Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection

Abstract

Polymorphism in the interleukin-28B (IL28B) gene region, encoding interferon (IFN)-λ3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty-five patients received IFN-based antiviral therapy. The CC IL28B variant was less common in the chronic HCV-infected recipients than in non-HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi-square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D-non-CC/R-non-CC = 3/19 [16%] versus D-CC/R-non-CC = 11/22 [50%] versus D-non-CC/R-CC = 5/12 [42%] versus R-CC/D-CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver-related).

Conclusion: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN-based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection.

Copyright © 2010 American Association for the Study of Liver Diseases.

Figures

Figure 1

Sustained virological response rates according to IL28B genotype are shown. The rate of SVR was strongly associated with the IL28B genotype of both the recipient and donor liver. The rate of SVR according to recipient IL28B genotype was 58% vs 47% vs 0% for CC vs CT vs TT, OR = 3.43, 95%CI 1.42 - 8.3, P=0.0062 (Figure 1A). The rate of SVR according to donor genotype was 59% vs 30% vs 0% for CC vs CT vs TT, OR = 4.00, 95%CI = 1.46 - 10.98, P=0.0071 (Figure 1B). SVR was lowest in non-CC recipients of a non-CC donor liver, increased if either the recipient or the donor was CC at the IL28B polymorphism and was maximal in the setting of CC recipients of a CC liver (SVR rates 3/19 (16%) vs 11/22 (50%) / 5/12 (42 %) vs 6/7 (86%), P=0.0095, Figure 1C).

Figure 1

Sustained virological response rates according to IL28B genotype are shown. The rate of SVR was strongly associated with the IL28B genotype of both the recipient and donor liver. The rate of SVR according to recipient IL28B genotype was 58% vs 47% vs 0% for CC vs CT vs TT, OR = 3.43, 95%CI 1.42 - 8.3, P=0.0062 (Figure 1A). The rate of SVR according to donor genotype was 59% vs 30% vs 0% for CC vs CT vs TT, OR = 4.00, 95%CI = 1.46 - 10.98, P=0.0071 (Figure 1B). SVR was lowest in non-CC recipients of a non-CC donor liver, increased if either the recipient or the donor was CC at the IL28B polymorphism and was maximal in the setting of CC recipients of a CC liver (SVR rates 3/19 (16%) vs 11/22 (50%) / 5/12 (42 %) vs 6/7 (86%), P=0.0095, Figure 1C).

Figure 1

Sustained virological response rates according to IL28B genotype are shown. The rate of SVR was strongly associated with the IL28B genotype of both the recipient and donor liver. The rate of SVR according to recipient IL28B genotype was 58% vs 47% vs 0% for CC vs CT vs TT, OR = 3.43, 95%CI 1.42 - 8.3, P=0.0062 (Figure 1A). The rate of SVR according to donor genotype was 59% vs 30% vs 0% for CC vs CT vs TT, OR = 4.00, 95%CI = 1.46 - 10.98, P=0.0071 (Figure 1B). SVR was lowest in non-CC recipients of a non-CC donor liver, increased if either the recipient or the donor was CC at the IL28B polymorphism and was maximal in the setting of CC recipients of a CC liver (SVR rates 3/19 (16%) vs 11/22 (50%) / 5/12 (42 %) vs 6/7 (86%), P=0.0095, Figure 1C).

Figure 2

Overall survival (combined mortality and graft loss) according to IL28B recipient (Figure 2A) and donor (Figure 2B) genotype is shown. There was no significant effect of recipient or donor IL28B genotype on overall survival (P=0.15 for recipient and P=0.59 donor IL28B genotype).

Figure 2

Overall survival (combined mortality and graft loss) according to IL28B recipient (Figure 2A) and donor (Figure 2B) genotype is shown. There was no significant effect of recipient or donor IL28B genotype on overall survival (P=0.15 for recipient and P=0.59 donor IL28B genotype).

Figure 3

Occurrence over time of the combined endpoint (fibrosis stage (FS) >/=2, retransplantation and/or liver related death is shown (percent experiencing endpoint shown on y-axis) according to recipient IL28B genotype are shown. The analysis was censored for antiviral therapy. The clinical composite endpoint was significantly associated with recipient and donor, IL28B genotype (p=0.047 and 0.040 for recipient and donor CC vs. TT genotypes respectively).