Initial study results point to genetic marker related to drug-induced liver injury

Operating for a little under two years now, and publishing initial results from its first phase of research on the subject of serious drug-induced liver injury (DILI), the International Serious Adverse Events Consortium (SAEC) has reported that HLA-B*5701 is a major determinant of liver injury induced by flucloxacillin and thus a potential genetic marker for predicting which populations and individual patients may be at risk for DILI. HLA-B is one of a number of highly variable genes responsible for immune function.

Jeffrey Bouley
CHICAGO—Operating for a little under two years now, and publishing initial results from its first phase of research on the subject of serious drug-induced liver injury (DILI), the International Serious Adverse Events Consortium (SAEC) has reported that HLA-B*5701 is a major determinant of liver injury induced by flucloxacillin and thus a potential genetic marker for predicting which populations and individual patients may be at risk for DILI. HLA-B is one of a number of highly variable genes responsible for immune function.

In a Nature Genetics paper published online May 31, the SAEC and Newcastle University in the United Kingdom noted that an analysis of a subset of DNA patients shows that HLA-B*5701 is a major determinant of liver injury induced by flucloxacillin, an antibiotic widely used in Europe and Australia, mainly in the treatment of staphylococcal infections. In fact, the study found that individuals carrying at least one copy of HLA-B*5701 were 80 times to 100 times more likely than non-carriers to develop DILI in response to use of this antibiotic. 

The researchers point out that this risk-associated variant is relatively common in Europe, but less prevalent in Africa and East Asia. In addition to HLA-B*5701, variations on chromosome 3 were also found to influence the risk for DILI. However, while possession of this gene mutation presents a substantially higher risk of DILI than is seen among than non-carriers, only a small proportion of the people with this mutation actually develop liver problems in response to flucloxacillin.

As a result, the researchers stress that further analysis and research will be needed to determine whether a clinically useful biomarker test could be developed for this susceptibility. Still, they note, these findings provide initial insights into the mechanism of DILI and may have help them or other researchers to identify people at an increased risk for flucloxacillin-related liver injury. 

Interestingly, the HLA-B*5701 mutation is also associated with hypersensitivity reactions to the use of the drug abacavir, a nucleoside analog reverse transcriptase inhibitor (NRTI) used to treat HIV and AIDS, says Arthur L. Holden, founder and chairman of the SAEC, further suggesting that this discovery may have utility for other drug-related adverse events.

The SAEC is a non-profit research corporation, launched in the fall of 2007, comprised of and funded by 10 leading pharmaceutical companies and the Wellcome Trust. The U.S. Food and Drug Administration (FDA) also contributes to the scientific and strategic direction of this research effort. The collection and initial characterization of the DILI cases supporting these results was performed by the U.K.-based DILIGEN network, led by professor Ann Daly and colleagues at Newcastle University, but also involving researchers at the University of Liverpool and at Queen's Medical Centre in Nottingham.

Holden notes that his consortium is only midway through the first phase of their research, looking at people with DILI and the potential genetic markers associated with it. That work should be done in another six months, he says, to be followed by research that will expand the range of adverse conditions and reactions that are studied, as well as to expand the study cohorts into non-Caucasian directions and get a better handle on ethnic variances associated with DILI and other adverse drug reactions.

Patients respond differently to medicines, Holden pointed out, and all medicines can have adverse effects in some people. His organization's work is based on the hypothesis that many of these differences have a genetic basis.

"We are pleased to be able to provide these initial results to the research community, to both improve the productivity of drug development and to begin the critical process of developing validated biomarkers to forecast patients who may be at risk for DILI," Holden says. "To date, in conjunction with our collaborators, we have assembled one of the largest DILI research collections in the world. We expect additional important DILI genetic findings to emerge from these research efforts over the next 12 to 18 months."

"Our aim is to ensure that commonly prescribed drugs can be used more safely," adds Daly. "This is an important step in developing a test that can be used prior to prescribing flucloxacillin. We look forward to making further progress in the area of DILI research with our international collaborators."

The work of the SAEC and others in this area is critical, Holden notes, because the emergence of liver-related problems in even a handful of patients during drug development can easily scuttle an entire program and cost a company millions of dollars. The ability to determine if there are clearly definable subgroups who are likely to respond negatively to a given candidate drug could be a huge boon to companies looking to minimize risk both to clinical trial participants, final consumers, and themselves.

Because the risk of DILI even among carriers of HLA-B*5701 is low, Daly notes that she would not suggest at this point that that patients needing treatment with flucloxacillin should be genotyped before start of treatment. In general, the drug is inexpensive and generally safe and effective. But she does note that genotyping might possibly be useful for patients who present with liver disease of unknown cause, especially if there has been recent treatment with flucloxacillin.

Jeffrey Bouley

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