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.
