Indolfi G, Azzari C, Resti M. Polymorphisms in the IFNL3/IL28B gene and hepatitis C: From adults to children. World J Gastroenterol 2014; 20(28): 9245-9252 [PMID: 25071317 DOI: 10.3748/wjg.v20.i28.9245]
Corresponding Author of This Article
Dr. Giuseppe Indolfi, Paediatric and Liver Unit, Meyer Children’s University Hospital of Florence, Viale Pieraccini 34, I-50139 Firenze, Italy. g.indolfi@meyer.it
Research Domain of This Article
Pediatrics
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Topic Highlight
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Giuseppe Indolfi, Massimo Resti, Paediatric and Liver Unit, Meyer Children’s University Hospital of Florence, I-50139 Florence, Italy
Chiara Azzari, Immunology Unit and Laboratory at Meyer Children’s University Hospital of Florence, I-50139 Florence, Italy
Chiara Azzari, Department of Health Sciences, University of Florence, I-50139 Florence, Italy
ORCID number: $[AuthorORCIDs]
Author contributions: All of the authors contributed equally to the conception, design and drafting of the article and approved the final version of the work.
Correspondence to: Dr. Giuseppe Indolfi, Paediatric and Liver Unit, Meyer Children’s University Hospital of Florence, Viale Pieraccini 34, I-50139 Firenze, Italy. g.indolfi@meyer.it
Telephone: +39-55-5662410 Fax: +39-55-5662400
Received: October 25, 2013 Revised: February 24, 2014 Accepted: May 23, 2014 Published online: July 28, 2014 Processing time: 284 Days and 14.7 Hours
Abstract
The purpose of the present review is to summarise the current knowledge on the association between single nucleotide polymorphisms (SNPs) in the interferon L3 (IFNL3) gene and hepatitis C virus (HCV) infection in children. Many studies in adults have demonstrated that genetic variation in IFNL3 is a strong predictor of the virological response in treatment-naive patients with HCV genotype 1 who were treated with Pegylated-IFN-α and ribavirin. Genetic variation in IFNL3 is also associated with the spontaneous clearance of HCV. Thus far, few paediatric studies have explored the association between variations in the IFNL3 gene and either spontaneous or treatment-induced clearance of HCV. The CC genotype of the rs12979860 SNP is associated with the spontaneous clearance of HCV in children independently of HCV genotype. Four paediatric studies have shown that both the CC genotype of the rs12979860 SNP and the TT genotype of the rs8099917 SNP are associated with the treatment-induced (IFN monotherapy and Pegylated-IFN-α and ribavirin association) clearance of HCV, while the rs12980275 SNP did not affect the virological response. The possible role of IFNL3 gene variation as a pre-treatment and on-treatment predictor of virological response in children is highly attractive but still undetermined. Further paediatric studies are needed to evaluate if testing for SNPs in IFNL3, either alone or together with other predictors of response to treatment, could be used to direct treatment strategies, including an avoidance of unnecessary protease inhibitor therapy and the duration of treatment.
Core tip: Single nucleotide polymorphisms in the interferon L3 (IFNL3) gene have been associated with both spontaneous and treatment-induced clearance of hepatitis C virus in children. Data from adult studies suggest a role of IFNL3 testing in the decision-making process of whether to treat a patient, the use of two or three drugs and whether the standard duration of treatment or a shorter duration should be proposed. These options are attractive if applicable to children. While waiting for the approval of new interferon-free regimens, paediatric collaborative studies to evaluate the possible role of genetic polymorphisms of IFNL3 as pre-treatment and on-treatment predictors of response, alone or together with other predictors, are highly needed.
Citation: Indolfi G, Azzari C, Resti M. Polymorphisms in the IFNL3/IL28B gene and hepatitis C: From adults to children. World J Gastroenterol 2014; 20(28): 9245-9252
The major aims of the present review are (1) to provide paediatricians with a brief overview of the current knowledge on the association between single nucleotide polymorphisms (SNPs) in the interferon L3 (IFNL3) gene and hepatitis C virus (HCV) infection in adults; and (2) to summarise the data available in children with regards to future possible research endeavours and the possible impact of these data on the management of chronic HCV infection in children.
