Interferon-stimulated gene expression and hepatitis C viral dynamics during different interferon regimens

Asahina, Yasuhiro; Izumi, Namiki; Uchihara, Masakatsu; Noguchi, Osamu; Nishimura, Yuki; Inoue, Kazunari; Ueda, Ken; Tsuchiya, Kaoru; Hamano, Kenzo; Itakura, Jun; Miyake, Shozo

doi:10.1016/s0168-8278(03)00287-3

Cited by 24 publications

(26 citation statements)

References 28 publications

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“…In contrast, MxA gene expression was only detectable at very low levels before onset of treatment. This is consistent with an earlier study that showed an increase in MxA expression as early as 4 hr after administration of IFN to the patients [Asahina et al, 2003] and indicates that MxA is a specific and sensitive marker to measure type I IFN bioactivity.…”

Section: Discussionsupporting

confidence: 92%

Rapid and simple detection of IFN‐neutralizing antibodies in chronic hepatitis C non‐responsive to IFN‐α

Jorns

Holzinger

Thimme

et al. 2005

Journal of Medical Virology

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Different mechanisms have been proposed for the failure of interferon (IFN) therapy in patients with chronic hepatitis C and multiple sclerosis, for example, the presence of IFN-neutralizing antibodies. In this study, a novel assay system based on the IFN-inducible Mx-promoter was used to detect IFN-neutralizing antibodies in sera of patients with chronic hepatitis C. To monitor IFN bioactivity in IFN-treated patients, a real-time RT-PCR for MxA gene expression in PBMCs was established. Using these two methods, patients with chronic hepatitis C virus (HCV) infection receiving IFN therapy and patients with treatment induced HCV clearance were monitored. Importantly, neutralizing anti-IFN antibodies were detected in the sera of 3 of 38 chronically HCVinfected patients who failed to respond to therapy but none in sera of patients who cleared HCV after IFN therapy. Interestingly, the presence of these antibodies correlated with the lack of MxA induction in PBMCs after initiation of IFN-a therapy. Retrospective analysis of one patient's sera revealed that the anti-IFN-a antibodies had already developed after the first of four unsuccessful IFN therapies, suggesting that neutralizing antibodies may have contributed to the failure of previous IFN treatments. In summary, a novel screening assay was established that may be helpful for testing IFN non-responders for the presence of clinically relevant anti-IFN-a antibodies and for selecting alternative IFN preparations not neutralized by these antibodies.

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Section: Discussionsupporting

confidence: 92%

Rapid and simple detection of IFN‐neutralizing antibodies in chronic hepatitis C non‐responsive to IFN‐α

Jorns

Holzinger

Thimme

et al. 2005

Journal of Medical Virology

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“…In Japan, interferon-β (IFN-β) can is approved for the treatment of chronic hepatitis C. A characteristic of IFN-β is that dividing its administration between equal morning and evening doses increases the HCV-RNA reduction rate [11][12][13][14][15] . Studies have reported that the administration of 3 million units each of IFN-β in the morning and evening for 2 wk reduces HCV-RNA levels by 3 Log IU/mL in many cases, whereas the coadministration of Peg-IFN and RBV decreases them by 1-2 Log IU/mL [16,17] , clearly indicating that the former regimen results in a higher rate of HCV-RNA decrease in the early phase of treatment.…”

Section: Introductionmentioning

confidence: 99%

Twenty four-week peginterferon plus ribavirin after interferon-β induction for genotype 1b chronic hepatitis C

Okushin

Morii²,

Uesaka³

et al. 2010

WJH

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AIM:To investigate the possibility of shortening the duration of peginterferon (Peg-IFN) plus ribavirin (RBV) combination therapy by incorporating interferon-β (IFN-β) induction therapy. METHODS:A one treatment arm, cohort prospective study was conducted on seventy one patients. The patients were Japanese adults with genotype 1b chronic hepatitis C, HCV-RNA levels of ≥ 5.0 Log IU/mL or 100 KIU/mL, and platelet counts of ≥ 90 000/µL. The treatment regimen consisted of a 2 wk course of twicedaily administration of IFN-β followed by 24 wk Peg-IFN plus RBV combination therapy. We prolonged the duration of the Peg-IFN plus RBV therapy to 48 wk if the patient requested it. RESULTS:The patients, including 44% males, were characterized by an median age of 63 years (range: 32-78 years), an median platelet count of 13.9 (range: 9.1-30.6) × 10 4 /µL, 62% IFN-naïve, and median HCV-RNA of 6.1 (range: 5.1-7.2) Log IU/mL. The sustained virologic response (SVR) rates were 34% (Peg-IFN: 1-24 wk, n = 61, 95% confidence interval (CI): 24%-47%) and 55% (Peg-IFN: 20-24 wk, n = 31, 95% CI: 38%-71%, P < 0.001; vs Peg-IFN: 1-19 wk). The SVR rate when the administration was discontinued early was 13% (Peg-IFN: 1-19 wk, n = 30, 95% CI: 5%-30%), and that when the administration was prolonged was 50% (Peg-IFN: 25-48 wk, n = 10, 95% CI: 24%-76%, P < 0.05; vs Peg-IFN: 1-19 wk). In the patients who received 20-24 wk of Peg-IFN plus RBV, only the higher platelet count (≥ 130 000/µL) was significantly correlated with the SVR (odds ratio:11.680, 95% CI: 2.3064-79.474, P = 0.0024). In 45% (14/31) of the patients with a higher platelet count (≥ 130 000/µL) before therapy, the HCV-RNA level decreased to below 3.3 Log IU/mL at the completion of IFN-β, and their SVR rate was 93% (13/14) after 20-24 wk administration of Peg-IFN plus RBV. CONCLUSION:These results suggest the possibilities of shortening the duration of Peg-IFN plus RBV combination therapy by actively reducing HCV-RNA levels using the IFN-β induction regimen. Okushin H, Morii K, Uesaka K, Yuasa S. Twenty four-week peginterferon plus ribavirin after interferon-β induction for genotype 1b chronic hepatitis C.

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“…Several studies have reported gene expression in peripheral blood mononuclear cells (PBMCs) during the course of therapy; however, gene induction in PBMCs may not be entirely reflective of events in the liver. [7][8][9] The addition of ribavirin to interferon (IFN) therapy significantly improves the treatment response rates; however, the mechanism by which this occurs is poorly understood. Numerous mechanisms of action for ribavirin have been proposed, including inosine-5-monophosphate dehydrogenase inhibition (IMPDH), direct viral inhibition, increased mutagenesis leading to error catastrophe, and promotion of a Th1 immune response.…”

mentioning

confidence: 99%

Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response

et al. 2007

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The 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 (

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Interferon-stimulated gene expression and hepatitis C viral dynamics during different interferon regimens

Cited by 24 publications

References 28 publications

Rapid and simple detection of IFN‐neutralizing antibodies in chronic hepatitis C non‐responsive to IFN‐α

Rapid and simple detection of IFN‐neutralizing antibodies in chronic hepatitis C non‐responsive to IFN‐α

Twenty four-week peginterferon plus ribavirin after interferon-β induction for genotype 1b chronic hepatitis C

Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response

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