Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human hepatitis PBMC C patients treated with Peg-interferon alfa-2b plus ribavirin during the first 10 weeks of treatment

ABSTRACT: Study of PBMC gene expression during the first 10 weeks of therapy with Pegylated-interferon-alfa2b (PegIntronTM) and ribavirin (administered by weight) in HCV patients. This study compared the kinetics of gene expression during the first 10 weeks of therapy with Pegylated-interferon-alfa2b (PegIntronTM) and ribavirin (administered by weight) in HCV patients with the recently completed Virahep C study (9999) in which Peginterferon-alfa2a and ribavirin was administered. RNA was isolated from peripheral blood monocytes from twenty treatment-naÃ¯ve patients just before treatment (day 0,) and at days 3, 6, 10, 13, 27, 42 and 70 days after treatment. Gene expression at each time was compared to that of day 0 using Affymetrix DNA-micro-arrays. Focusing upon genes that changed at least 1.5-fold and p<0.001, the numbers were high at day 3 (300 probes) and 10 (255) but dropped at days 6 (128) and 13 (142) but were steady at later time points. A large number of genes continued to be up regulated throughout the trial period. A second group of genes, including CXCL10, chemokine receptor 1, TRAIL, IL1 R and genes associated with complement and lipid metabolism, were transiently induced. 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. Genes down regulated were related to ribosomal proteins and eukaryotic translation complexes. By week 10, 50% of the patients demonstrated a positive response to therapy. Conclusions: The response to pegintron/ribavirin was similar to that reported for Pegasys/ribavirin, although the extent of gene induction was less. No differences were found between patients responding to treatment or non-responders during this period. Our data suggest that more than once a week dosing might be desirable early on during treatment. Experiment Overall Design: Time course, 20 individuals, samples taken before first treatment (day 0) and days 3, 6, 10, 13, 27, 42 and 70.

ORGANISM(S): Homo sapiens

SUBMITTER: Milton Taylor

PROVIDER: E-GEOD-11342 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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.

Taylor Milton W MW Tsukahara Takuma T McClintick Jeanette N JN Edenberg Howard J HJ Kwo Paul P

Journal of translational medicine 20081105

<h4>Background and aims</h4>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.<h4>Methods</h4>RNA was isolated from peripheral blood monocytes (PBMC) from twenty treatment-naïve patients just before treatment (day 1) and at ...[more]

PMID: 18986530

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Project description:Time series of gene expression arrays before and during treatment of Hepatitis C; days 0, 1, 2, 7, 14 and 28 for 69 participants (IDs 1 through 69 are used). Treating chronic hepatitis C using peginterferon alpha and ribavirin leads to sustained clearance of virus and clinical improvement in approximately 50% of patients. Response rates are lower among patients with genotype 1 than with genotypes 2 and 3 and among African American ( AA) compared to Caucasian (CA) patients. Using DNA microarrays, gene expression was assessed in a group of 33 African American and 36 Caucasian American patients with chronic hepatitis C, genotype 1 during the first 28 days of treatment. Results were examined with respect to treatment responses and to race. Patients showed a response to treatment at the gene expression level in RNA isolated from PBMC irrespective of degree of decrease in hepatitis C virus (HCV) RNA levels. However, gene expression responses were relatively blunted in patients with poor viral response (< 1.5 log10 IU/ml decrease at 28 days) compared to those in patients with a marked (> 3.5 log10 decrease) or intermediate (1.5 to 3.5 log10 decrease) response. The number of genes that were up- or down-regulated by peginterferon and ribavirin treatment was fewer in patients with a poor response compared to those with an intermediate or marked viral response. However AA patients had a stronger interferon response than CA patients in general. The induced levels of known ISGs such as OAS, MX1, IRF-7 and the toll like receptor TLR-7 was lower in poor response patients than in marked or intermediate response patients. Thus, the relative lack of viral response to interferon therapy of hepatitis C is associated with blunted interferon cell signaling. No specific regulatory gene could be identified as responsible for this global blunting or racial differences. Experiment Overall Design: Eligible patients were naÃ¯ve to interferon and ribavirin treatment, had detectable HCV RNA in serum, and nearly all had a liver biopsy performed within the previous 18 months showing chronic hepatitis. Only patients who were born in the United States and designated themselves as âAfrican American/Blackâ or âCaucasian/Whiteâ were eligible. The clinical protocol called for participants to be treated for up to 48 weeks with peginterferon alpha-2a (Pegasysâ¢, Roche Pharmaceuticals Nutley, NJ) in a dose of 180 Âµg weekly by self-administered subcutaneous injection and ribavirin (Copegusâ¢, Roche) orally in a dose of 1000 or 1200 mg daily based on body weight of less than 75 kg or equal to or greater than 75 kg. Peripheral blood mononuclear cells (PBMC) were collected from patients before treatment (day 0) and on days 1 (after the initial supervised injection of peginterferon), 2, 7, 14 and 28. From the Virahep-C cohort, 72 patients who did not have dose reductions of either peginterferon or ribavirin in the first 28 days of treatment were selected such that 12 patients were included in each race (CA, AA) by virological response category. The three categories of response were: marked, defined as a decrease in HCV RNA levels of more than 3.5 log10 IU/ml or to undetectable on day 28; intermediate, defined as a decrease of 1.4 to 3.5 log10 IU/ml on day 28; and poor, defined as less than 1.4 log10 IU/ml decline on day 28 relative to baseline. These definitions were made a priori in an attempt to analyze the biological basis for virological responses. Of these, adequate RNA was not obtained from 3 patients to provide gene expression information. Of these 72, 69 were analyzed.

Dataset Information

Transcription profiling of human hepatitis PBMC C patients treated with Peg-interferon alfa-2b plus ribavirin during the first 10 weeks of treatment

Publications

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.

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