NOMENCLATURE AND CORRECT DEFINITION OF THE IFNL3/IL28B GENE
Two major SNPs, rs12979860 and rs8099917, have been identified on chromosome 19q13.13 as variants that are associated with both spontaneous HCV clearance and response to treatment with Pegylated-IFN-α (Peg-IFN-α) combined with ribavirin[1,2]. The rs12979860 SNP is located 3 kilobases upstream of the promoter region of the IFNL3 gene as well as of the IFNL1 and IFNL2 genes. The rs8099917 SNP lies between IFNL3 and IFNL2, about 8 kilobases downstream from IFNL3 and about 16 kb upstream from IFNL2. IFNL1, IFNL2 and IFNL3 are three closely related genes (known as IFN-λ genes) that are located in close proximity to each other on chromosome 19. The IFNL1, IFNL2 and IFNL3 genes were formerly known as IL29, IL28A and IL28B, respectively, and encode for type-III IFNs (IFN-λ1, IFN-λ2 and IFN-λ3 formerly IL29, IL28A and IL28B, respectively)[3-6]. The nomenclature that was used to describe the IFN-λ family reflects its structural similarity to the IL-10 superfamily and its close functional correlation to type-I IFNs[7]. Recently, Prokunina-Olsson et al[8] described a dinucleotide variant upstream of the IFNL3 gene in ss469415590 (TT or HG) that is in strong linkage disequilibrium with rs12979860. In individuals of African ancestry, the IFNL4-generating ss469415590[ΔG] allele was shown to be superior to the rs12979860[T] allele in predicting poorer response to the treatment of chronic hepatitis C with Peg-IFN-α and ribavirin. This SNP results in a frame shift mutation that leads to a novel gene product designated as IFN-λ4, which has a high (40.8%) amino acid sequence homology with IFN-λ3[8].
Although the majority of the articles published on this topic refer to the IL28B gene and IL28B, which are the accepted names, IFNL3 gene and IFN-λ3 will be used in this review.
BIOLOGY AND MECHANISM OF ACTION OF TYPE-III IFNS
IFNs have a direct antiviral activity on viral replication and an indirect antiviral activity that is mediated by the activation of host genes that regulate an immune response against the virus[9-12]. The binding of type III IFNs to their receptor complexes activates Janus kinase (JAK) and protein tyrosine kinase 2, which leads to the activation of the signal transducer and activator of transcription (STAT) protein kinases[13]. Activation of the JAK-STAT pathway leads, in turn, to the induction of genes with immunomodulatory functions, namely, IFN-stimulated genes that are responsible for the antiviral activity of IFN-λs (Figure 1)[13]. Although types I and III IFNs share the same second messengers (i.e., JAK/STAT), the IFN-λs are known to induce the expression of IFN-stimulated genes in a manner different from that of type I IFNs[13]. The rs12979860 T/C polymorphism, with its particular location upstream of the promoter region for the IFNL3 gene as well as its proximity to the IFNL1 and IFNL2 genes, can theoretically influence all three IFN-lambda genes. Thus, the rs12979860 T/C polymorphism has been hypothesised and tested as a surrogate marker of altered promoter activity in this particular region. Although early studies failed to find altered mRNA expression of IFNL3 associated with the rs12979860 SNP, the specificity of real-time PCR primers for IFNL3 has increased (to distinguish between IFN-λ3 and the closely related IFN-λ2). It is now clear that SNPs in the IFNL3 gene do affect the expression of IFN-λ3 within the liver, peripheral blood mononuclear cells and whole blood, with the unfavourable T allele resulting in less IFN-λ3 expression[13].
Figure 1 Type III interferons bind to their receptor complexes and activate Janus kinase and protein tyrosine kinase 2, which leads to activation of the signal transducer and activator of transcription protein kinases.
Activation of the JAK-STAT pathway leads, in turn, to the induction ISGs, which have immunomodulatory functions and are responsible for the antiviral activity of IFN-λs (see text for more details). IFNs: Interferons; JAK: Janus kinase; Tyk2: Tyrosine kinase 2; STAT PKs: Signal transducer and activator of transcription protein kinases; ISGs: IFN-stimulated genes.
