Hepatic Gene Expression Discriminates Responders and Nonresponders in Treatment of Chronic Hepatitis C Viral Infection

doi:10.1053/j.gastro.2005.01.059

Gastroenterology

Volume 128, Issue 5, May 2005, Pages 1437-1444

https://doi.org/10.1053/j.gastro.2005.01.059 Get rights and content

Background & Aims: Pegylated interferon (IFN)-α plus ribavirin is the most effective treatment of chronic hepatitis C but has unpleasant side effects and high costs. A large proportion of patients do not respond to therapy for reasons that are unclear. We used gene expression profiling to investigate the molecular basis for treatment failure. Methods: Expression profiling was performed on percutaneous needle liver biopsy specimens taken before therapy. Gene expression levels were compared among 15 nonresponder, 16 responder, and 20 normal liver biopsy specimens. Differential gene expression was confirmed using real-time polymerase chain reaction. Results: We identified 18 genes whose expression differed significantly between all responders and all nonresponders (P < .005). Many of these 18 genes are IFN sensitive and 2 (ISG15/USP18) are linked in a novel IFN-regulatory pathway, suggesting a possible rationale for treatment resistance. Using a number of independent classifier analyses, an 8-gene subset accurately predicted treatment response for 30 of 31 patients. The classifier analyses were applicable to patients with genotype 1 infection and were not correlated with viral load, disease activity, or fibrosis. Conclusions: Hepatic gene expression profiling identified consistent differences in patients who subsequently fail treatment with pegylated IFN-α plus ribavirin: up-regulation of a specific set of IFN-responsive genes predicts nonresponse to exogenous therapy. These data may be of use in predicting clinical responses to treatment.

Section snippets

Chronic HCV

Thirty-one patients with chronic HCV (23 genotype 1, 4 genotype 2, 3 genotype 3, and 1 genotype 6) were treated at University Health Network from October 2001 to May 2004. All treatment-naive patients considering treatment with IFN/ribavirin underwent percutaneous liver biopsy (via a 15-gauge needle) and had baseline viral loads determined. Treatment consisted of pegylated IFN-α2a/2b 180 μg weekly by subcutaneous injection and oral ribavirin 800–1200 mg daily (depending on genotype and weight)

A Gene Expression Profile That Discriminates Rs and NRs

The patients in this study were well matched for most clinical variables with the exception of viral genotype and sex (Table 2). There were no significant differences between R and NR patients when compared for age, baseline viral load, disease activity, hepatic fibrosis, compliance to therapy, or dose reduction. Patients with genotype 1 infection had the highest failure rate with therapy and accounted for all NR patients in our cohort.

To define which genes discriminate between HCV infection of

Discussion

Our study compared hepatic gene expression profiles from liver biopsy specimens taken from 31 patients before treatment with pegylated IFN-α plus ribavirin. We identified 18 genes, confirmed by real-time PCR, with expression levels that differed consistently between NR and R liver tissue and were not correlated to any obvious clinical parameter. The raw data set can be accessed at http://142.150.56.35/∼LiverArrayProject/home.html. Levels for these 18 genes in R liver were closer to uninfected

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: L.C. and I.B. contributed equally to the studies presented in this report.

: Supported by grants from the PSI Foundation and the Canadian Institute of Health Research (no. 62488).

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Microarrays and other technologyHepatic Gene Expression Discriminates Responders and Nonresponders in Treatment of Chronic Hepatitis C Viral Infection

Section snippets

Chronic HCV

A Gene Expression Profile That Discriminates Rs and NRs

Discussion

Lancet

Virology

Virology

Hepatology

Hepatology

J Biol Chem

Gastroenterology

J Biol Chem

Biochem Biophys Res Commun

J Biol Chem

National Institutes of Health Consensus Development Conference Statementmanagement of hepatitis

Hepatology

Activation of the interferon-inducible 2′-5′-oligoadenylate synthetase gene by hepatitis C virus core protein

J Virol

Number and position of mutations in the interferon (IFN) sensitivity-determining region of the gene for nonstructural protein 5A correlate with IFN efficacy in hepatitis C virus genotype 1b infection

J Infect Dis

Effect of interferon treatment on serum 2′-5′-oligoadenylate synthetase levels in hepatitis C-infected patients

J Med Virol

Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infectionroles of MxA, OAS-1 and PKR

Genes Immun

Microarrays and other technology
Hepatic Gene Expression Discriminates Responders and Nonresponders in Treatment of Chronic Hepatitis C Viral Infection