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

Using hepatitis C virus (HCV) and interferon (IFN) resistance as a proof of concept, we have devised a new method for calculating the effect of a drug on a viral population, as well as the resistance of the population's individual intrahost variants. By means of next‐generation sequencing, HCV variants were obtained from sera collected at nine time points from 16 patients during the first 48 h after injection of IFN‐α. IFN‐resistance coefficients were calculated for individual variants using changes in their relative frequencies, and for the entire intrahost viral population using changes in viral titer. Population‐wide resistance and presence of IFN‐resistant variants were highly associated with pegylated IFN‐α2a/ribavirin 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 intrahost viral variants during a short observation time.

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