SNPS IN THE IFNL3 GENE AND HEPATITIS C IN ADULTS
The association between SNPs of the IFNL3 gene and the outcome of HCV infection was first described in September 2009 by Ge et al[1] (Table 1). The authors performed a genome wide association study of more than 1600 adults with chronic infections of genotype 1 HCV who underwent combined treatment with Peg-IFN-α and ribavirin. A SNP on chromosome 19q13.13, rs12979860, was associated with a sustained virological response (SVR, defined as an undetectable level of HCV RNA 24 wk after the end of treatment). The authors found that the CC genotype of the rs12979860 SNP was associated with an improved response to treatment in all of the patients, independent of their ethnicities, when compared to the CT and the TT genotypes[1]. The highest genome-wide significance was found in the European-American population sample (CC vs CT and TT odds ratio, OR = 7.3; 95%CI: 5.1-10.4; P = 1.06 × 10-25)[1]. Then, Thomas et al[2] determined the effect of rs12979860 variation on the outcome of HCV infection in a cohort of more than 1000 adults with either persistent infection or spontaneous clearance. The C allele and the CC genotype of the rs12979860 SNP were associated with spontaneous resolution of HCV infection among individuals of both European and African ancestry (CT vs CC, OR = 0.35; 95%CI: 0.25-0.48; P = 4 × 10-11; TT vs CC, OR = 0.29; 95%CI: 0.18-0.47; P = 4 × 10-7). Interestingly, in the same study, the geographic frequency of distribution of the different alleles was explored in 2371 individuals with unknown HCV status from 51 populations worldwide[2]. The protective C allele was more frequent and fixed in East Asians (range 90%-100%), had an intermediate frequency in Europeans (range 52%-85%) and was the minor allele in Africans (range 23%-54%)[2]. The pattern of distribution of the C allele closely reflected the heterogeneity in response to IFN-based treatments in different ethnic groups[14-16], supporting the hypothesis that this genetic polymorphism explains much of the variation that exists within a population in response to treatment with Peg-IFN-α combined with ribavirin[2]. Since October 2009, multiple studies have confirmed and reinforced the association between the C allele of the rs12979860 SNP and the spontaneous and treatment-induced clearance of HCV in adults (for a comprehensive review see Lange and Zeuzem[3]).
Table 1 Selected studies exploring the association between single nucleotide polymorphisms in the interferon L3 gene and spontaneous and treatment-induced clearance of hepatitis C virus in adults.
The T allele of the rs8099917 SNP and the A allele of the rs12980275 SNP were associated with response to treatment with Peg-IFN-α and ribavirin Japanese patients
null virological response vs SVR for rs12980275, OR = 26.7; 95%CI: 9.3-76.5; P = 7.41 × 10-13 and for rs8099917 OR = 36.5; 95%CI: 11.6-114.6; P = 5 × 10-14
The T allele was associated with response to treatment with Peg-IFN-α and ribavirin in Australian patients
OR = 1.98; 95%CI: 1.57-2.52; P = 9.25 × 10-9
At around the same time of the publication by Ge et al[1], two other groups each led by Tanaka et al[17] and Suppiah et al[18], reported the results of genome wide association studies to determine the SVR of patients who were treated for HCV genotype 1 infection. Tanaka et al[17] found that the rs12980275 and the rs8099917 SNPs in the IFNL3 gene were associated with an SVR within a Japanese population (null virological response vs SVR for rs12980275, OR = 26.7; 95%CI: 9.3-76.5; P = 7.41 × 10-13 and for rs8099917, OR = 36.5; 95%CI: 11.6-114.6; P = 5 × 10-14). The role of the rs8099917 SNP was confirmed by Suppiah et al[18] in an Australian cohort with HCV genotype 1 infection, where those who were homozygous for the T allele had a greater chance to eradicate the virus as a result of treatment with Peg-IFN-α combined with ribavirin than patients carrying the G allele (OR = 1.98; 95%CI: 1.57-2.52; P = 9.25 × 10-9)[18]. Subsequent studies confirmed the relationships between the rs8099917 SNP and HCV clearance, but fewer data are available on rs12980275[3].
Although the initial observations that were described were found in patients who were infected and treated for HCV genotype 1 infection, different studies have since confirmed the major role of these SNPs on the outcome of treatment for genotype 4 infection and the minor role in the treatment outcomes of patients infected with HCV genotypes 2 and 3[3].
