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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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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.
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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.

Mentions: Not a single IFN-resistant variant was found in patients with RVR and only one of six cEVR patients showed IFN-resistant variants (Table 2 and Figure 4A). In contrast, patients with pEVR and NR were infected with an average number of 3.25 and 3.5 IFN-resistant intra-host variants, respectively (Figure 4A). The average number of IFN-resistant variants was significantly associated with the four outcomes (p = 0.0114), being 16.6 times lower for non-responders (pEVR and NR) than for responders (RVR and cEVR) (p = 0.0014). The average total fraction of reads with positive IFN-resistance values was also significantly different among the four outcomes (p = 0.0014) (Figure 4C). These observations suggest that the absence or presence of IFN-resistant variants and their frequency prior to single-dose IFN injection are strong predictors of treatment outcome.


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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

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.
Mentions: Not a single IFN-resistant variant was found in patients with RVR and only one of six cEVR patients showed IFN-resistant variants (Table 2 and Figure 4A). In contrast, patients with pEVR and NR were infected with an average number of 3.25 and 3.5 IFN-resistant intra-host variants, respectively (Figure 4A). The average number of IFN-resistant variants was significantly associated with the four outcomes (p = 0.0114), being 16.6 times lower for non-responders (pEVR and NR) than for responders (RVR and cEVR) (p = 0.0014). The average total fraction of reads with positive IFN-resistance values was also significantly different among the four outcomes (p = 0.0014) (Figure 4C). These observations suggest that the absence or presence of IFN-resistant variants and their frequency prior to single-dose IFN injection are strong predictors of treatment outcome.

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