Genes predict treatment response in hepatitis C.

MONTREAL -- A genetic signature involving 18 genes can reliably predict response to pegylated interferon [alpha] plus ribavirin therapy in patients infected with hepatitis C, reported Dr. Limin Chen at Canadian Digestive Diseases Week.

This finding "could form the basis for a diagnostic tool to encourage treatment compliance," Dr. Chen said in an interview. The results also confirm the findings of in vitro studies by Dr. Chen's group from the University of Toronto.

His group previously identified gene expression differences in the pretreatment liver biopsies of hepatitis C virus (HCV) patients who subsequently responded and those who failed to respond to pegylated interferon [alpha] plus ribavirin, showing that these two groups "differ fundamentally in their innate [interferon] response to HCV infection" (Gastroenterology 2005;128:1437-44).

Upregulation of an 18-gene signature known as USP18 predicted lack of response to treatment, and another study by the same group showed that silencing this gene signature in vitro could improve treatment response.

"We were able to show that if we silence this USP18 gene, the virus actually gets more sensitive to interferon. In other words, we can use much less interferon to kill the virus," Dr. Chen said.

The group's latest work validates the findings from a prospective cohort study of 78 HCV patients (mean age, 51 years): 23 nonresponders and 55 responders. Using pretreatment liver biopsies, "we confirmed that USP18 is more highly expressed in nonresponders," he said.

The study showed that the genetic evaluation of pretreatment liver biopsies with regard to this gene signature can predict treatment response with a positive predictive value of 96%. However, the sensitivity was only 50%. "Therefore, you cannot use it to exclude patients from treatment," he said.

Current combination treatment with pegylated interferon [alpha] plus ribavirin has only a 50% success rate, and patient compliance is jeopardized by the significant side effects and expense, Dr. Chen explained. Genetic markers such as USP18 that predict good treatment response might help physicians encourage compliance in certain patients, he said at the meeting, sponsored by the Canadian Association of Gastroenterology.

BY KATE JOHNSON

Montreal Bureau