Hepatic gene expression before and during interferon and ribavirin combination therapy
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PROVIDER: S-DIXA-D-1037 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Patients who cleared HCV viremia early during therapy tended to show favorable outcomes, whereas patients who needed a longer period to clear HCV had poorer outcomes. We explored the mechanisms of treatment resistance by comparing hepatic gene expression before and during treatment
2009-12-31 | GSE17183 | GEO
Project description:Patients who cleared HCV viremia early during therapy tended to show favorable outcomes, whereas patients who needed a longer period to clear HCV had poorer outcomes. We explored the mechanisms of treatment resistance by comparing hepatic gene expression before and during treatment We explored the mechanisms of treatment resistance by comparing hepatic gene expression before and during treatment. Liver biopsy was performed in 30 patients before and one week after starting combination therapy with IFN + Rib. Hepatocytes and liver-infiltrating lymphocytes (LILs) were obtained from 12 patients using laser capture micro dissection (LCM).
2009-12-30 | E-GEOD-17183 | biostudies-arrayexpress
Project description:Treating chronic hepatitis C virus (HCV) infection using pegylated alpha interferon 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) patients compared to Caucasian (CA) patients. Using DNA microarrays, gene expression was assessed for a group of 33 African-American and 36 Caucasian American patients with chronic HCV genotype 1 infection 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 peripheral blood mononuclear cells irrespective of degree of decrease in HCV RNA levels. However, gene expression responses were relatively blunted in patients with poor viral response (<1.5 log(10)-IU/ml decrease at 28 days) compared to those in patients with a marked (>3.5 log(10)-IU/ml decrease) or intermediate (1.5 to 3.5 log(10)-IU/ml decrease) response. The number of genes that were up- or down-regulated by pegylated interferon and ribavirin treatment was fewer in patients with a poor response than in 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 interferon-stimulated genes such as the 2'5'-oligoadenylate synthetase, MX1, IRF-7, and toll-like receptor TLR-7 genes 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 virus infection is associated with blunted interferon cell signaling. No specific regulatory gene could be identified as responsible for this global blunting or the racial differences.
| S-EPMC1866036 | biostudies-literature
Project description:We present an analysis of the selective forces acting on two hepatitis C virus genome regions previously postulated to be involved in the viral response to combined antiviral therapy. One includes the three hypervariable regions in the envelope E2 glycoprotein, and the other encompasses the PKR binding domain and the V3 domain in the NS5A region. We used a cohort of 22 non-responder patients to combined therapy (interferon alpha-2a plus ribavirin) for which samples were obtained before initiation of therapy and after 6 or/and 12 months of treatment. A range of 25-100 clones per patient, genome region and time sample were sequenced. These were used to detect general patterns of adaptation, to identify particular adaptation mechanisms and to analyze the patterns of evolutionary change in both genome regions. These analyses failed to detect a common adaptive mechanism for the lack of response to antiviral treatment in these patients. On the contrary, a wide range of situations were observed, from patients showing no positively selected sites to others with many, and with completely different topologies in the reconstructed phylogenetic trees. Altogether, these results suggest that viral strategies to evade selection pressure from the immune system and antiviral therapies do not result from a single mechanism and they are likely based on a range of different alternatives, in which several different changes, or their combination, along the HCV genome confer viruses the ability to overcome strong selective pressures.
