The TEAEs associated Gemcitabine with either group in this 12-week regimen generally were mild and manageable. Overall, only 2 (1.1%) treated patients discontinued treatment because of AEs, and the 5 serious TEAEs reported in 4 patients were considered to be unrelated to study drug by the investigators. As expected, known RBV AEs (fatigue,

nausea, insomnia, rash, anemia, and increased bilirubin level) were statistically more prevalent in group 1, although the frequency and severity appeared to be reduced compared with when RBV was combined with pegIFN.7 and 18 Hemoglobin level decreases also were more frequent in group 1 although few (2.2%) reached clinical significance, and AEs leading to RBV dose reduction occurred in only 4 patients. Increased bilirubin levels in group 1

predominantly were caused by indirect bilirubinemia, consistent with the hemolysis associated with RBV and the known effect of ABT-450 on the bilirubin ABT-263 in vitro transporter OATP1B1, although a lack of sustained bilirubin increases in group 2 suggest the predominant cause was RBV-related hemolysis. Liver enzyme level normalization was consistent with the high rate of virologic response. The SVR12 rates reported here compare favorably with published reports of other interferon-free regimens using the NS5B RNA polymerase inhibitor sofosbuvir in combination with NS5A inhibitors (daclatasvir or ledipasvir), or with an Fossariinae NS3/4A protease inhibitor (simeprevir). Combinations of sofosbuvir plus daclatasvir with or without RBV have shown 95% or greater SVR12 in 41 treatment-experienced genotype 1 patients, of whom only 8 patients were genotype 1b.19 Similar SVR12 rates have been reported in treatment-experienced genotype

1 patients with sofosbuvir plus ledipasvir with (21 of 21; 100%) or without (18 of 19; 95%) RBV, although only 6 genotype 1b patients were included.20 In 13 genotype 1b–infected patients receiving the combination of simeprevir plus sofosbuvir with or without RBV, 100% SVR8 was reported.21 A larger study of daclatasvir in combination with asunaprevir in pegIFN/RBV treatment-experienced genotype 1b–infected patients showed SVR12 rates of 80% (70 of 87) with patients not achieving an SVR primarily owing to a lack of efficacy and AEs.22 Together with the results from PEARL-II, these data support a multitargeted approach to achieve SVR. Additionally, PEARL-II assessed efficacy exclusively in 179 genotype 1b-infected patients and was powered to analyze the contribution of RBV in treatment-experienced patients.