Genetic
Variation Helps Explain Differences in Response to Interferon-based Therapy for
Hepatitis C  | Researchers
recently reported that a genetic polymorphism in the human genome is associated
with favorable response to interferon-based therapy for chronic hepatitis C virus
(HCV). Reporting in the August
6, 2009 advance online edition of Nature, the study authors estimated
that this variation -- which is much more common among patients of European compared
with African descent -- may account for about half of the well-known difference
in response rates between white and black hepatitis C patients. |
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By
Liz Highleyman  Numerous
studies have confirmed that black patients do not respond as well as whites to
hepatitis C treatment using conventional
or pegylated interferon plus ribavirin, while people of East Asian descent
appear to respond slightly better. To date, however, researchers have not determined
the reasons underlying these differences.
Because
hepatitis C treatment is of limited efficacy in hard-to-treat patients and involves
considerable side effects and expense, it is useful to be able to predict in advance
whether a particular individual is likely to respond well to therapy. The
authors of the present study analyzed genetic material from 1671 patients with
HCV genotype 1 in the IDEAL study, a randomized clinical trial comparing pegylated
interferon alfa-2a (Pegasys) versus 2 different doses of pegylated
interferon alfa-2b (PegIntron), all with weight-adjusted ribavirin. As
recently reported in the New England Journal of Medicine, the study
showed that the 2 forms of pegylated interferon worked equally well. The
researchers determined that a genetic polymorphism -- or variation in a single
nucleotide building block at a specific position in the genome -- was associated
with an approximately 2-fold increase in response to treatment. Rather
than directly targeting HCV itself, interferons -- synthetic versions of immune
system proteins that are the mainstay of hepatitis C treatment -- work by stimulating
the body's natural immune response against the virus. The flu-like side effects
are similar to symptoms to occur when the immune system is fighting an invader.
The variation identified in this study occurs near the IL28B gene, which encodes
interferon-lambda-3 The
variation involves a nucleotide switch from a C (cytosine) to a T (thymine). Since
people inherit DNA from both parents, each individual carries 2 gene "versions,"
or alleles, at any given position. At the pinpointed location, a person can have
1 of 3 possible combinations: CC, TT, or CT. In this analysis, individuals who
carried the CC genotype had a sustained virological response rate of about 80%,
compared with about 30% for those who lacked the polymorphism. The
IL28B polymorphism was linked to good treatment response in both whites and blacks
-- in fact, African-Americans who had the favorable genotype had a higher sustained
response rate than Caucasians who did not (53% vs 33%). But people of European
ancestry are significantly more likely than African-Americans to carry this variation.
The favorable pattern is even more common among East Asians, while Latinos/Hispanics
fall somewhere between blacks and whites. "Because
the genotype leading to better response is in substantially greater frequency
in European than African populations, this genetic polymorphism also explains
approximately half of the difference in response rates between African-Americans
and patients of European ancestry," the investigators concluded. The
researchers also found, unexpectedly, that having the favorable "CC"
genotype was associated with higher baseline HCV viral load -- a factor usually
associated with poorer treatment response. "It
was thrilling to discover such an important biological marker related to response
to hepatitis C treatments, but at the same time, the findings tell us there is
a lot more work to do before we can fully understand how patients' immune systems
protect them from the virus," co-investigator John McHutchison, MD, from
the Duke Clinical Research Institute said in a media announcement issued by the
university. This
study is the latest in a growing body of knowledge about how genetic differences
influence disease and its treatment. Further research in this area may, in the
future, allow clinicians to predict which specific patients will respond to a
given therapy, allowing for truly individualized treatment rather than educated
guesswork based on larger, less accurate categories such as race/ethnicity or
gender.
"For geneticists, understanding response to treatment for
hepatitis C infection has been almost like a Holy Grail," said senior author
David Goldstein, PhD, from Duke's Center for Human Genome Variation. "This
discovery enables us to give patients valuable information that will help them
and their doctors decide what is best for them. This is what personalized medicine
is all about." Institute
for Genome Sciences & Policy, Center for Human Genome Variation, Duke University,
Durham, NC; Duke Clinical Research Institute and Division of Gastroenterology,
School of Medicine, Duke University, Durham, NC; Schering-Plough Research Institute,
Kenilworth, NJ; Johns Hopkins University School of Medicine, Baltimore, MD. 8/21/09 Reference
D
Ge, J Fellay, AJ Thompson, and others. Genetic variation in IL28B predicts hepatitis
C treatment-induced viral clearance. Nature. August 16, 2009 [Epub ahead
of print]. (Abstract).
Other
source
Duke
University. New Biomarker Predicts Response To Hepatitis C Treatment. Press release.
August 16, 2009.
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