ACG: Gene Expression Predicts Sustained Response in Chronic Hepatitis C

PHILADELPHIA, Oct. 18 -- A panel of gene expression biomarkers can identify patients with chronic hepatitis C genotype 1 who are likely to achieve sustained virologic response to interferon-based therapy, results of a study reported here suggest.
Within seven days after the start of treatment, the gene expression panel had a sensitivity of 100% within 24 hours and a specificity of 92% for sustained virologic response, Zobair Younossi, M.D., of Inova Fairfax Hospital in Falls Church, Va., told attendees at the American College of Gastroenterology.
The biomarkers predicted response independent of conventional prognostic factors such as obesity and ethnicity, he added.
An estimated 75% to 80% of patients infected with HCV in the United States are genotype 1, which tends to confer the greatest resistance to treatment. Conventional clinical, demographic, and environmental prognostic factors have fairly limited utility for early identification of patients who will respond to treatment.
Dr. Younossi and colleagues performed mRNA profiling using six housekeeping genes and 317 mRNA transcripts from 160 genes. They performed logistic regression analysis to identify genes associated with response to therapy. They also evaluated patterns of gene expression in patients before and during treatment.
The researchers then developed predictive models that they applied to 44 patients chronically infected with HCV genotype 1. The study group comprised 19 treatment-naive patients and 25 who had not responded to prior therapy. Gene expression patterns were evaluated in each patient at baseline and then at days one, seven, 28, and 56.
Dr. Younossi reported data from analyses of gene expression models for predicting sustained virologic response before treatment, 24 hours after initiation of treatment, and seven days after starting treatment. Treatment consisted of pegylated interferon-alfa plus ribavirin.
In the treatment-naive cohort, a two-gene panel consisting of EP300 and SOC56 had a sensitivity of 86% and a specificity of 91% for predicting response before treatment.
During the first 24 hours after initiation of treatment, the combination of IL1B and ADAM9 yielded a sensitivity of 86% and a specificity of 91% for sustained virologic response.
At seven days a model focusing on changes in expression of PRKRIR yielded a sensitivity of 100% and a specificity of 75%.
Dr. Younossi said pretreatment gene expression in the treatment-experienced patients included upregulation of IFR-2 a negative regulator of interferon signaling. After initiation of therapy, changes in activity were observed in a variety of signaling cascades involved in apoptosis, proliferation, and lymphocyte metabolism.
IRF-2 provided the best pretreatment prognostic accuracy for the treatment-experienced patients. The model had a sensitivity of 62.5% and a specificity of 87.5%.
At 24 hours after the start of treatment, a model derived from expression patterns of two genes-IFIT2 and JAK1-resulted in a sensitivity of 100% and a specificity of 75%.
At seven days, a six-gene panel had a sensitivity of 100% and a specificity of 92.3% for predicting sustained virologic response.
Although the results are promising, Dr. Younossi said the prognostic strategy requires validation in additional studies involving more patients.
Dr. Younossi disclosed no conflicts. The study was supported by Celera Diagnostics in Alameda, Calif., and several of the investigators are Celera employees. Primary source: American College of GastroenterologySource reference: Yousonni Z et al. "Gene expression biomarkers can predict sustained virologic response early after initiation of pegylated interferon alfa and ribavirin in patients with genotype 1 chronic hepatitis C." American College of Gastroenterology Annual Meeting and Postgraduate Course. Oct. 12-17, 2007. Philadelphia. Abstract 29.