Certain Genes May Predict Hep Therapy Response: Study

     by John C. Martin
    Article Date: 05-18-05

While there are some indicators that may help physicians predict which of
their patients may or may not respond to hepatitis C treatment, such as a
particular strain of virus that's infected a person,1 it hasn't always been
easy to accomplish.

Now, a new study from Canada suggests that identifying a certain set of
genes in a patient may predict whether he or she will respond to therapy.2
The genes could also serve as a basis for a simple test in the future to
help doctors make treatment response predictions, the investigators wrote.

The current standard therapy using pegylated interferon and ribavirin is
successful in about 50 percent of people with the genotype 1 strain of HCV,
the most common strain in North America.3

"Our results demonstrate that a relatively small number of genes can predict
response to therapy," said Ian McGilvray, MD, PhD, a transplant surgeon at
Toronto General Hospital who led the study. "These genes may be important to
the ability of the patient to eliminate the virus, so studying these genes
in more detail will hopefully lead to novel antiviral treatments."

'Theragnostics' Focus
There currently is no test available for hepatitis C patients to help
doctors determine who may respond to therapy and who may not. This study is
still preliminary, and the findings must still be confirmed in patients
before any clinical application can be developed. But the results could pave
the way toward such an application someday.

The idea that genetics plays a role in therapy response has become more
prevalent in recent years in a number of diseases, explained McGilvray, who
is also an assistant professor of Surgery at the University of Toronto.
"It's one of the bases for what's called 'theragnostics'," he said.
"Essentially, it's combining therapeutics with diagnostics."

The approach is centered around the ability to tailor treatments to
individual patients based on their unique genetic profile, explained
McGilvray, in a telephone interview. He and his colleagues had been
interested in this approach relative to other liver diseases, and so it made
sense to investigate whether this was possible in hepatitis C, as well.

Gene Quest
The study followed 31 patients with chronic hepatitis C who were treated at
a Toronto-area hospital between 2001 and 2004. Liver biopsies were performed
on the patients before therapy, and the results were compared to 20 biopsies
that had also been performed on a group of people with healthy livers. All
patients were well matched by age, level of virus and extent of liver
disease, McGilvray and his colleagues reported. In the end, 16 patients did
not respond to HCV therapy and the other 15 did.

Next, McGilvray's team wanted to find which genes discriminated between
those patients who responded to therapy and those who did not. They used a
special test to analyze the pattern of genes in the patients. Essentially,
the different genes' level of expression, or activity, is analyzed using
this unique technology. Thus, researchers can determine which of the genes
are "turned on" and which are "turned off." They can then rapidly identify
sensitive changes in the genes associated with the various stages of
hepatitis C progression.

"We went into this experiment without any hypothesis about what to look
for," said Aled Edwards, PhD, one of the study's investigators and a
professor in the Banting and Best Department of Medical Research at the
University of Toronto. "We cast a very wide net, looking at 19,000 genes of
each of the patients."

Eventually, the researchers learned that the difference between those
patients who did not respond to therapy and those who did amounted to a
group of 18 genes. In those who did not respond to therapy, 16 of the genes
were active and two were not. "They're quite consistent. In fact, it's
surprising how consistent they are," said McGilvray, in describing the
genes' definitive pattern.

Many of the 16 genes that were turned on are stimulated by interferon, a
protein produced by the body to fight off hepatitis C viral infection.
Synthetic interferon is used as the standard treatment for hepatitis C
today. "Paradoxically, in the non-responders, the liver is revved up and the
genes are responding like mad," said McGilvray. "But there is something
about the response that just does not work."

In the future, McGilvray and his team hope that their findings can be serve
as a basis for a unique diagnostic tool, such as a simple blood test, that
could help clinicians determine which patients may respond to treatment, and
which may not. A blood test would be easier for people than a liver biopsy,
he said.

Confirming the Results
In the meantime, a second phase of this study-expected to last at least 12
months-is involving a larger number of patients who are currently taking
hepatitis C medication with the aim of validating the findings. The patients
have undergone liver biopsies and their gene profiles have been documented.
Now, the investigators will want to confirm that the gene patterns match up
with those who will eventually respond to treatment and those who won't. All
patients for this phase of the trial have been enrolled, according to the
investigators.

What's the study's take-home message? For one thing, it doesn't mean people
who are not likely to respond to therapy based on their genetic profile
would be refused treatment, McGilvray stressed. "Nobody would deny anyone
treatment on the basis of a blood test. It just doesn't make sense," he
said. "But on the other hand, if you test as a responder, it does give
people a rationale to continue on."

"Fundamentally, one of the reasons we got into this in the first place is
because treatment [for HCV] is pretty grueling," McGilvray added.

1. Trepo C. Genotype and viral load as prognostic indicators in the
treatment of hepatitis C. J Viral Hepat 2000 Jul;7(4):250-7.
2. Chen L, Borozan I, Feld J et al. Hepatic gene expression discriminates
responders and nonresponders in treatment of chronic hepatitis C viral
infection. Gastroenterology 2005 May;128(5):1437-44.
3. Shiffman ML. Management of patients with chronic hepatitis C virus
infection and previous nonresponse. Rev Gastroenterol Disord 2004;4 Suppl
1:S22-30.

John Martin is a long-time health journalist and an editor for Priority
Healthcare. His credits include overseeing health news coverage for the
website of Fox Television's The Health Network, and articles for the New
York Post and other consumer and trade publications.