Homo sapiens
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PROVIDER: PRJNA193148 | ENA |
REPOSITORIES: ENA
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Project description:Intrahepatic miRNA/mRNA expression in non-responders to pegylated interferon plus ribavirin combination therapy for chronic hepatitis C
| PRJNA182751 | ENA
Project description:Background/Aims: Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. Methods: 70 treatment-naïve patients were randomized to 4 weeks of ribavirin (1000-1200 mg/d) or none, followed by PEG-IFN alfa-2a and ribavirin at standard doses and durations. Patients were randomized to undergo a liver biopsy either 24 hours before, or 6 hours after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by the nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. Results: After four weeks of ribavirin monotherapy, HCV levels decreased by 0.5±0.5 log10 (p=0.009 vs. controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting the induction of ISGs by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs. 22% non-responders, p=0.01; early virological response, 100% vs. 68%, p=0.03, sustained virological response 83% vs. 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. Conclusion: Ribavirin is a weak antiviral but its clinical effect in combination with PEG-IFN seems to be mediated by a separate, indirect mechanism, which may act to reset the interferon responsiveness in HCV-infected liver. Ribavirin pretreatment does not alter the clinical outcome of subsequent combination therapy. Analysis of liver biopsy samples from 52 patients under 4 different treatment conditions.
2013-03-08 | E-GEOD-38663 | biostudies-arrayexpress
Project description:Background/Aims: Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. Methods: 70 treatment-naïve patients were randomized to 4 weeks of ribavirin (1000-1200 mg/d) or none, followed by PEG-IFN alfa-2a and ribavirin at standard doses and durations. Patients were randomized to undergo a liver biopsy either 24 hours before, or 6 hours after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by the nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. Results: After four weeks of ribavirin monotherapy, HCV levels decreased by 0.5±0.5 log10 (p=0.009 vs. controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting the induction of ISGs by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs. 22% non-responders, p=0.01; early virological response, 100% vs. 68%, p=0.03, sustained virological response 83% vs. 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. Conclusion: Ribavirin is a weak antiviral but its clinical effect in combination with PEG-IFN seems to be mediated by a separate, indirect mechanism, which may act to reset the interferon responsiveness in HCV-infected liver. Ribavirin pretreatment does not alter the clinical outcome of subsequent combination therapy.
2013-03-08 | GSE38663 | GEO
Project description:The combination of peginterferon and ribavirin is the standard treatment for chronic hepatitis C. Our recent clinical study suggests that ribavirin augments the induction of interferon stimulated genes (ISGs) in patients treated for HCV infection [1]. In order to further characterize the mechanisms of action of ribavirin, we examined the effect of ribavirin treatment on ISG induction in cell culture. In addition, the effect of ribavirin on infectious HCV cell culture systems was also studied. Similar to interferon-alpha, ribavirin potently inhibits JFH-1 infection of Huh7.5.1 cells in a dose-dependent manner, which spans the physiological concentration of ribavirin in vivo. Microarray analysis and subsequent quantitative PCR assays demonstrated that ribavirin treatment resulted in the induction of a distinct set of ISGs. These ISGs, including IRF7 and IRF9 are known to play an important role in anti-HCV responses. When ribavirin is used in conjunction with interferon, induction of specific ISGs is synergistic when compared to either drug applied separately. Direct up-regulation of these antiviral genes by ribavirin is mediated by a novel mechanism different from those associated with interferon signaling and intracellular double stranded RNA sensing pathways such as RIG-I and MDA5. RNA interference studies excluded the activation of the Toll-like receptor and NF-KappaB pathways in the action of ribavirin. In conclusion, our study suggests that ribavirin, acting via a novel innate mechanism, potentiates the anti-HCV effect of interferon. Understanding the mechanism of action of ribavirin would be valuable in identifying novel antivirals. RNA from three samples were treated with Ribavirin and compared to three PBS treated samples
2012-01-01 | E-GEOD-23031 | biostudies-arrayexpress
Project description:The combination of peginterferon and ribavirin is the standard treatment for chronic hepatitis C. Our recent clinical study suggests that ribavirin augments the induction of interferon stimulated genes (ISGs) in patients treated for HCV infection [1]. In order to further characterize the mechanisms of action of ribavirin, we examined the effect of ribavirin treatment on ISG induction in cell culture. In addition, the effect of ribavirin on infectious HCV cell culture systems was also studied. Similar to interferon-alpha, ribavirin potently inhibits JFH-1 infection of Huh7.5.1 cells in a dose-dependent manner, which spans the physiological concentration of ribavirin in vivo. Microarray analysis and subsequent quantitative PCR assays demonstrated that ribavirin treatment resulted in the induction of a distinct set of ISGs. These ISGs, including IRF7 and IRF9 are known to play an important role in anti-HCV responses. When ribavirin is used in conjunction with interferon, induction of specific ISGs is synergistic when compared to either drug applied separately. Direct up-regulation of these antiviral genes by ribavirin is mediated by a novel mechanism different from those associated with interferon signaling and intracellular double stranded RNA sensing pathways such as RIG-I and MDA5. RNA interference studies excluded the activation of the Toll-like receptor and NF-KappaB pathways in the action of ribavirin. In conclusion, our study suggests that ribavirin, acting via a novel innate mechanism, potentiates the anti-HCV effect of interferon. Understanding the mechanism of action of ribavirin would be valuable in identifying novel antivirals.
