Drug resistance of a viral population and its individual intrahost 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.
Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
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Campo
Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
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Skums
Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
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Dimitrova
Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
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Vaughan
Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
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Forbi
Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
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Teo
Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
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Khudyakov
Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
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Lau
D000465:Algorithms; D000998:Antiviral Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000502:physiology*; D004359:Drug Therapy, Combination; D014644:Genetic Variation; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008969:Molecular Sequence Data; D010802:Phylogeny; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011153:Population; D011237:Predictive Value of Tests; D012367:RNA, Viral / Q000235:genetics / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load
D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a