Genomic medicine reaches HCV-related liver transplantation: Hopes and clinical and public health implications
Authors: F. Xavier López-Labrador, Marina Berenguer
Journal: Journal of Hepatology (2011)

Impact of donor and recipient IL28B rs12979860 genotypes on hepatitis C virus liver graft reinfectionJournal of HepatologyVol. 55Issue 2PreviewRecent studies have described a major impact of genetic variations near the IL28B gene on the natural course and outcome of antiviral therapy in chronic hepatitis C. We therefore, aimed to explore the impact of donor and recipient genotypes of these polymorphisms on hepatitis C virus (HCV) liver graft reinfection. Full-Text PDF The enormous advances in genomic technologies since the sequencing of the human genome have propelled biomedical researchers to examine the role of genetic variation on both the risk of developing disease and in response to therapies [[1]Collins F.S. Medical and societal consequences of the human genome project.N Engl J Med. 1999; 341: 28-37Crossref PubMed Scopus (638) Google Scholar]. Although great success has been accomplished with monogenic disorders, gene-disease association studies on common diseases have been somewhat disappointing [[2]Burton P.R. Tobin M.D. Hopper J.L. Key concepts in genetic epidemiology.Lancet. 2005; 366: 941-951Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar]. Examples of success, such as in hereditary haemochromatosis [[3]Feder J.N. Gnirke A. Thomas W. Tsuchihashi Z. Ruddy D.A. Basava A. et al.A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.Nat Genet. 1996; 13: 399-408Crossref PubMed Scopus (3366) Google Scholar] will probably just increase with time, especially with accumulating sequenced genomes [[4]Donnelly P. Progress and challenges in genome-wide association studies in humans.Nature. 2008; 456: 728-731Crossref PubMed Scopus (299) Google Scholar]. To a limited degree, pharmacogenomics have also succeeded. Examples such as variants of cytochrome P450 linked with the rate of drug elimination, and associations between genotypes and treatment response in other diseases such as asthma and multiple sclerosis hold great promise for the eventual development of individually tailored therapies [[4]Donnelly P. Progress and challenges in genome-wide association studies in humans.Nature. 2008; 456: 728-731Crossref PubMed Scopus (299) Google Scholar]. The past two years turned out to be the time for a genomics breakthrough on hepatitis C virus (HCV) infection. Chronic hepatitis C (CHC) is a major public health problem, due to its progressive nature and the limited efficacy of antiviral therapy. Mechanisms involved in the achievement of sustained virological response (SVR) to pegylated interferon plus ribavirin (peg-IFNα + RBV) include viral genotype, presumably viral sequence in the Core and NS5A regions, baseline viremia and fibrosis, viral kinetics, and treatment adherence. A potential role for the genetic background of the host in determining treatment success as well as the outcome of viral infection has always been suspected. During 2009 and 2010, data were provided giving strong evidence for the association of single nucleotide polymorphisms (SNPs) on chromosome 6 near the IL28B gene (IFNλ3, a type III interferon) with spontaneous and treatment-related clearance of HCV infection, reviewed in [[5]Balagopal A. Thomas D.L. Thio C.L. IL28B and the control of hepatitis C virus infection.Gastroenterology. 2010; 139: 1865-1876Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar]. In homozygous individuals with the favourable (major) alleles, (i) spontaneous clearance of acute infection is common; and (ii) SVR using either peg-IFNα + RBV or triple therapy with newer antiviral agents is achieved in a significantly higher number of CHC treated patients [5Balagopal A. Thomas D.L. Thio C.L. IL28B and the control of hepatitis C virus infection.Gastroenterology. 2010; 139: 1865-1876Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 6Akuta N. Suzuki F. Hirakawa M. Kawamura Y. Yatsuji H. Sezaki H. et al.Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin.Hepatology. 2010; 52: 421-429Crossref PubMed Scopus (238) Google Scholar]. Hepatologists were awaiting data extending these important findings to the transplant field. Indeed, CHC is the leading cause of liver transplantation (LT) in most centres but recurrent HCV has a negative impact on the outcome. Moreover, the natural history of hepatitis C in the graft is highly variable and successful antiviral therapy targeted to patients with recurrent disease has only a limited efficacy (12–40% amongst HCV genotype 1 and 60–75% in HCV genotype non-1 infected patients) and poor tolerability [[7]Berenguer M. Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin.J Hepatol. 2008; 49: 274-287Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar]. LT provides a unique opportunity to investigate the role of IL28B SNPs both on the course of the disease and in the response to antiviral therapy. Indeed, HCV-hepatitis progresses more rapidly in transplanted patients, the time of infection is known, multiple serum samples are available for testing, and histological assessment is frequent. In addition, in the transplant model it is possible to investigate the impact of the genetic background of not only the recipient but also the donor liver, information that can be very helpful to advance our understanding of the biological mechanisms implicated in disease progression and viral eradication. In this issue of the Journal, Lange et al. [[8]Lange C.M. Moradpour D. Doehring A. Lehr H.A. Mullhaupt B. Bibert S. et al.Impact of donor and recipient IL28B rs12979860 genotypes on hepatitis C virus liver graft reinfection.J Hepatol. 2011; 55: 322-327Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar] determined the IL28B rs12979860 genotype of both the allograft and the recipient in 91 European transplanted patients for end-stage CHC, 47 of which were treated with peg-IFNα + RBV. The major findings can be summarised as follows (i) response to antiviral therapy was strongly associated with the donor's IL28B major genotype (T/T) but only weakly with the recipient's IL28B genotype; (ii) recipients with the favourable donor genotype (C/C) had significantly higher peak ALT and HCV-RNA concentrations in serum as compared to those with the unfavourable donor genotypes C/T or T/T; but no associations were found with the recipient IL28B genotype; (iii) no association was found between the donor or recipient IL28B genotype and graft or patient survival; (iv) the distribution of IL28B alleles in donors was comparable to that of a non-transplanted control population with CHC, whereas the adverse minor allele (C/T or T/T) was more frequently detected in patients requiring LT due to end-stage liver disease (ESLD). Hence, in this study, the major driver of SVR was the genetic background of the donor graft as opposed to that of the recipient. Three other studies have reported results on IL28B genotypes in LT donor/recipient pairs. Fukuhara et al. determined the IL28B SNPs rs129802750 and rs8099917 SNPs in 67 Japanese living-donor recipients and 41 donors and found that not only the donor but also the recipient's favourable IL28B genotype were significantly associated with increased SVR rates, as compared with the presence of the minor allele (54% vs. 11% in recipients and 44% vs. 9% in grafts with favourable or unfavourable genotypes, respectively). Combined analysis of recipient/donor genotypes indicated that ETR/SVR rates in the different possible pairs (major/major, major/minor or minor/major, and minor/minor allele combinations) were 90%/56%, 50%/10%, and 0%/0%, respectively [[9]Fukuhara T. Taketomi A. Motomura T. Okano S. Ninomiya A. Abe T. et al.Variants in IL28B in liver recipients and donors correlate with response to peg-interferon and ribavirin therapy for recurrent hepatitis C.Gastroenterology. 2010; 139: 1577-1585Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar]. Coto-Llerena et al. determined the IL28B SNPs rs12979860 and rs8099917 in 128 European recipient/donor pairs and found that SVR rates were 59% vs. 25% in recipients with favourable or unfavourable genotypes, respectively, and that a favourable donor genotype improved the chance for SVR post-LT [[10]Coto-Llerena M, Pérez-del-Pulgar S, Crespo G, Carrión JA, Martínez SM, Sánchez-Tapias JM, Martorell J, et al. Donor and recipient IL28B polymorphisms in HCV-infected patients undergoing antiviral therapy before and after liver transplantation. Am J Transplant 2011, in press.Google Scholar]. Finally, Charlton et al. studied 189 North-American donor/recipient pairs, of whom 65 were treated. They found that a favourable IL28B genotype of the donor and the recipient were both independently associated with higher rates of SVR [[11]Charlton M.R. Thompson A. Veldt B.J. Watt K. Tillmann H. Poterucha J.J. et al.Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection.Hepatology. 