SNPS IN THE IFNL3 GENE AND VIRAL KINETICS OF RESPONSE TO TREATMENT
The data described above demonstrate that genetic variation of IFNL3 is a strong predictor of a SVR in treatment-naive patients who are infected with HCV genotype 1 who are treated with Peg-IFN-α and ribavirin. SNPs in the IFNL3 gene together with race, gender, age, weight, serum glucose, hepatic steatosis, liver fibrosis stage and adherence to therapy are pre-treatment predictors of virological response[19]. In addition to pre-treatment predictors, the likelihood of a SVR is associated with on-treatment predictors, particularly with the rate of virological decline during therapy, commonly referred to as “viral kinetics of response”. Rapid virological response (RVR, an undetectable level of HCV RNA after 4 wk of treatment) and early virological response (undetectable level of HCV RNA acid after 12 wk of treatment) predict the likelihood of achieving an SVR[19,20]. For patients who achieve an RVR, SVR rates are higher than 70%, and therapy can be shortened[21,22]. There is evidence that the CC genotype of the rs12979860 SNP in the IFNL3 gene is associated with significantly higher rates of viral clearance after 2, 4, 12 and 48 wk of treatment and a lower virological relapse rate[23]. The correlation between RVR and the CC genotype of the IFNL3 gene is so close that recently these two on-treatment predictors have been considered to drive one another to promote an SVR[24]. It is worth noting that evaluation of the rs8099917 SNP is important for adults who do not achieve an RVR because although the CC genotype is predictive of an SVR in this group of patients, it is not associated with an SVR for those individuals who have achieved an RVR[24]. These findings suggest that testing for IFNL3 SNPs can be useful for making informed decisions about whether to continue therapy for patients who do not achieve an RVR.
SNPS OF THE IFNL3 GENE AND HCV PROTEASE INHIBITORS IN ADULTS
Recently, two direct-acting antiviral agents, boceprevir[20,25-27] and telaprevir[20,27-29] have been approved for combined use with Peg-IFN-α and ribavirin in adults with chronic genotype 1 hepatitis C. Triple therapy has been proven to be more effective than combined dual treatment, but the role of SNPs in the IFNL3 gene in the context of the increased SVR rates after triple therapy has been debated. Regardless, it has become increasingly evident that the response to triple therapy is also affected by polymorphisms in the IFNL3 gene[30,31]. Retrospective analyses from both of the boceprevir[32] and the telaprevir[33,34] registration trials showed that, although the presence of a direct-acting antiviral agent does attenuate the difference, treatment-naive individuals with the rs12979860 CC genotype responded better in that they had higher SVR rates, better viral kinetics of response and a consequent lower risk of selection of resistance-associated HCV variants compared with individuals with the CT and TT genotypes[32-34]. In addition, the major benefit of direct-acting antiviral agents is that they allow for a shorter treatment duration (24-28 wk) with response-guided therapy. Furthermore, it is evident that patients with the CT and TT genotypes are those who might benefit more from the addition of a third drug. In treatment-experienced patients who are scheduled to receive boceprevir/telaprevir therapy, there may be little utility for IFNL3 genotyping once patients have been stratified based on a response to prior treatment[32,34].
SNPS IN THE IFNL3 GENE AND SPONTANEOUS CLEARANCE OF HCV IN CHILDREN
Thus far, three studies have been published on the association between spontaneous clearance of HCV in children and SNPs in the IFNL3 gene (Table 2). Ruiz-Extremera et al[35] explored the role of rs12979860 in 8 children with chronic infection and 7 with transient viremia. All of the children included in the study acquired the infection perinatally from their mothers and were infected with the HCV genotype 1. The CC genotype was present in 5/7 children with transient viremia (83%) and in 1/8 (17%) with chronic infection (P = 0.04)[35]. The same correlation between the rs12979860 SNP in the IFNL3 gene and the spontaneous clearance of HCV in children was subsequently established for infection with HCV genotypes 2 and 3 in a cohort of 28 Italian children who were infected perinatally[36]. Again, the CC genotype was found in 3/4 (75%) and in 4/20 (20%) of the children with spontaneous clearance and chronic infection, respectively (CC vs CT and TT, OR = 15; 90%CI: 1.2-376; P = 0.04)[36]. These two studies demonstrated for the first time that the rs12979860 SNP in the IFNL3 gene is associated with the spontaneous clearance of HCV independently of age and HCV genotype. These preliminary results have been confirmed in two recently closed cross-sectional multicentre collaborative studies[37,38]. In one of these studies, 177 Italian children were enrolled[38]. Thirty children with spontaneous clearance of HCV and 147 children with persistent infection were compared with a population sample of ethnically matched controls with unknown hepatitis C status obtained using data from the 1000 Genomes Project. The children with spontaneous clearance had greater frequencies of the C allele and the C/C genotype (76.7% and 56.7%, respectively) compared with both children with viral persistence (C allele 56.5%, P 0.004; C/C genotype 32.7%, P = 0.02) and to the ethnically matched individuals (C allele 59.7%, P = 0.02; C/C genotype 34.7%, P = 0.03). Children with the C/C genotype were 2 times more likely to show clearance of the hepatitis C virus relative to children with the C/T and T/T genotypes combined (OR = 2.7; 90%CI: 1.3-5.8)[38].
