Genetic Variant Predicts Success of Treatment in Chronic Hepatitis C

Jacquelyn K. Beals, PhD

August 21, 2009

August 21, 2009 — Researchers have identified a genetic variant that predicts the difference between white and black patients' responses to treatment for hepatitis C. The favorable genotype, which is associated with a 2-fold better response to treatment, is more common in white populations and accounts for about half the difference between the 2 ethnic groups with respect to treatment efficacy.

The new study, published online August 16 in Nature, identified a single nucleotide polymorphism (SNP) in a genomewide association study of more than 1600 American patients with chronic hepatitis C infection. Most patients were drawn from a study that compared treatment regimens including peginterferon-α-2b (PegIFN-α-2b) or PegIFN-α-2a in combination with ribavirin.

The criterion for successful treatment was sustained virological response (SVR), defined as the absence of detectable virus at the end of follow-up evaluation. SVR was assessed by a real-time polymerase chain reaction assay 24 weeks after the end of treatment (or by undetectable viral levels after 12 weeks if follow-up was unavailable).

Genotyping identified rs12979860, a SNP on chromosome 19 near IL28B — the gene that codes for interferon-λ-3 — that is highly associated with SVR in each population group (P = 1.06 × 10−25 in white patients; P = 2.06 × 10−3 in black patients; P for combined populations = 1.37 × 10−28). In each group, the highest percentage SVR occurred in patients with the CC genotype, response rates were intermediate in patients with the CT genotype, and patients with the TT genotype demonstrated the lowest percentage SVR.

"Eighty percent of those [patients] with the favorable response genotype eradicated the virus," senior author David Goldstein, PhD, director of the Center for Human Genome Variation, Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina, said in a statement. "[O]nly about 30 percent with the less favorable response genotype did so. With differences of that magnitude, patients considering therapy may want to know what their genotype is before they start treatment," he suggested.

The findings gain further support from the observation that patients of East Asian ancestry show higher SVR rates than do whites, and the C-allele is more frequent in East Asian populations, the researchers comment. In fact, a nearly linear relationship exists between percentage SVR and the C-allele frequency for (in ascending order) blacks, Hispanics, whites, and East Asians.

"Because [the CC genotype] appears significantly more often among Caucasian populations than it does among African populations, we feel it explains much of the difference in response rates we see between African-Americans and those of European ancestry," observed Dr. Goldstein. "This tells us that individual genetic makeup is a much more important determinant of response to treatment than is race or ethnicity."

Treatment for chronic hepatitis C infection typically requires 48 weeks of PegIFN-α-2b or PegIFN-α-2a in combination with ribavirin. Many patients experience only mild reactions, but others are unable to complete the therapy. Among the side effects are flulike symptoms, depression, nausea and vomiting, dehydration, fatigue, anemia, neutropenia, loss of appetite, skin reactions, and diarrhea. "The side effects of hepatitis treatment can be brutal, and about half the time the treatment fails to eradicate the virus," said Dr. Goldstein.

However, Mary Carrington, PhD, director of SAIC's Basic Research Program, SAIC-Frederick, Inc, National Cancer Institute, Frederick, Maryland, commented on the importance of treatment in an email to Medscape Gastroenterology. "Permanent liver damage and liver cancer can be fatal, so treatment is generally a good option, especially since its success rate is about 40 to 80 percent, though [it is] more like 30 percent in African-Americans," she said.

"[T]reatment for HCV infection overall can be awfully difficult," said Dr. Carrington, but he added: "If I were infected, I would want treatment regardless of my genotype. If I had a very difficult time tolerating the drugs, I would feel more inclined to continue if I had the CC genotype. One of the beauties of this study is that it presents the possibility that interferon-λ-3 may provide an alternative treatment regimen that could be easier to tolerate and that may be more successful in clearing the virus." Dr. Carrington also mentioned that a recent phase 2 study with interferon-λ-1 suggests that this product may have fewer side effects.

The present study demonstrated that the effect of the polymorphism on the efficacy of hepatitis C treatment was consistent in the Hispanics, whites, and blacks studied, and the SVR rates correlated strongly with the C-allele frequency in these groups, as well as in East Asians, say the researchers. Although at least 2 other SNPs in IL28B were too closely correlated with rs12979860 to completely resolve their effects, it seems clear that a polymorphism in IL28B contributes significantly to the variation in SVR rates across multiple ethnic groups.

"This discovery enables us to give patients valuable information that will help them and their doctors decide what is best for them," concluded Dr. Goldstein. "This is what personalized medicine is all about."

Dr. Goldstein is a paid consultant for Schering-Plough, which markets the interferon treatment. He is also an inventor on a patent for the IL28B polymorphisms as a potential diagnostic for interferon treatment response and would receive royalties if such tests are marketed. Dr. Carrington has disclosed no relevant financial relationships.

Nature. Published online August 16, 2009.


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