Genes Tied to Gap in Treatment of Hepatitis C

By NICHOLAS WADE

The standard treatment for infection with the Hepatitis C virus is a grueling 48-week course of the antiviral drugs interferon and ribavirin that gives some patients flulike symptoms and severe depression. The treatment varies in its effectiveness, being much more successful in Americans of European descent than in African-Americans.

A Duke University team has now uncovered the principal reason for the disparity between the races. It lies not in differing compliance to the treatment or access to health care, as some have assumed, but in genetics.

Using a genetic test called a genome-wide association study, the Duke team, led by David B. Goldstein and John McHutchison, found that the coding at a single site on the DNA, out of the three billion sites in the human genome, made all the difference in people’s response to the treatment.

The site is close to the gene for a special kind of interferon, known as interferon-lambda-3, and may help control the gene’s activity. Some people have the DNA unit T at this site, and others have C. Since a person inherits two copies of the genome, one from each parent, individuals may have T’s on both copies, C’s on both, or one T and one C.

People with the CC version, or allele, respond much better to the standard hepatitis treatment than do those with the TT allele. The C versions are more common in Europeans than in Africans, and this explains half of the difference in the response between the two races, the Duke team said in a report released Sunday on the Web site of the journal Nature.

The C versions are even more common among East Asians, about 75 percent of whom respond well to the standard treatment, compared with 55 percent of European-Americans and 25 percent of African-Americans.

People with the CC versions may produce more interferons, which are virus-fighting substances produced by cells, than those with TT, though the exact mechanism has yet to be worked out.

Dr. Goldstein, a population geneticist, said the different frequencies of the T and C versions were the result of natural selection, which is particularly effective in the case of disease resistance.

“We have clearly had very strong selection in the human population for resistance to different infectious agents, which have been of different importance in different parts of the world,” he said.

Presumably in the past some virus struck with particular severity in East Asia but was less potent in Europe and even milder in Africa. Dr. Goldstein said this virus might not have been the hepatitis C virus, which is spread by blood-to-blood contact, as when needles are shared, a practice common only in modern times. But he said he did not know what other virus might have been responsible.

He and Dr. McHutchison, a clinician, said a genetic test based on the finding would be of great interest to patients and physicians as a component of the decision on whether to undergo the standard treatment.

The study was financed by Schering-Plough, which owns the intellectual property rights on any diagnostic test developed from the discovery. Robert Consalvo, a spokesman for the company, said that the finding was an important first step but that he did not know of immediate plans to develop a diagnostic test. “Schering-Plough is not a diagnostic company,” Mr. Consalvo said.

Dr. McHutchison said a test would not be used to deny anyone treatment, but rather to determine a patient’s best options.

People who have a lower chance of benefiting from the grueling treatment because they have the TT allele might decide to wait until better drugs become available, especially if their liver damage is not severe. On the other hand, African-Americans with the CC allele might be more confident in accepting the treatment, Dr. McHutchison said.