Table 2 Paediatric studies exploring the association between single nucleotide polymorphisms in the interferon L3 gene and treatment-induced clearance of hepatitis C virus.
The CC genotype of rs12979860 and the T/T genotype of rs8099917 were associated with treatment-induced (IFN monotherapy and Peg-IFN-α and ribavirin association) clearance of HCV (viral genotype data not provided)
The CC genotype of rs12979860 and the T/T genotype of rs8099917 were associated with treatment-induced (Peg-IFN-α and ribavirin association) clearance of HCV (viral genotypes 1 and 4; OR = 6.81; 95%CI: 1.98-23.42; P = 0.001 and OR = 3.14; 95%CI: 1.26-7.85; P = 0.013, respectively)
The rs12980275 SNP was not associated with virological response.
The rs8099917 SNP was not associated with treatment-induced (response-guided IFN monotherapy and/or Peg-IFN-α and ribavirin association) clearance of HCV (viral genotypes 1, 2, 3 and 4)
The CC genotype of rs12979860 was associated with treatment-induced (Peg-IFN-α and ribavirin association) clearance of HCV (viral genotype 4)
OR = 2.45; 95%CI not reported; P = 0.02
SNPS IN THE IFNL3 GENE AND TREATMENT-INDUCED CLEARANCE OF HCV IN CHILDREN
In 2011, at the Annual Meeting of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition, Hierro et al[39] presented the result of a study that explored the rs12979860 and rs8099917 SNPs in the IFNL3 gene in a cohort of 92 Spanish children with chronic hepatitis C. Both the CC genotype of the rs12979860 SNP and the TT genotype of the rs8099917 SNP were associated with a response to treatment in the 69 children who received treatment (7 with IFN and 62 with Peg-IFN-α and ribavirin; overall SVR 59% for CC vs 25% for non-CC, P = 0.01 and SVR 52% for TT vs 21% non-TT, P = 0.009)[39].
Subsequently, 3 further studies (Table 2) were published that investigated the association between SNPs in the IFNL3 gene and treatment outcomes for HCV infection in children[40-42]. In 82 Polish children infected with HCV genotypes 1 and 4 and who were treated with Peg-IFN-α and ribavirin, the rs12979860 CC and the rs8099917 TT genotypes were associated with higher SVR rates (OR = 6.81; 95%CI: 1.98-23.42; P = 0.001 and OR = 3.14; 95%CI: 1.26-7.85; P = 0.013, respectively), while the rs12980275 SNP was not found to be significantly associated with a SVR[40]. Interestingly, early virological response was associated with the rs12979860 CC genotype[40]. This observation suggests that, as in adults, variations in the IFNL3 gene influence early on-treatment viral kinetics in children.
The rs8099917 SNP in the IFNL3 gene was evaluated in 63 Japanese children with mixed genotypes who were treated with response-guided Peg-IFN as a monotherapy or combined with ribavirin[41]. In this study, the duration of the treatment was not the standard 48 wk for genotypes 1 and 4 and 24 wk for genotypes 2 and 3, but rather, it was determined based on when the levels of HCV RNA became undetectable in serum. No association was found between the rs8099917 SNP and SVR in the children who were treated[41]. These results are in agreement with the observation that, in adults, different IFNL3 SNPs appeared to have limited potential for response-guided treatment strategies[43,44].
Finally, very recently, rs12979860 was found to be associated with a response to combined dual treatment in 34 Egyptian children infected with HCV genotype 4. Children with the CC genotype were found to be 2 times more likely to achieve an SVR compared to those with CT and TT genotypes together (OR = 2.45; 95%CI not reported; P = 0.02)[42].
