This observation remained valid after sensitivity analysis, which involved the removal of the 30 patients with mRVR who were rerandomized to what was found to be a suboptimal treatment duration (24 weeks). The finding that initiation of PegIFN/RBV prior to HCV

PI had a negative effect was unexpected. Interestingly, in two randomized controlled trials (one with boceprevir; one with telaprevir), addition of HCV PI after 4 weeks of PegIFN/RBV therapy (LI) was not associated with a decrease or increase in the proportion of patients achieving SVR. The underlying mechanism learn more for impaired viral response with the 3-day LI in our study is not known; further investigation is ongoing. Given the observed negative effect of 3-day PegIFN/RBV LI, simultaneous start of faldaprevir and PegIFN/RBV will be incorporated into current and future studies Y-27632 price of this agent. Faldaprevir was well tolerated at the 240 mg QD dose. At this dose, the main faldaprevir-related AEs were mild-to-moderate skin rash, photosensitivity reactions, and gastrointestinal events, which tended to occur during the first weeks after faldaprevir initiation up to week 12. Only 6% and 4% of patients discontinued

faldaprevir due to AEs in the 240 mg QD/LI and 240 mg QD treatment groups, respectively. However, a much higher rate of discontinuation due to AEs was observed with the MCE公司 240 mg BID dose (23%) without improved efficacy; thus, this dose will not be investigated in phase 3 studies. Faldaprevir is associated with incidences of jaundice related to increases in unconjugated bilirubin. Similar to some other HCV PIs in development,14 faldaprevir-mediated inhibition of normal bilirubin uptake (OATP-1), processing (UGT1A1), and elimination (MRP-2) appear to drive this event.15 Jaundice was rapidly reversible

after cessation of faldaprevir and was not associated with increases in serum ALT, AST, or other markers of liver injury; only three patients discontinued the trial due to jaundice and indirect bilirubin elevation. Skin rash in the 240 mg QD dose groups was mainly mild to moderate and managed without treatment modifications in most instances. In the 240 mg QD dose groups, only one patient discontinued treatment due to rash; however, 10 patients discontinued treatment with the 240 mg BID dose because of rash. In conclusion, addition of 240 mg QD faldaprevir for 24 weeks to 48-week PegIFN/RBV therapy was safe and tolerable and produced SVR rates of up to 50% in even the hardest-to-cure patients, i.e., GT-1 patients with null or partial response to prior PegIFN/RBV. Phase 3 trials testing 120 mg and 240 mg QD faldaprevir without LI, in combination with PegIFN/RBV, for treatment-naïve patients and patients with prior treatment failure are ongoing.