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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

HCV RNA level across all time-points. Patients are grouped according to treatment outcomes.
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Figure 1: HCV RNA level across all time-points. Patients are grouped according to treatment outcomes.

Mentions: HCV RNA level was measured at each time-point (Figure 1) and interpolated over the entire 48 hours. The titer declined in all patients, starting from an average of 4.76 hours after IFN injection (standard deviation [SD] 2.23 hours), with the lowest point being observed at 30.03 hours (S.D. 4.66 hours), and an average drop of 1.67 log10 IU/ml. The HCV RNA titer rised at 48 hours in all patients with an average increase of 0.86 log10 IU/ml compared to the lowest titer, which likely corresponded to the gradual clearance of the administered IFN (Figure 1). All calculations conducted in this paper used all time-points, but we found four time-points (0, 24, 36 and 48 hours) which are particularly critical for the calculation of resistance. This is due to the fact that the most important changes in viral titer occur around these time-points.


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)

HCV RNA level across all time-points. Patients are grouped according to treatment outcomes.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: HCV RNA level across all time-points. Patients are grouped according to treatment outcomes.
Mentions: HCV RNA level was measured at each time-point (Figure 1) and interpolated over the entire 48 hours. The titer declined in all patients, starting from an average of 4.76 hours after IFN injection (standard deviation [SD] 2.23 hours), with the lowest point being observed at 30.03 hours (S.D. 4.66 hours), and an average drop of 1.67 log10 IU/ml. The HCV RNA titer rised at 48 hours in all patients with an average increase of 0.86 log10 IU/ml compared to the lowest titer, which likely corresponded to the gradual clearance of the administered IFN (Figure 1). All calculations conducted in this paper used all time-points, but we found four time-points (0, 24, 36 and 48 hours) which are particularly critical for the calculation of resistance. This is due to the fact that the most important changes in viral titer occur around these time-points.

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