| S-EPMC2518109 | biostudies-literature
Project description:UnlabelledThe reasons for hepatitis C treatment failure remain unknown but may be related to different host responses to therapy. In this study, we compared hepatic gene expression in patients prior to and during peginterferon and ribavirin therapy. In the on-treatment group, patients received either ribavirin for 72 hours prior to peginterferon alpha-2a injection or peginterferon alpha-2a for 24 hours, prior to biopsy. The patients were grouped into rapid responders (RRs) with a greater than 2-log drop and slow responders (SRs) with a less than 2-log drop in hepatitis C virus RNA by week 4. Pretreatment biopsy specimens were obtained from a matched control group. The pretreatment patients were grouped as RRs or SRs on the basis of the subsequent treatment response. Gene expression profiling was performed with Affymetrix microarray technology. Known interferon-stimulated genes (ISGs) were induced in treated patients. In the pretreatment group, future SRs had higher pretreatment ISG expression than RRs. On treatment, RRs and SRs had similar absolute ISG expression, but when it was corrected for the baseline expression with the pretreatment group, RRs showed a greater fold change in ISGs, whereas SRs showed a greater change in interferon (IFN)-inhibitory pathways. The patients pretreated with ribavirin had heightened induction of IFN-related genes and down-regulation of genes involved in IFN inhibition and hepatic stellate cell activation.ConclusionThese data suggest that ISG inducibility is important for the treatment response and that ribavirin may improve outcomes by enhancing hepatic gene responses to peginterferon. Collectively, these mechanisms may provide a molecular basis for the improved efficacy of combination therapy.
| S-EPMC2808168 | biostudies-literature
Project description:Despite advance in interferon-based treatment for chronic hepatitis C, difficult-to-treat patients remain in existence yet. To identify key genes involved in difficult-to-treat characteristics, gene expression patterns of miRNA and RNA were analyzed by profiling pretreatment liver tissues from five sustained virological responders (SVR), three relapsers (R) and four non-responders (NR). Expression levels of miRNA and mRNA were compared between SVR/R and NR groups by using microarray, respectively. Quantitative real-time reverse-transcriptase polymerase chain reaction and statistical analyses validated genes with significantly differential expression levels in 50 liver tissues: proliferation-, inflammation- and anti-apoptosis-related mRNA expression levels increased significantly in NR, compared to SVR/R. Of miRNA with significantly differential expression levels on microarray, several miRNA were correlated inversely with those significant mRNA. In vitro studies by using miRNA inhibitors and mimics verified the inverse correlation between the miRNA and mRNA. These findings enhance our understanding of the difficult-to-treat molecular mechanism and identification of target molecules for novel treatments. Moderated t-statistics based on the empirical Bayes approach were performed to identify mRNA or miRNA differentially expressed between SVRs/relapses and NVRs using the “limma” package from BioConductor software (http://www.bioconductor.org/) under R statistical software version 2.12.1 (http://www.r-project.org/). Because of multiple hypothesis testing, p values were adjusted by the Benjamini-Hochberg false discovery rate (FDR) method. Related miRNA expression data are in GSE45179.
2014-05-14 | E-GEOD-42697 | biostudies-arrayexpress
Project description:Despite advance in interferon-based treatment for chronic hepatitis C, difficult-to-treat patients remain in existence yet. To identify key genes involved in difficult-to-treat characteristics, gene expression patterns of miRNA and RNA were analyzed by profiling pretreatment liver tissues from five sustained virological responders (SVR), three relapsers (R) and four non-responders (NR). Expression levels of miRNA and mRNA were compared between SVR/R and NR groups by using microarray, respectively. Quantitative real-time reverse-transcriptase polymerase chain reaction and statistical analyses validated genes with significantly differential expression levels in 50 liver tissues: proliferation-, inflammation- and anti-apoptosis-related mRNA expression levels increased significantly in NR, compared to SVR/R. Of miRNA with significantly differential expression levels on microarray, several miRNA were correlated inversely with those significant mRNA. In vitro studies by using miRNA inhibitors and mimics verified the inverse correlation between the miRNA and mRNA. These findings enhance our understanding of the difficult-to-treat molecular mechanism and identification of target molecules for novel treatments.
