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. 2014 Jun;95(6):627-35.
doi: 10.1038/clpt.2014.20. Epub 2014 Jan 31.

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

D S Campo  1 , P Skums  1 , Z Dimitrova  1 , G Vaughan  1 , J C Forbi  1 , C G Teo  1 , Y Khudyakov  1 , D T-Y Lau  2
Affiliations

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

D S Campo et al. Clin Pharmacol Ther. 2014 Jun.

Abstract

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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Conflict of interest statement

Conflicts of interest: The authors disclose no conflicts.

Figures

Figure 1
Figure 1
HCV RNA level across all time-points. Patients are grouped according to treatment outcomes.
Figure 2
Figure 2
A) Number of patients by IL28B status and therapy outcome. B) Population IFN-resistance for each patient. Blue: RVR; red: cEVR; yellow: pEVR; and green: NR. C) Average population IFN-resistance of patients for each outcome, bars correspond to standard error of the mean. D) Number of reads obtained by NGS from each patient and each time-point.
Figure 3
Figure 3
Relative frequencies of persistent variants over time in all patients.
Figure 4
Figure 4
Average IFN-resistance calculated over the patients of each therapy outcome. A) Number of IFN-resistant variants. B) IFN-resistance coefficient of the major variant. C) Fraction of the total number of reads that are IFN-resistant. D) Maximum IFN-resistance found. Bars correspond to standard error of the mean.
Figure 5
Figure 5
Maximum likelihood trees of all the sequences from patients with resistant variants. Red: IFN-resistant variants; blue: IFN-sensitive variants.
See this image and copyright information in PMC

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