746 NARLAPREVIR AND PEGINTERFERON ALFA-2B FOR 2 WEEKS IN CHRONIC HEPATITIS C GENOTYPE 1 PATIENTS, FOLLOWED BY PEGINTERFERON ALFA-2B AND RIBAVIRIN FOR 24/48 WEEKS: FINAL RESULTS

POSTERSsignificantly decreased in most of them (mean: -2.3±1.0 log IU/ml), but none became HCV RNA undetectable on silibinin monotherapy.Full-length RdRp was sequenced at baseline and on treatment in HCV RNA-positive samples.A number of amino acid changes occurred relative to baseline in 8 of the 13 patients who still had HCV RNA levels >1000 IU/ml on silibinin administration, including S19A, V144I, S231R, V235I, A238E, A327T, P461L, R465G and K535Q.None of these substitutions was found in more than one patient, except S19A in two patients, and none was associated with a virological breakthrough.They were naturally rare, as a Genbank search among 520 deposited sequences found them in 0% to 1.5% of cases.In a 3D reconstruction of the NS5B RdRp, the observed substitutions did not cluster and all of them were located at more than 18 angstroms of the GDD catalytic motif.ii.In vitro resistance: HCV genotype 1b replicons were treated with silibinin, 5X-10X the in vitro IC50, and passaged over 16 weeks of culture.HCV replicon variants harboring RdRp substitutions N110S, L285P, A442T and R498G were selected in silibinin treated cells, but not in untreated cultures.These substitutions did not match with the changes observed in vivo.Conclusion: Silibinin treatment selects for amino acid substitutions that may confer in vitro resistance in the replicon model.Other substitutions have been observed upon 14-21 days of in vivo administration, but none of them appeared to confer in vivo resistance.Further in vitro analysis of these substitutions is underway in the replicon system and an RdRp enzyme assay.