2014-05-14 | GSE42697 | GEO
Project description:We aimed to examine the relationship between renal dysfunction and anaemia that may develop during combination therapy involving pegylated interferon, ribavirin and telaprevir (PEG-IFN/RBV/TVR) for the treatment of chronic hepatitis C. Sixty-eight patients with genotype 1b high viral loads were treated with PEG-IFN/RBV/TVR. Peg-IFN and RBV doses were administered according to body weight. TVR was prescribed at 2250 mg/day for 44 patients and at 1500 mg/day for 24 patients who had low haemoglobin level (<12 g/dL). When anaemia had developed, the RBV dose was decreased. The serum TVR concentration at day 8 was measured, and the serum RBV concentration was measured serially. The estimated glomerular filtration rate (eGFR) was estimated to assess renal function. At week 1, serum TVR concentration was not correlated with a decrease in eGFR; however, the TVR dose, on a weight basis (mg/kg), and eGFR were correlated (r = 0.2691; P = 0.0265). Moreover, there was a negative correlation between eGFR and RBV serum concentration (r = −0.3694; P = 0.0025), and the serum RBV concentration and decrease in the haemoglobin were significantly correlated from week 1 to week 8. In triple therapy, the TVR dose per weight is correlated with a decline in renal function. Thus, the serum concentration of RBV increases, with a concomitant decrease in haemoglobin. It is important to adjust the doses of TVR and RBV to avoid excessive serum RBV levels and the development of severe anaemia, to achieve a good clinical effect.
| S-EPMC4282353 | biostudies-literature
Project description:AIM:To evaluate the implication of substitutions in the hepatitis C virus (HCV) non-structural 5A (NS5A) protein in the resistance of HCV during mono-interferon (IFN) or combined IFN-ribavirin (IFN-R) therapy. Although NS5A has been reported to interact with the HCV RNA-dependent RNA polymerase, NS5B, as well as with many cellular proteins, the function of NS5A in the life cycle of HCV remains unclear. METHODS:HCV quasispecies were studied by cloning and sequencing of sequential isolates from patients infected by HCV genotype 1b. Patients were treated by IFN-alpha2b for 3 mo followed by IFN-alpha2b alone or combined IFN-R therapy for 9 additional months. Patients were categorized into two groups based on their response to the treatments: 7 with sustained virological response (SVR) (quasispecies = 150) and 3 non-responders (NR) to IFN-R (quasispecies = 106). RESULTS:Prior to treatment, SVR patients displayed a lower complexity of quasispecies than NR patients. Most patients had a decrease in the complexity of quasispecies during therapy. Analysis of amino acids substitutions showed that the degree of the complexity of the interferon sensitivity-determining region (ISDR) and the V3 domain of NS5A protein was able to discriminate the two groups of patients. Moreover, SVR patients displayed more variability in the NS5A region than NR patients. CONCLUSION:These results suggest that detailed molecular analysis of the NS5A region may be important for understanding its function in IFN response during HCV 1b infection.
| S-EPMC4146993 | biostudies-literature
Project description:OBJECTIVES:The mechanism explaining the strong association between IL28B rs12979860 polymorphisms and treatment outcome in chronic hepatitis C remains unclear. We explore whether IL28B protein [interferon (IFN)-?3] plasma levels may vary according to IL28B genotype and/or following pegylated IFN-?/ribavirin therapy. PATIENTS AND METHODS:A total of 112 HIV/hepatitis C virus (HCV)-coinfected patients who completed a course of pegylated IFN-?/ribavirin therapy were examined. Sustained virological response (SVR) was achieved by 56% of patients. IL28B rs12979860 alleles were genotyped using the 5' nuclease assay with specific TaqMan probes. A specific enzyme immunoassay was used to measure IFN-?3 plasma levels before initiating anti-HCV therapy and at week 4 of treatment. RESULTS:No significant differences between CC and non-CC IL28B carriers were found at baseline, either in the proportion of patients with detectable IFN-?3 plasma levels or in their median values. In contrast, median IFN-?3 plasma levels at week 4 of therapy significantly increased with respect to baseline in CC carriers [34.3 (16.7-56.3) versus 15.6 (15.6-30.3) pg/mL, respectively; P < 0.0001], but not in CT/TT carriers. Unexpectedly, increases in IFN-?3 at week 4 of therapy did not predict SVR. CONCLUSIONS:The exogenous administration of IFN-? may induce IFN-?3 release in IL28B CC carriers, but not in CT/TT carriers. However, this finding does not account for the link between IL28B polymorphisms and treatment outcome.
| S-EPMC3695611 | biostudies-literature