Liver transplantation and hepatitis C: Will understanding the interleukin-28B polymorphisms improve outcomes?

Abstract

The prediction of treatment outcomes for patients with chronic hepatitis C virus (HCV) infection has been revolutionized by the finding of a strong association between single-nucleotide polymorphisms (SNPs) near the interleukin-28B (IL-28B) gene and sustained virological response (SVR) after pegylated interferon and ribavirin-based therapy for HCV genotype 1 infection. This startling finding came from 3 independent studies that were published almost simultaneously in the second half of 2009; they were conducted in the United States, in Japan, and by an Australia-based collaborative group. 1-3 These genome-wide association studies essentially reported the same finding: certain SNPs near the region encoding IL-28B [interferon type 3 or interferon-k (IFN-k)] were associated with either nonresponse or SVR with odds ratios of approximately 2.0 in unselected populations. Although some SNPs were shared between studies, others differed because the suppliers and the resolutions of the chips employed by the genome-wide association studies differed. Patients who were homozygous for a favorable SNP had an SVR rate of approximately 60%, whereas patients who were homozygous for an unfavorable allele had an SVR rate of 30%. The details of these findings have been the subject of several commentaries, 4-7 and the original findings will not be discussed further here. Thus far, the exact mechanisms by which this association results in higher SVR rates remain unclear; however, these data have invigorated research into both the prediction of treatment outcomes and the mechanisms controlling HCV replication and clearance. Since the publication of the original studies, several other findings have emerged, and these include associations of the favorable SNPs with the following:

Meta‐analysis: IL28B polymorphisms predict sustained viral response in HCV patients treated with pegylated interferon‐α and ribavirin

“…Among the 60 initially identified studies with potential relevance, 24 were excluded based on the study population having: spontaneous clearance of HCV ( n = 6); HIV co‐infection ( n = 6); liver transplant ( n = 6); decompensated liver cirrhosis or HCC ( n = 3); treatment with non‐PEG IFN ( n = 1); and no SVR data for IL28B rs12979860 or rs8099917 polymorphisms ( n = 2). In addition, 11 articles were excluded for being: reviews ( n = 10); and an earlier publication of a multi‐published trial ( n = 1).…”

Early viral load and recipient interleukin-28B rs12979860 genotype are predictors of the progression of hepatitis C after liver transplantation

“…Although 1 study showed equal effects of donor and recipient IL‐28B genotypes on the virological response,23 another publication demonstrated a more dominant impact of the donor IL‐28B genotype on the treatment outcome 24. Very few available data suggest that the IL‐28B polymorphism may determine the severity of the histological recurrence of HCV 23, 24, 34, 35. One recent study reported that the recipient IL‐28B genotype (but not the donor IL‐28B genotype) was significantly predictive of the fibrosis stage, with the T/T genotype being associated with more rapid fibrosis 23.…”

“…24 Very few available data suggest that the IL-28B polymorphism may determine the severity of the histological recurrence of HCV. 23,24,34,35 One recent study reported that the recipient IL-28B genotype (but not the donor IL-28B genotype) was significantly predictive of the fibrosis stage, with the T/T genotype being associated with more rapid fibrosis. 23 Our data confirm that the recipient IL-28B polymorphism (rather than the donor IL-28B polymorphism) influences the severity of HCV recurrence.…”