Hepatitis C virus (HCV) infection is a problem worldwide affecting approximately 170 million individuals. HCV causes chronic hepatitis leading to cirrhosis and hepatocellular carcinoma (HCC). The incidence of HCC caused by HCV is increasing in European countries and the USA, with HCV infection a leading cause of liver transplantation in industrialized countries Citation[1]. More than 20 years have passed since the discovery of HCV by Houghton and colleagues Citation[2]. In the last decade, the efficacy of therapy for chronic hepatitis C has improved. Interferon (IFN) treatment enables the eradication of HCV in chronically infected patients. In genotype 1-naive patients with a high viral load, the ratio of sustained virological response (SVR), defined as undetectable HCV RNA 6 months after IFN therapy, has gone from approximately 10% with standard IFN for 6 months to approximately 50% with a combination of pegylated IFN (PEG-IFN) and ribavirin (RBV) for 1 year, which is the current standard therapy Citation[3].
Efficacy of IFN treatment is determined by a number of factors associated with the virus, host and IFN Citation[4]. Genetic variance could influence the difference in treatment response; however, to date, few single nucleotide polymorphisms (SNPs) have been identified. Recently it has become possible to examine the association of genetic variation with observable traits in the analysis of around 500,000 SNPs across a whole genome, although not all known SNPs (currently in excess of 25 million SNPs) can be analyzed.
Between August 2009 and January 2010, four research groups independently identified SNPs in the IL-28B region as associated with response to PEG-IFN plus RBV treatment among HCV-infected individuals of European, African and Asian ancestry Citation[5–8]. Ge et al. identified rs12979860 (located ∼3 kb upstream of IL-28B) as the variant most strongly associated with SVR Citation[5]. In their study, patients of European ancestry showed an association of the CC genotype with a twofold (95% CI: 1.8–2.3) greater rate of SVR than the TT genotype. The rate of SVR was found to be similar in people of African–American ancestry with a threefold (95% CI: 1.9–4.7) greater rate of SVR and in Hispanics a twofold (95% CI: 1.4–3.2) greater rate of SVR. The frequency of the CC genotype was 39, 16 and 35% in European–Americans, African–Americans and Hispanics, respectively, indicating that the genome frequency is quite different among these populations, which might explain the distinct response rates to PEG-IFN and RBV among them Citation[5].
Suppiah et al., Tanaka et al. and Rauch et al. found the strongest association with rs8099917 (located ∼8 kb upstream of IL-28B), which is in linkage disequilibrium with rs12979860 Citation[6–8]. Suppiah et al. and Rauch et al. demonstrated IL-28B polymorphisms in European cohorts, which was associated with an effect on treatment response (odds ratio [OR]: 2.0; 95% CI: 1.6–2.5) and on treatment failure (OR: 5.2; 95% CI: 2.9–9.3), respectively Citation[6,7]. In the study by Suppiah et al., SVR was achieved in 55.9% of 442 patients with the TT genotype, in 36.4% of 357 with the GT genotype and 30.6% of 49 with the GG genotype Citation[6].
Tanaka et al. identified IL-28B SNP rs8099917 to be associated with SVR in Japanese patients (OR: 12.1; 95% CI: 6.5–22.4), which is a more profound effect than in European cohorts Citation[8]. SVR was achieved in 63.8% of 196 patients with the TT genotype, in 13.3% of 113 with the GT genotype and none of the five patients with the GG genotype. They also showed that the rs8099917 G allele was the most significant factor for predicting nonvirological response (OR: 37.7; 95% CI: 16.7–83.9) after adjusting for confounding factors, suggesting that Japanese patients with the G allele must wait to receive new antiviral therapy.
Approximately 70% of infected individuals develop chronic infection, but the mechanism of persistence remains to be elucidated. The IL-28B SNP mentioned previously was also reported to be associated with spontaneous clearance of HCV Citation[7,9]. Thomas et al. compared the rs12979860 variation in HCV cohorts of individuals who spontaneously cleared the virus or had persistent infection, and showed that patients with the CC genotype were associated with better treatment response and were three times more likely to clear HCV relative to patients with the CT and TT genotypes of European and African ancestry Citation[9]. Furthermore, they analyzed the rs12979860 C allele frequency by genotyping 2371 individuals from 51 populations worldwide and showed a striking global pattern of allele frequencies: highest frequency (>90%) in East Asia and Oceania, lowest frequency (<50%) in Africa, and intermediate frequency in Europe Citation[9]. This global difference of allele frequency might explain the different frequency in viral clearance and treatment response among these populations.
