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HCV Response Linked Strongly to Gene Variant

BOSTON -- Additional analysis has confirmed that a polymorphism in an interferon-related gene is strongly associated with responses to standard treatments for hepatitis C virus (HCV) infection, a researcher said here.

Not only is the so-called CC variant of the IL28B gene associated with long-term responses to treatment with pegylated interferon (Pegasys, PEGIntron) and ribavirin (Rebetol), but it also predicts the speed of response, said Alexander J. Thompson, MD, of Duke University .

Thompson was part of a group that, in August, reported online in Nature that the CC genotype of IL28B, which encodes the lambda-3 form of interferon, is associated with sustained suppression of HCV. (See Gene Variant Predicts HCV Treatment Success)

Speaking here at the American Association for the Study of Liver Diseases meeting, Thompson reported on further analyses of the group's data, focusing on virologic responses after four and 12 weeks, referred to as rapid and early responses, respectively.

Thompson also provided additional insights into the effects on sustained responses, which were assessed 24 weeks after a 48-week treatment period with interferon and ribavirin.

As in the Nature report, the analysis used data on more than 1,600 participants in a clinical trial called IDEAL which compared the 2a and 2b forms of pegylated interferon in patients infected with HCV genotype 1. Genome-wide association studies were performed on tissue samples from these individuals, correlating their virologic responses to a large number of gene polymorphisms.

As Thompson reported here, sustained virologic response rates in patients with the CC genotype of IL28B were 69% in Caucasians, 48% in African-Americans, and 56% in Hispanics. For each group, these response rates were substantially higher than for two other genotypes, TC and TT.

Those ranged from 27% to 33% in whites, 13% to 15% in blacks, and 27% to 38% in Hispanics.

Overall, the adjusted odds ratio for sustained virologic response associated with CC versus the other genotypes was 5.2 (95% CI 4.1 to 6.7), the largest odds ratio of any pretreatment predictor.

Other baseline factors predicting sustained response rates included viral loads, white or Hispanic versus black ethnicity, baseline liver fibrosis, and fasting blood sugar.

Thompson said the IL28B genotype explained about half the difference in sustained response rates between Caucasians and African-Americans -- a difference that had been observed previously and which had never been adequately explained.
He reported that CC-genotype patients also responded more quickly to treatment in each ethnic group, compared with the TC and TT genotypes. At treatment week two, whites with the CC variant already showed log10 reductions in viral loads of 2.5, whereas white patients with the other genotypes had not yet achieved one-log reductions.

Differences were also apparent at weeks four and 12, Thompson said. However, the rate of decline in viral loads was about the same for all genotypes after week four.

The same pattern was seen in African-Americans and Hispanics, he said.

Another new finding was that the CC genotype predicted sustained responses in white patients who had not shown viral clearance by week four.

Those patients were 86% of the sample. More than half had the TC genotype and another 13% had the TT variant. In contrast, those who did achieve rapid virologic responses were predominantly the CC genotype (77%).

Nevertheless, in those not achieving rapid responses, 66% of those with the CC variant eventually obtained a sustained response, compared with 31% of TC and 24% of TT genotypes (P<0.0001), Thompson said.

Other researchers said the findings, when validated, would likely be practice-changing.

Scott Friedman, MD, president of AASLD and a hepatologist at Mount Sinai School of Medicine in New York City , predicted that IL28B genotype testing would become part of the standard of care once a test becomes clinically available.

Schering-Plough, which sells pegylated interferon-alfa-2b (PEGIntron), owns commercial rights to develop the genotype test.

A spokesman said the company was evaluating how best to bring it to market. He said Schering-Plough, which has little experience in developing or marketing diagnostic tests, was primarily interested in making it available as soon as possible.

He said the company had discussed nonexclusive licensing arrangements with other firms with the relevant capabilities, but no decisions had been made.

Friedman pointed out that, although genotype testing looked to be extremely useful in the short term, whether it would remain so when direct antiviral drugs for HCV become available -- expected in the next several years -- was unclear.
Thompson agreed that the IL28B polymorphism's effect on treatment response would have to be reevaluated for regimens including direct antivirals.

Other research needs include studies of the polymorphism in patients with nongenotype 1 HCV and whether it predicts responses to personalized duration of therapy.

In his presentation here, Thompson offered no new insights into the mechanism underlying the IL28B polymorphism's effects on treatment responses, beyond what the Nature paper had suggested -- namely, that interferon-lambda-3 helps mediate innate control of HCV.

This form of interferon appears to have its own unique receptor, but the downstream signalling path is believed to converge with that of interferon-alfa, the researchers said.

Primary source: American Association for the Study of Liver Diseases
Source reference:
Thompson A, et al "Genome wide analysis of patients from the IDEAL study identifies a polymorphism upstream of the Il28B (=IFNλ-3) gene that is strongly associated with SVR in patients with HCV-1" AASLD 2009; Abstract LB5. 

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