2011; 53: 317-324Crossref PubMed Scopus (200) Google Scholar]. Thus, in the three studies, both recipient and donor genotypes seemed to influence the response to peg-IFNα + RBV, in contrast with the data from Lange et al. Whether these differences may be explained by the small sample size of the cohorts evaluated, ethnic differences, or whether it might be due to differences in the time of treatment initiation or the use of cadaveric vs. living-donor organs is at present unknown, but requires further investigation. The second aim of the study by Lange et al. was to assess the impact of IL28B polymorphisms on transplant outcome, including the natural history of recurrent hepatitis C. The data on the impact of the genetic background of the host and/or the graft are unfortunately much less conclusive than that reported on treatment outcome due to the lack of liver biopsy protocols or cause of death or graft failure, together with the small sample size. Interestingly, the two European and the North-American (but not the Japanese) studies found a significantly higher frequency of the unfavourable IL28B genotypes in recipients than in donors, or in non-LT HCV-infected patients, suggesting that CHC patients with unfavourable IL28 genotypes may be more likely to progress to ESLD, a finding with potential important public health implications but that requires confirmation in larger cohorts. In addition, in the study by Charlton et al., analysis of a subset of patients one year post-transplantation suggested that recipient (but not donor) unfavourable IL28B rs12979860 genotype was associated with more rapid fibrosis, although not with decreased survival [[11]Charlton M.R. Thompson A. Veldt B.J. Watt K. Tillmann H. Poterucha J.J. et al.Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection.Hepatology. 2011; 53: 317-324Crossref PubMed Scopus (200) Google Scholar]. The findings of an association between the IL28B polymorphism and response to antiviral therapy obtained in the three transplant studies parallel those obtained in large cohorts of CHC immune competent patients or of HCV-HIV coinfected individuals (reviewed in [[5]Balagopal A. Thomas D.L. Thio C.L. IL28B and the control of hepatitis C virus infection.Gastroenterology. 2010; 139: 1865-1876Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar]), highlighting the potential application of IL28B genotyping for treatment tailoring in all these settings. How can the effect of IL28B genotype be so strong, even in individuals with suppression of the cellular immune response? A likely explanation is that the enhanced sensitivity to IFNα in individuals with favourable IL28B genotypes relies more on innate rather than in cellular adaptive immunity, though the mechanism behind them remains elusive. Type III IFNs (IFNλ1, IFNλ2, and IFNλ3, also known as interleukin 29, 28A, and 28B) are not highly homologous to type I IFNs, but their biological activities are similar. Although type I and type III IFNs signal through distinct receptor complexes, they both trigger the Jak-STAT pathway leading to transcriptional activation of basically the same set of interferon-stimulated genes (ISGs) to induce an antiviral state [[12]Pestka S. Krause C.D. Walter M.R. Interferons, interferon-like cytokines, and their receptors.Immunol Rev. 2004; 202: 8-32Crossref PubMed Scopus (1299) Google Scholar]. IFNλ was shown earlier to inhibit HCV and hepatitis B virus (HBV) replication in vitro and, very recently, HCV replication in humans [13Robek M.D. Boyd B.S. Chisari F.V. Lambda interferon inhibits hepatitis B and C virus replication.J Virol. 2005; 79: 3851-3854Crossref PubMed Scopus (395) Google Scholar, 14Muir A.J. Shiffman M.L. Zaman A. Yoffe B. de la Torre A. Flamm S. et al.Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection.Hepatology. 2010; 52: 822-832Crossref PubMed Scopus (218) Google Scholar]. The current paradigm is that in IFNα non-responders (NR), baseline intrahepatic ISG expression is inappropriately pre-activated potentially being not only ineffective, but also impeding the response to therapy, most likely by inducing a refractory state of the IFN signalling pathway [15Asselah T. Bieche I. Narguet S. Sabbagh A. Laurendeau I. Ripault M.-P. et al.Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C.Gut. 2008; 57 ([Epub 2007 Sep 25]): 516-524Crossref PubMed Scopus (193) Google Scholar, 16Sarasin-Filipowicz M. Oakeley E.J. Duong F.H.T. Christen V. Terracciano L. Filipowicz W. et al.Interferon signaling and treatment outcome in chronic hepatitis C.Proc Natl Acad Sci USA. 2008; 105: 7034-7039Crossref PubMed Scopus (578) Google Scholar]. Whether the IL28B genotype influences the expression of IL28B mRNA or ISGs in the liver is just being elucidated, and whether ISG expression is driven by the IL28B genotype of the host, the virus, or both, is unclear [17Honda M. Sakai A. Yamashita T. Nakamoto Y. Mizukoshi E. Sakai Y. et al.Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C.Gastroenterology. 2010; 139: 499-509Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar, 18Dill M.T. Duong F.H. Vogt J.E. Bibert S. Bochud P.Y. Terracciano L. et al.Interferon-induced gene expression is a stronger predictor of treatment response than IL28B genotype in patients with hepatitis C.Gastroenterology. 2011; 140: 1021-1031Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 19Urban T.J. Thompson A.J. Bradrick S.S. Fellay J. Schuppan D. Cronin K.D. et al.IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C.Hepatology. 2010; 52: 1888-1896Crossref PubMed Scopus (348) Google Scholar]. To add more pieces to the puzzle, Shebl et al. found no evidence of an association between IL28B genotype and expression of ISGs in liver tissue from subjects uninfected with HCV (N = 960), suggesting that the association between IL28B genotype and ISG expression in liver appears to depend on infection with HCV [[20]Shebl F.M. Maeder D. Shao Y. Prokunina-Olsson L. Schadt E.E. O'Brien T.R. In the absence of HCV infection, interferon stimulated gene expression in liver is not associated with IL28B genotype.Gastroenterology. 2010; 139: 1422-1424Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar]. The only data available in LT patients suggest that intrahepatic expression of IL28 mRNA is lower both in donors and recipients carrying IL28B rs8099917 minor alleles [[9]Fukuhara T. Taketomi A. Motomura T. Okano S. Ninomiya A. Abe T. et al.Variants in IL28B in liver recipients and donors correlate with response to peg-interferon and ribavirin therapy for recurrent hepatitis C.Gastroenterology. 2010; 139: 1577-1585Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar]. Importantly, the authors demonstrated microchimerism of donor and recipient cells in the graft. Their results may explain: (i) partial restoration of sensitivity to IFNα in an unfavourable IL28B genotype recipient and, conversely, in an unfavourable genotype donor background; and (ii) the previous observation of change in response to therapy after transplantation occurring in a subset of patients [[21]Feliu A. Carrión J.A. Massaguer A. Martínez-Bauer E. García-Retortillo M. González P. et al.Sensitivity to antiviral therapy may change after liver transplantation in patients with chronic hepatitis C virus infection.J Viral Hepat. 2006; 13: 544-551Crossref PubMed Scopus (15) Google Scholar]. Thus, optimal graft/recipient matching depending on IL28B alleles may improve the sensitivity to antiviral therapy post-transplantation. In conclusion, in this setting of variable responsiveness and clinical heterogeneity, high-profile pharmacogenomic research such as that reported by Lange et al. is fundamental for uncovering mechanistic processes in order to potentially achieve an individualized approach to antiviral therapy. There are many questions which remain open at present. Will population-based genetic screening be useful to identify CHC patients more likely to progress to ESLD? Unfortunately, as with early gene-association studies and most studies performed in the LT setting, small sample size represents a major limitation to draw strong meaningful conclusions. Do we need to modify the graft allocation system by determining the IL28B genotype of potential donors so as to identify the most favourable grafts for specific HCV recipients? This strategy may result in significant benefits by improving both patient outcomes and treatment cost-effectiveness but we still need more evidence on the independent weight of both the recipient and graft IL28B genotype on CHC graft progression (particularly compared to donor age) as well as treatment response (vs. treatment adherence, disease severity at baseline, viral kinetics, or donor age). Furthermore, whether the same results will be sustained in transplant patients treated with novel direct-acting antivirals needs to be investigated in the future. Hope is to wish, and many of us hope that our wish of applying IL28 genetic testing becomes a reality. The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. This work was supported by the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spanish Ministry of Science (PI05/0981, PS09/01707, and CIBERESP/CIBEREHD). F.X.L. holds a P.I. position supported by the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spanish Ministry of Science.