with Napabucasin HCV genotype 1a and experienced maximal HCV RNA declines of ≥2.9 log10. HCV RNA remained detectable in all of the
patients, and viral breakthrough was observed at the end of treatment (Fig. 1D). The preexisting resistance variant, Q30R, was detected (∼10%) at baseline in patient M (Table 3D). However, continuous HCV RNA decline suggests that this variant was, at least initially, suppressed by the 60-mg dose of BMS-790052 (Fig. 1D). At day 14, a variant with Q30H and Y93H linkage was detected in this patient (Table 3D). The level of resistance of genotype 1a variant Q30H-Y93H was high, with an EC50 value of 409.8 ng/mL or ∼553 nM (Table 2). For patients N and O, Q30E and Y93N were observed at day 14. These variants conferred substantial resistance to BMS-790052 (EC50 values: 110.9 or 150 nM and 208.9 ng/mL or 282 nM, respectively;
Table 2). For patient P, a Q30R variant was first detected 12 hours post–first dose and became the only variant detected at day 14 (Table 3D). Because the plasma exposure of BMS-790052 at day 14 in this patient was 86.8 ng/mL or ∼117 nM (data not shown), and the EC50 value for a genotype 1a replicon containing the Q30R substitution in NS5A is ∼7 nM or 5.4 ng/mL (Table 2), a rigorous investigation was triggered to understand the basis of the resistance observed in patient P. A detailed analysis of this resistant variant
will be presented elsewhere. All patients (3 infected with genotype 1a ZD1839 [patients Q, R, and S] and 1 with genotype 1b [patient T]) experienced HCV RNA declines ≥3.5 log10 (Fig. 1E). Preexisting resistance variants were not detected in the 3 patients (Q, R, and S; Table 3E) infected with the genotype 1a virus. Variants with substitutions that yield low or moderate levels of resistance, such as M28T/V, Q30H, and H58D, were detected at early time points (Table 3E); variants with substitutions yielding higher levels of resistance, such as Q30E and Q30R-H58D (EC50 value: 1,867 ng/mL or ∼2,521 nM), became apparent to at later time points (Tables 1 and 3E). For the genotype 1b patient T, population sequencing revealed that Q54H and Y93H substitutions were present at ∼100% in all time points analyzed. This variant was clearly suppressed by BMS-790052 at early time points (Fig. 1E). Q54H did not confer resistance, whereas Q54H-Y93H displayed a resistance profile similar to the Y93H variant (Table 1). At day 14, L31V, Q54H, and Y93H were all present at ∼100%, indicating linkage of these resistant variants in the rebounding virus (Table 3E). The genotype 1b L31V-Q54H-Y93H variant conferred a moderate level of resistance, with an EC50 value of 36.1 ng/mL or 48.7 nM (Table 1). HCV RNA remained detectable in 2 patients infected with genotype 1a virus (patients U and V; Fig. 1F).