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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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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.
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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.

Mentions: The demographics and clinical features of the 16 study patients are summarized in Table 1, which includes their gender, race, grade of hepatic inflammation and fibrosis, IL28 genotype (see also figure 2A) and therapy outcome according to the clinical criterion of treatment success11, 12: (i) Rapid Virological Response (RVR) is defined as having undetectable HCV RNA by week 4 of therapy (n=4); (ii) Early Virological Response (cEVR): undetectable HCV RNA by week 12 of therapy (n=6); (iii) partial Early Virological Response (pEVR): a decrease of HCV RNA more than 2 log10 but still detectable after 12 weeks of therapy (n=4); and (iv) non-response (NR): decrease of HCV RNA less than 2 log10 after 12 weeks of therapy (n=2). The inefficiency of IL28B as the sole predictor of IFN-based therapeutic response is highlighted in Figure 2A, which displays the number of patients by IL28B status and therapy 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)

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.
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Related In: Results  -  Collection

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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.
Mentions: The demographics and clinical features of the 16 study patients are summarized in Table 1, which includes their gender, race, grade of hepatic inflammation and fibrosis, IL28 genotype (see also figure 2A) and therapy outcome according to the clinical criterion of treatment success11, 12: (i) Rapid Virological Response (RVR) is defined as having undetectable HCV RNA by week 4 of therapy (n=4); (ii) Early Virological Response (cEVR): undetectable HCV RNA by week 12 of therapy (n=6); (iii) partial Early Virological Response (pEVR): a decrease of HCV RNA more than 2 log10 but still detectable after 12 weeks of therapy (n=4); and (iv) non-response (NR): decrease of HCV RNA less than 2 log10 after 12 weeks of therapy (n=2). The inefficiency of IL28B as the sole predictor of IFN-based therapeutic response is highlighted in Figure 2A, which displays the number of patients by IL28B status and therapy 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