Cyclic changes in gene expression induced by Peg-interferon alfa-2b plus ribavirin in peripheral blood monocytes (PBMC) of hepatitis C patients during the first 10 weeks of treatment

Milton W. Taylor, Takuma Tsukahara, Jeanette McClintick, Howard Edenberg, Paul Kwo

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Abstract

Background and Aims: This study determined the kinetics of gene expression during the first 10 weeks of therapy with Pegylated-interferon-alfa2b (PegIntron™) and ribavirin (administered by weight) in HCV patients and compared it with the recently completed Virahep C study 12 in which Peginterferon-alfa2a (Pegasys™) and ribavirin were administered. Methods: RNA was isolated from peripheral blood monocytes (PBMC) from twenty treatment-naïve patients just before treatment (day 1) and at days 3, 6, 10, 13, 27, 42 and 70 days after treatment. Gene expression at each time was measured using Affymetrix microarrays and compared to that of day 1. Results: The expression of many genes differed significantly (p ≤ 0.001 and changed at least 1.5-fold) at days 3 (290 probes) and 10 (255 probes), but the number dropped at days 6 (165) and 13 (142). Most genes continued to be up regulated throughout the trial period. A second group of genes, including CXCL10, CMKLR1 (chemokine receptor 1), TRAIL, IL1Rα and genes associated with complement and lipid metabolism, was transiently induced early in treatment. CDKN1C (cyclin kinase inhibitor 1) was induced early but repressed at later times. Genes induced at later times were mostly related to blood chemistry and oxygen transport. By week 10, 11 of the patients demonstrated a positive response to therapy, and the final sustained viral response (SVR) was 35%. The levels of gene induction or decrease was very similar to that previously reported with Pegasys/ribavirin treatment. Conclusion: The response to Pegintron/ribavirin was similar to that reported for Pegasys/ribavirin despite some differences in the amount administered. We did not detect major differences at the genomic level between patients responding to treatment or non-responders, perhaps because of limited power. Gene induction occurred in a cyclic fashion, peaking right after administration of interferon and declining between administrations of the drug. Our data suggest that more than once a week dosing might be desirable early during treatment to maintain high levels of response as measured by gene expression.

Original languageEnglish
Article number66
JournalJournal of Translational Medicine
Volume6
DOIs
StatePublished - Nov 5 2008

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interferon alfa-2b
Ribavirin
Hepatitis C
Gene expression
Monocytes
Blood
Genes
Gene Expression
Interferons
Therapeutics
Patient treatment
Cyclins
Chemokine Receptors
Microarrays

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

@article{2783d0d2a1bc497ebf8b065244d6f5db,
title = "Cyclic changes in gene expression induced by Peg-interferon alfa-2b plus ribavirin in peripheral blood monocytes (PBMC) of hepatitis C patients during the first 10 weeks of treatment",
abstract = "Background and Aims: This study determined the kinetics of gene expression during the first 10 weeks of therapy with Pegylated-interferon-alfa2b (PegIntron™) and ribavirin (administered by weight) in HCV patients and compared it with the recently completed Virahep C study 12 in which Peginterferon-alfa2a (Pegasys™) and ribavirin were administered. Methods: RNA was isolated from peripheral blood monocytes (PBMC) from twenty treatment-na{\"i}ve patients just before treatment (day 1) and at days 3, 6, 10, 13, 27, 42 and 70 days after treatment. Gene expression at each time was measured using Affymetrix microarrays and compared to that of day 1. Results: The expression of many genes differed significantly (p ≤ 0.001 and changed at least 1.5-fold) at days 3 (290 probes) and 10 (255 probes), but the number dropped at days 6 (165) and 13 (142). Most genes continued to be up regulated throughout the trial period. A second group of genes, including CXCL10, CMKLR1 (chemokine receptor 1), TRAIL, IL1Rα and genes associated with complement and lipid metabolism, was transiently induced early in treatment. CDKN1C (cyclin kinase inhibitor 1) was induced early but repressed at later times. Genes induced at later times were mostly related to blood chemistry and oxygen transport. By week 10, 11 of the patients demonstrated a positive response to therapy, and the final sustained viral response (SVR) was 35{\%}. The levels of gene induction or decrease was very similar to that previously reported with Pegasys/ribavirin treatment. Conclusion: The response to Pegintron/ribavirin was similar to that reported for Pegasys/ribavirin despite some differences in the amount administered. We did not detect major differences at the genomic level between patients responding to treatment or non-responders, perhaps because of limited power. Gene induction occurred in a cyclic fashion, peaking right after administration of interferon and declining between administrations of the drug. Our data suggest that more than once a week dosing might be desirable early during treatment to maintain high levels of response as measured by gene expression.",
author = "Taylor, {Milton W.} and Takuma Tsukahara and Jeanette McClintick and Howard Edenberg and Paul Kwo",
year = "2008",
month = "11",
day = "5",
doi = "10.1186/1479-5876-6-66",
language = "English",
volume = "6",
journal = "Journal of Translational Medicine",
issn = "1479-5876",
publisher = "BioMed Central",

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TY - JOUR

T1 - Cyclic changes in gene expression induced by Peg-interferon alfa-2b plus ribavirin in peripheral blood monocytes (PBMC) of hepatitis C patients during the first 10 weeks of treatment

AU - Taylor, Milton W.

AU - Tsukahara, Takuma

AU - McClintick, Jeanette

AU - Edenberg, Howard

AU - Kwo, Paul

PY - 2008/11/5

Y1 - 2008/11/5

N2 - Background and Aims: This study determined the kinetics of gene expression during the first 10 weeks of therapy with Pegylated-interferon-alfa2b (PegIntron™) and ribavirin (administered by weight) in HCV patients and compared it with the recently completed Virahep C study 12 in which Peginterferon-alfa2a (Pegasys™) and ribavirin were administered. Methods: RNA was isolated from peripheral blood monocytes (PBMC) from twenty treatment-naïve patients just before treatment (day 1) and at days 3, 6, 10, 13, 27, 42 and 70 days after treatment. Gene expression at each time was measured using Affymetrix microarrays and compared to that of day 1. Results: The expression of many genes differed significantly (p ≤ 0.001 and changed at least 1.5-fold) at days 3 (290 probes) and 10 (255 probes), but the number dropped at days 6 (165) and 13 (142). Most genes continued to be up regulated throughout the trial period. A second group of genes, including CXCL10, CMKLR1 (chemokine receptor 1), TRAIL, IL1Rα and genes associated with complement and lipid metabolism, was transiently induced early in treatment. CDKN1C (cyclin kinase inhibitor 1) was induced early but repressed at later times. Genes induced at later times were mostly related to blood chemistry and oxygen transport. By week 10, 11 of the patients demonstrated a positive response to therapy, and the final sustained viral response (SVR) was 35%. The levels of gene induction or decrease was very similar to that previously reported with Pegasys/ribavirin treatment. Conclusion: The response to Pegintron/ribavirin was similar to that reported for Pegasys/ribavirin despite some differences in the amount administered. We did not detect major differences at the genomic level between patients responding to treatment or non-responders, perhaps because of limited power. Gene induction occurred in a cyclic fashion, peaking right after administration of interferon and declining between administrations of the drug. Our data suggest that more than once a week dosing might be desirable early during treatment to maintain high levels of response as measured by gene expression.

AB - Background and Aims: This study determined the kinetics of gene expression during the first 10 weeks of therapy with Pegylated-interferon-alfa2b (PegIntron™) and ribavirin (administered by weight) in HCV patients and compared it with the recently completed Virahep C study 12 in which Peginterferon-alfa2a (Pegasys™) and ribavirin were administered. Methods: RNA was isolated from peripheral blood monocytes (PBMC) from twenty treatment-naïve patients just before treatment (day 1) and at days 3, 6, 10, 13, 27, 42 and 70 days after treatment. Gene expression at each time was measured using Affymetrix microarrays and compared to that of day 1. Results: The expression of many genes differed significantly (p ≤ 0.001 and changed at least 1.5-fold) at days 3 (290 probes) and 10 (255 probes), but the number dropped at days 6 (165) and 13 (142). Most genes continued to be up regulated throughout the trial period. A second group of genes, including CXCL10, CMKLR1 (chemokine receptor 1), TRAIL, IL1Rα and genes associated with complement and lipid metabolism, was transiently induced early in treatment. CDKN1C (cyclin kinase inhibitor 1) was induced early but repressed at later times. Genes induced at later times were mostly related to blood chemistry and oxygen transport. By week 10, 11 of the patients demonstrated a positive response to therapy, and the final sustained viral response (SVR) was 35%. The levels of gene induction or decrease was very similar to that previously reported with Pegasys/ribavirin treatment. Conclusion: The response to Pegintron/ribavirin was similar to that reported for Pegasys/ribavirin despite some differences in the amount administered. We did not detect major differences at the genomic level between patients responding to treatment or non-responders, perhaps because of limited power. Gene induction occurred in a cyclic fashion, peaking right after administration of interferon and declining between administrations of the drug. Our data suggest that more than once a week dosing might be desirable early during treatment to maintain high levels of response as measured by gene expression.

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