Drug-resistance of a viral population and its individual intra-host variants during the first 48 hours of therapy

Using HCV and IFN-resistance as a proof of concept, we have devised a new methodology for calculating the effect of a drug over a viral population and the resistance of its individual intra-host variants. By means of next-generation sequencing, HCV variants were obtained from sera collected at 9 time-points from 16 patients during the first 48 hours after injection of IFN-α. IFN-resistance coefficients were calculated for individual variants using changes in their relative frequencies, and for the entire intra-host viral population using changes in viral titer during the initial 48 hours. Population-wide resistance and presence of IFN-resistant variants were highly associated with pegIFN-α2a/RBV treatment outcome at week 12 (p = 3.78×10(-5) and 0.0114, respectively). This new method allows an accurate measurement of resistance based solely on changes in viral titer or the relative frequency of intra-host viral variants during a short observation time.