In the study by Rauch et al., the frequencies of the rs8099917 TT, GT and GG genotypes were 0.78, 0.21 and 0.01 among patients with spontaneous clearance, 0.68, 0.29 and 0.03 among chronically infected patients with SVR, and 0.42, 0.51 and 0.07 among those without SVR, respectively, suggesting that the minor G allele is associated with both persistence of infection and treatment failure Citation[7].
The IL-29, IL-28A and IL-28B genes are located on chromosome 19 and encode IFN-λ1, -λ2, and -λ3, respectively, a new family of IFN-related cytokines recently described Citation[10,11]. IFN-λ interacts with a transmembrane receptor, IFNλR1/IL-10R2, and activates downstream JAK–STAT and MAPK pathways to induce potent antiviral responses Citation[12]. The receptor of IFN-α/β isIFNαR1/IFNαR2 and is different from that of IFN-λ, but the downstream signaling pathway is common. Marcello et al., however, reported that the kinetics of IFN-λ-mediated STAT activation and induction of potential effector genes were distinct from those of IFN-α Citation[13] and that these two proteins, IFN-λ and IFN-α, might have complementary roles in the suppression of HCV. The presence of IL-28B minor alleles, leading to an unfavorable treatment response, was reported to be associated with lower expression of IL-28 mRNA in peripheral blood cells Citation[6,8]. Therefore, a treatment regimen of both IFN-α and IFN-λ might be more promising than the current IFN-α therapy. Pagliaccetti et al. reported a cooperative activity of IFN-λ1 and IFN-α or IFN-γ in inhibiting HCV replication and inducing antiviral gene expression Citation[14]. A Phase Ib clinical trial of IL-29 (IFN-λ1) has reported antiviral effects against HCV and low toxicity Citation[15]. A Phase II trial is planned.
The efficacy of recently developed antiviral drugs such as NS3/4A protease inhibitor or NS5A polymerase inhibitor will have no relation to the genetic variant, but these new drugs should be administered in combination with PEG-IFN plus RBV because resistance to them can easily develop. Therefore information on this genetic variant could also be useful for future therapy. For example, patients with a major allele could be treated with standard PEG-IFN plus RBV while patients with a minor allele could be treated with a new drug in combination with PEG-IFN plus RBV.
In conclusion, four independent studies have clearly shown a close association of IL-28B SNPs with treatment response to PEG-IFN plus RBV, with consistent results among patients of different ethnic origin. This will open a window for genotype-based personalized medicine for patients with chronic hepatitis C. We should keep in mind, however, that treatment response is predicted by many factors likely to be unrelated to IL-28B SNPs, such as age, gender, viral genotype, fibrosis and compliance.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect. Dis.5, 558–567 (2005).
- Choo QL, Kuo G, Weiner AJ et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science244, 359–362 (1989).
- Hadziyannis SJ, Sette H Jr, Morgan TR et al. Peginterferon-αlpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann. Intern. Med.140, 346–355 (2004).
- Manns MP, McHutchison JG, Gordon SC et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet358, 958–965 (2001).
- Ge D, Fellay J, Thompson AJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature461, 399–401 (2009).
- Suppiah V, Moldovan M, Ahlenstiel G et al. IL28B is associated with response to chronic hepatitis C interferon-αlpha and ribavirin therapy. Nat. Genet.41, 1100–1104 (2009).
- Rauch A, Kutalik Z, Descombes P et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure – a genome-wide association study. Gastroenterology138(4), 1338–1345 (2010).
- Tanaka Y, Nishida N, Sugiyama M et al. Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nat. Genet.41, 1105–1109 (2009).
- Thomas DL, Thio CL, Martin MP et al. Genetic variation in IL28B and to spontaneous clearance of hepatitis C virus. Nature461, 798–801 (2009).
- Kotenko SV, Gallagher G, Baurin VV et al. IFN-λ mediate antiviral protection through a distinct class II cytokine receptor complex. Nat. Immunol.4, 69–77 (2003).
- Sheppard P, Kindsvogel W, Xu W et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat. Immunol.4, 63–68 (2003).
- Li M, Liu X, Zhou Y et al. Interferon-λs: the modulators of antivirus, antitumor, and immune responses. J. Leukoc. Biol.86, 23–32 (2009).
- Marcello T, Grakoui A, Brba-Spaeth G et al. Interferons α and λ inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology131, 1887–1898 (2006).
- Pagliaccetti NE, Eduardo R, Kleinstein SH et al. Interleukin-29 functions cooperatively with interferon to induce antiviral gene expression and inhibit hepatitis C virus replication. J. Biol. Chem.283, 30079–30089 (2008).
- Shiffnan M, Lawitz E, Zaman A. PEG-IFN-λ: antiviral activity and safety profile in a 4-week Phase 1b study in relapsed genotype 1 hepatitis C infection. J. Hepatol.50, S237 (2009).