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

Campo DS, Skums P, Dimitrova Z, Vaughan G, Forbi JC, Teo CG, Khudyakov Y, Lau DT - Clin. Pharmacol. Ther. (2014)

Bottom Line: 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).

View Article: PubMed Central - PubMed

Affiliation: Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

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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Related in: MedlinePlus

Relative frequencies of persistent variants over time in all patients.
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Figure 3: Relative frequencies of persistent variants over time in all patients.

Mentions: Sequences of intra-host HCV variants were not expected to accrue mutations over 48 hours of observation. However, we found that the relative frequencies of persistent variants changed during the time period in all patients (Figure 3). The developed mathematical model allowed calculation of the IFN resistance coefficient for each persisting intra-host HVR1 variant based on its relative frequency variations. IFN-resistance varied broadly among intra-host variants in all patients.


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

Campo DS, Skums P, Dimitrova Z, Vaughan G, Forbi JC, Teo CG, Khudyakov Y, Lau DT - Clin. Pharmacol. Ther. (2014)

Relative frequencies of persistent variants over time in all patients.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4215939&req=5

Figure 3: Relative frequencies of persistent variants over time in all patients.
Mentions: Sequences of intra-host HCV variants were not expected to accrue mutations over 48 hours of observation. However, we found that the relative frequencies of persistent variants changed during the time period in all patients (Figure 3). The developed mathematical model allowed calculation of the IFN resistance coefficient for each persisting intra-host HVR1 variant based on its relative frequency variations. IFN-resistance varied broadly among intra-host variants in all patients.

Bottom Line: 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).

View Article: PubMed Central - PubMed

Affiliation: Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

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.

Show MeSH
Related in: MedlinePlus