IFN-BASED TREATMENT IN CHILDREN WITH CHRONIC HEPATITIS C AND SNPS IN THE IFNL3 GENE: TO TREAT OR NOT TO TREAT?
Children who develop a chronic hepatitis C infection usually experience a mild disease[45-47]. In the largest paediatric observational study that has been conducted thus far, end-stage liver disease was described in a small subgroup (3%) of children with chronic HCV infection[45]. Although HCV can lead to advanced liver disease during childhood, the vast majority of children with chronic infection experience a slow, progressive disease. In the majority of these children, there is no clear indication for antiviral therapy[48,49]. For this reason, whether to treat children is a complex decision that should be individualised for each child and based on the efficacy of the treatment and on rate and severity of treatment-related adverse events. In that context, the possible role of IFNL3 gene variations as pre-treatment and on-treatment predictors of an SVR in children is highly attractive. For adults, as for children, the initial hope to improve the prediction of response to poorly tolerated IFN-based regimens using IFNL3 gene testing was the same. Currently, it is clear that for adult patients, the positive predictive value of IFNL3 association with response to treatment cannot be translated into a sufficiently sensitive or specific test that can be used independently to predict the outcomes for individual patients.
GENETIC VARIATION OF THE IFNL3 GENE IN CHILDREN: POSSIBLE FUTURE RESEARCH SCENARIOS
The natural history of HCV infection in children is different compared to that in adults[45]. Today, the majority of children infected by HCV acquire the infection perinatally from their mothers[45,50-52]. Spontaneous clearance of HCV is an unpredictable event that occurs in the first 30 mo of life in less than 20% of the infected children[45,47,53]. The association between genetic variation of IFNL3 and spontaneous clearance of HCV in children supports the hypothesis that innate immunity plays an important role in children as in adults in the spontaneous elimination of the virus[54]. Future research efforts should be oriented towards elucidating the role of innate immunity in the successful eradication of HCV infection as well as its ineffective control in the majority of children who develop a chronic infection.
With regards to treatment-induced clearance of HCV, IFNL3 testing is not sufficiently sensitive to be used alone to predict the outcome of treatment for individual patients. To achieve this goal, a consideration of both multiple pre-treatment and on-treatment factors seems to be an appropriate research strategy to be developed further. The likelihood of achieving such treatment algorithms is unrealistic for adults in the context of a rapidly evolving scenario of new, highly effective IFN-free treatments. The time-lapse to new treatments in children will be longer; therefore, the determination of the role of IFNL3 genotype variation is still possible. Additional paediatric studies are needed to evaluate whether IFNL3 genotype testing alone or together with other predictors of response to treatment with Peg-IFN-α and ribavirin, with or without direct-acting antiviral agents, could provide useful information as to whether a patient should avoid treatment, avoid protease inhibitor therapy entirely or undergo a shorter duration of triple therapy.
Footnotes
P- Reviewer: Muoz-Valle JF, Yin JY S- Editor: Ma YJ L- Editor: A E- Editor: Wang CH
Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, Langer JA, Sheikh F, Dickensheets H, Donnelly RP. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.Nat Immunol. 2003;4:69-77.
[PubMed] [DOI][Cited in This Article: ]
Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, Kuestner R, Garrigues U, Birks C, Roraback J. IL-28, IL-29 and their class II cytokine receptor IL-28R.Nat Immunol. 2003;4:63-68.
[PubMed] [DOI][Cited in This Article: ]
Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Hergott D, Porter-Gill P, Mumy A, Kohaar I. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.Nat Genet. 2013;45:164-171.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 701][Cited by in F6Publishing: 733][Article Influence: 66.6][Reference Citation Analysis (0)]
Marcello T, Grakoui A, Barba-Spaeth G, Machlin ES, Kotenko SV, MacDonald MR, Rice CM. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics.Gastroenterology. 2006;131:1887-1898.
[PubMed] [DOI][Cited in This Article: ]
Robek MD, Boyd BS, Chisari FV. Lambda interferon inhibits hepatitis B and C virus replication.J Virol. 2005;79:3851-3854.
[PubMed] [DOI][Cited in This Article: ]
Muir AJ, Shiffman ML, Zaman A, Yoffe B, de la Torre A, Flamm S, Gordon SC, Marotta P, Vierling JM, