Changes in Gene Expression during Pegylated Interferon and Ribavirin Therapy of Chronic Hepatitis C Virus Distinguish Responders from Nonresponders to Antiviral Therapy

Taylor, Milton W.; Teratani, Takuma; Brodsky, Leonid; Schaley, Joel E.; Sanda, Corneliu; Stephens, Matthew J.; McClintick, Jeanette N.; Edenberg, Howard J.; Li, Lang; Tavis, John E.; Howell, Charles D.; Belle, Steven H.

doi:10.1128/jvi.02640-06

Cited by 116 publications

(131 citation statements)

References 32 publications

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“…These findings in human patients are in accordance with observations in chimpanzees chronically infected with HCV (19). A human study reported a blunted response to IFN␣ in PBMCs of patients with a relative lack of viral response to treatment (26). In our group of 16 patients, we also detected a difference in the number of genes significantly changed at P Ͻ 0.05 in PBMCs between RR and non-RR patients ( Fig.…”

Section: Discussionsupporting

confidence: 81%

Interferon signaling and treatment outcome in chronic hepatitis C

Sinnreich

Oakeley²,

Duong³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

596

604

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Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The current standard therapy for chronic hepatitis C (CHC) consists of a combination of pegylated IFN alpha (pegIFN␣) and ribavirin. It achieves a sustained viral clearance in only 50 -60% of patients. To learn more about molecular mechanisms underlying treatment failure, we investigated IFN-induced signaling in paired liver biopsies collected from CHC patients before and after administration of pegIFN␣. In patients with a rapid virological response to treatment, pegIFN␣ induced a strong up-regulation of IFN-stimulated genes (ISGs). As shown previously, nonresponders had high expression levels of ISGs before therapy. Analysis of posttreatment biopsies of these patients revealed that pegIFN␣ did not induce expression of ISGs above the pretreatment levels. In accordance with ISG expression data, phosphorylation, DNA binding, and nuclear localization of STAT1 indicated that the IFN signaling pathway in nonresponsive patients is preactivated and refractory to further stimulation. Some features characteristic of nonresponders were more accentuated in patients infected with HCV genotypes 1 and 4 compared with genotypes 2 and 3, providing a possible explanation for the poor response of the former group to therapy. Taken together with previous findings, our data support the concept that activation of the endogenous IFN system in CHC not only is ineffective in clearing the infection but also may impede the response to therapy, most likely by inducing a refractory state of the IFN signaling pathway.Jak-STAT signaling ͉ liver ͉ viral hepatitis

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Section: Discussionsupporting

confidence: 81%

Interferon signaling and treatment outcome in chronic hepatitis C

Sinnreich

Oakeley²,

Duong³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

596

604

View full text Add to dashboard Cite

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“…Studies also highlight that protein kinase (PKR) mRNA levels in peripheral blood mononuclear cells (PBMC) and the liver correlated with nonresponse [Taylor et al 2007]. Recently, single nucleotide polymorphisms (SNPs) of suppressor of cytokine signalling 3 (SOCS3) was associated with variable response to antiviral therapy in hepatitis C virus (HCV) genotype-1-infected patients [Persico et al 2008].…”

Section: Genetic Diversitymentioning

confidence: 99%

Review: Predicting the probable outcome of treatment in HCV patients

Navaneethan

Kemmer

Neff

2009

Therap Adv Gastroenterol

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Hepatitis C virus (HCV) is a major cause of chronic liver disease infecting more than 170 million people worldwide. HCV produces a wide gamut of manifestations varying from mild self-limiting disease to cirrhosis and hepatocellular carcinoma. A variety of viral, environmental and host genetic factors contribute to the clinical spectrum of patients infected with HCV and influence response to interferon (IFN) therapy. Predicting the probable outcome of treatment in patients with HCV infection has always been a challenging task. Treatment of HCV by pegylated interferon (peg-IFN) plus ribavirin eradicates the virus in approximately 60% of patients HCV genotype 1 (4251% response rates) and genotypes 2 and 3 (7684% response rates); however, a significant number of patients do not respond to therapy or relapse following discontinuation of treatment or have significant side effects that preclude further treatment. Accurately predicting the patients who will respond to therapy is becoming increasingly important, both from the point of patient care and also with respect to the healthcare cost as clinicians need to continue treatment in patients who will respond and stop treatment in patients who are unlikely to respond. Viral RNA measurements and genotyping are used to optimize treatment as a low viral load and nongenotype 1 is more likely to be associated with sustained virological response (SVR). Rapid virological response (RVR) defined by undetectable HCV RNA at 4 weeks of treatment is increasingly being recognized as a powerful tool for predicting treatment response. A variety of host factors including single nuclear polymorphisms (SNPs) of IFN response genes, insulin resistance, obesity, ethnicity, human leukocyte antigens and difference in T-cell immune response has been found to modulate the response to antiviral treatment. The presence of severe fibrosis/cirrhosis on pretreatment liver biopsy predicts a poor response to treatment. Recent studies on gene expression profiling and characterization of the liver and serum proteome provide options to accurately predict the outcome of patients infected with HCV in the future. Future studies on the factors that predict treatment response and tailoring treatment based on this is required if we are to conquer this disease.

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“…Within 1 to 2 days, approximately 300 genes were modified by 2-fold or more (up-regulated or down-regulated). 51 No distinction in IFN-induced gene expression was identified by race or gender. However, fewer genes were modified in patients with a poor response in comparison to those with a marked or even intermediate viral response.…”

mentioning

confidence: 99%

Mechanisms of action of interferon and ribavirin in chronic hepatitis C: Summary of a workshop

et al. 2008

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The current recommended therapy for chronic hepatitis C is the combination of peginterferon and ribavirin, which results in a sustained clearance of hepatitis C virus (HCV) in at least half of patients. However, the mechanisms by which interferon alpha (IFN-α) and ribavirin act against HCV are not well defined. The importance of understanding the biological pathways, cellular effects, and antiviral activities of these agents is underscored by clinical observations that nonresponders frequently have little or no decrease in HCV RNA levels during treatment, suggesting intrinsic resistance to IFN-α. Cell culture and animal models of HCV have shown that the infection itself may block IFN-α induction and action. Still other findings suggest that individual innate and adaptive immune responses, host genetic factors, viral genetic diversity, and clinical comorbidities account for part of nonresponse to therapy. To provide an overview of the current knowledge of the mechanisms of action of IFN-α and ribavirin against HCV and offer guidance for future research, the American Association for the Study of Liver Diseases held a single topic conference entitled "Interferon and Ribavirin in Hepatitis C Virus Infection: Mechanisms of Response and Non-Response" on March [1][2][3] 2007. This article summarizes that conference. Interferons (IFNs): An OverviewThe IFNs (Dr. Howard Young, National Cancer Institute, National Institutes of Health)The type 1 IFNs [interferon alpha and beta (IFN-α/β)] comprise a family of distinct proteins1 that are produced by a wide variety of cells, including fibroblasts, epithelial cells, and hepatocytes, 2 although plasmacytoid dendritic cells (DCs) are probably the major source in most viral infections. In contrast, type II IFN [interferon gamma (IFN-γ)] is a single gene cytokine unrelated in structure to IFN-α/β that is produced largely by macrophages, natural Copyright © 2007 by the American Association for the Study of Liver Diseases.Address reprint requests to: Raymond T. Chung, M.D., Gastrointestinal Unit, GRJ724, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. rtchung@partners.org; fax: 617-643-0446.. Potential conflict of interest: Dr. Lemon is a consultant for Novartis, GlaxoSmithKline, Hoffman-LaRoche, Genelabs Technology, Abbott, Pharmasett. He also received grants from Schering-Plough and Tibotec. Dr. Chung received grants from Roche and ScheringPlough. NIH Public Access Author ManuscriptHepatology. Author manuscript; available in PMC 2009 December 29. Published in final edited form as:Hepatology. 2008 January ; 47(1): 306-320. doi:10.1002/hep.22070. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript killer (NK) cells, and T lymphocytes. Both types of IFNs interact with cells via distinct cellular receptors. The details of the signaling mechanisms by which IFN-α/β and IFN-γ induce the transcription of interferon-stimulated genes (ISGs) and depress the transcription of others are still being defined. 3 However, it is increasingly clear that the c...

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Changes in Gene Expression during Pegylated Interferon and Ribavirin Therapy of Chronic Hepatitis C Virus Distinguish Responders from Nonresponders to Antiviral Therapy

Abstract: Treating chronic hepatitis C virus (HCV) infection using pegylated alpha interferon and ribavirin leads to

Cited by 116 publications

References 32 publications

Interferon signaling and treatment outcome in chronic hepatitis C

Interferon signaling and treatment outcome in chronic hepatitis C

Review: Predicting the probable outcome of treatment in HCV patients

Mechanisms of action of interferon and ribavirin in chronic hepatitis C: Summary of a workshop

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