2012-01-01 | GSE23031 | GEO
Project description: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-naïve 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.
2009-05-03 | E-GEOD-11342 | biostudies-arrayexpress
Project description:Approximately 50% of patients with chronic hepatitis C (CHC) have a sustained virologic response (SVR) to treatment with pegylated interferon (pegINF)-α and ribavirin. Non-response to treatment is associated with constitutively increased expression of IFN-stimulated genes (ISGs) in the liver. Treatment of patients with acute hepatitis C (AHC) is more effective, with SVR rates >90%. We investigated mechanisms of the different responses of patients with CHC and AHC to pegIFN-α therapy. We analyzed IFN signaling and ISG expression in liver samples from patients with acute hepatitis C (AHC), patients with chronic hepatitis (CHC), and individuals without hepatitis C (controls) using microarray, immunohistochemical, and protein analyses. Findings were compared with those from primary human hepatocytes stimulated with IFN-α or IFN-γ, as reference sets. Expression levels of 100s of genes, primarily those regulated by IFN-γ, were altered in liver samples from patients with AHC compared with controls. Expression of IFN-γ–stimulated genes was induced in liver samples from patients with AHC, whereas expression of IFN-α–stimulated genes was induced in samples from patients with CHC. In an expression analysis of negative regulators of IFN-α signaling, we did not observe differences in expression of SOCS1 or SOCS3 between liver samples from patients with AHC and those with CHC. However, USP18 (another negative regulator of IFN-α signaling), was upregulated in liver samples of patients with CHC that did not respond to therapy, but not in AHC. In conclusion, differences in expression of ISGs might account for the greater response of patients with AHC, compared to those with CHC, to treatment with pegINF-α and ribavirin. Specifically, USP18 is upregulated in liver samples of patients with CHC that do not respond to therapy, but not in patients with AHC. (Interferon-γ Stimulated Genes, but not USP18, are Expressed in Livers of Patients with Acute Hepatitis C; Dill MT, Makowska Z et al, Gastroenterology 2012 (in press)) Primary human hepatocytes from 2 donors were analyzed. From each donor there are 5 samples: untreated cells, cells treated with interferon alpha (1000 IU/ml) for 6 and 24 hours and cells treated with interferon gamma (1000 IU/ml) for 6 and 24 hours.
2012-06-08 | E-GEOD-38147 | biostudies-arrayexpress
Project description:Hepatitis C virus (HCV) chronically infects 170 million people worldwide and is a leading cause of liver-related mortality due to hepatocellular carcinoma and cirrhosis1. Standard-of-care treatment is shifting from interferon-alpha (IFNM-NM-1)-based to IFNM-NM-1-free directly acting antiviral (DAA) regimens, which demonstrate improved efficacy and tolerability in clinical trials2,3. Virologic relapse after completion of DAA therapy is a common cause of treatment failure, although mechanisms are unclear2,3. We conducted a clinical trial using the DAA sofosbuvir with ribavirin (SOF/RBV)4, and report here detailed mRNA expression analysis of pre- and end-of-treatment (EOT) liver biopsies and blood samples. On-treatment viral clearance was accompanied by rapid down-regulation of interferon-stimulated genes (ISGs) in liver and blood. Analysis of paired liver biopsies from patients who achieved a sustained virologic response (SVR) revealed that viral clearance was accompanied by decreased expression of ISGs, IFNG, and IFNLs, but increased expression of IFNA2. Patients who achieved SVR had higher expression of a hepatic type-I interferon gene signature in unpaired EOT liver biopsies than patients who later relapsed. Together, these results support a model whereby restoration of type-I intrahepatic interferon signaling at the EOT is associated with sustained hepatic HCV suppression and prevention of relapse upon withdrawal of SOF/RBV. Sustained Virologic Response for Chronic Hepatitis C Patients Treated with Sofosbuvir and Ribavirin
2014-08-15 | E-GEOD-51699 | biostudies-arrayexpress
Project description: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-naïve 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. Keywords: Time Course, gene expression
2009-04-21 | GSE11342 | GEO
Project description:Gene profiling of responders and non-responders to antiviral therapies peg interferon and ribavirin against hepatitis C
| PRJNA98401 | ENA