SUMMARY: Variations in the IL28B gene, which are associated with spontaneous hepatitis C virus (HCV) clearance and response to interferon, also appear to influence the speed of HCV recurrence, treatment response, and complications after liver transplantation, according to 2 studies presented at the recent American Association for the Study of Liver Diseases "Liver Meeting" (AASLD 2010) in Boston. Transplant outcomes were linked not only to the IL28B pattern of the recipient, but also variations in the new donor liver.

By Liz Highleyman

In 2009 researchers first reported that variations in the human genetic code near the IL28B gene can help predict outcomes among people with hepatitis C.

Single nucleotide polymorphisms, or SNPs, are substitutions of a single nucleotide building block at a specific position in a DNA chain. A number of SNPs -- most often12979860 -- near the IL28B gene have been implicated. This gene encodes instructions for making interferon lambda, or interleukin 28.

Each individual carries 2 copies of every gene, one from each parent. The IL28B rs12979860 SNP has 2 variations, or alleles, "C" and "T." Hepatitis C patients with the homozygous or matching C/C pattern (2 copies of the "C" allele) are most likely to spontaneously clear HCV and have the best response to interferon-based therapy. People with the T/T pattern (2 "T" alleles) have the least favorable response, while those with the heterozygous or mixed C/T pattern (1 copy of each variation) fall in between.

A number of studies presented at this year's Liver Meeting indicated that IL28B variations may also predict extent of liver fibrosis and necro-inflammation.

Michael Charlton and colleagues looked at the prevalence and impact on clinical outcomes of donor and recipient IL28B gene patterns among 189 hepatitis C patients who underwent liver transplantation between 1995 and 2005 at the Mayo Clinic in Rochester; 65 of them received interferon-based therapy.

Results

	The rs12979860 C/C pattern was less common among liver recipients (33%) than it was in donor livers (47%), meaning some patients with a less favorable gene pattern got a new liver with a more favorable pattern.
	Recipients with the protective C/C pattern had a longer time before post-transplant HCV recurrence.
	The C/C pattern in either the recipient or the donor liver was independently associated with greater likelihood of sustained treatment response:
	Both recipient and donor with C/C: SVR 86%; Donor but not recipient with C/C: SVR 50%; Recipient but not donor with C/C: SVR 42%; Neither recipient nor donor with C/C: SVR 16%.
	IL28B gene pattern was not, however, significantly associated with overall survival or risk of liver-related death.

"Recipient IL28B genotype is associated with more rapid histological recurrence of HCV," the researchers concluded. "Recipient and donor liver IL28B genotype are strongly and independently associated with interferon-based treatment response in patients post-[transplant]."

"The data suggest that C/C donor livers might be preferentially allocated to patients with HCV infection," they recommended.

A related Spanish study also looked at the relationship between IL28B variations and liver transplant outcomes.

M. Coto-Llerens from IDIBAPS in Barcelona and colleagues investigated the influence of IL28B polymorphisms on response to interferon/ribavirin in 18 hepatitis C patients before (while on the waiting list) and after liver transplantation. They considered both rs12979860 and another nearby IL28B SNP, rs8099917.

Again, while transplant recipients were most likely to have a mixed IL28B pattern (68% for both rs12979860 C/T and rs8099917 G/T), donated livers were most likely to show the homozygous protective pattern (58% for rs12979860, 85% for rs8099917).

Before transplantation, everyone with the protective rs12979860 or rs8099917 pattern responded to treatment (HCV RNA decline of at least 2 log by week 12), as did 77% of patients with the mixed rs12979860 and 62% with the mixed rs8099917 patterns.

After transplantation, the likelihood of treatment response was higher among individuals who received new livers from donors with protective rs12979860 or rs8099917 patterns (82% and 73% response, respectively).

There were 3 pre-treatment responders who became post-treatment non-responders, and 4 people who changed from non-responders to responders. These 4 did not carry protective IL28B patterns themselves, but became responders after receiving donor livers that did.

This research team likewise suggested that, "the allocation of [liver] grafts with a favorable genetic background could improve sensitivity to therapy after liver transplantation."

Investigator affiliations:

Charlton study: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN; Duke Clinical Research Institute, Duke University Medical Centre, Durham, NC; Division of Transplantation Surgery, Mayo Clinic, Rochester, MN; Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, Netherlands.

Coto-Llerena study: Liver Unit, IDIBAPS, CIBEREHD, Hospital Clinic, Barcelona, Spain; Immunology Department, Centre de Diagnostic Biomedic, Hospital Clinic, Barcelona, Spain.

11/19/10

References

MR Charlton, AJ Thompson, BJ Veldt, and others. IL28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with HCV with HCV Infection. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 1.

M Coto-Llerena, S Perez-del-Pulga, G Crespo, and others. IL28B polymorphisms may improve response to hepatitis C therapy after liver transplantation. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 1140.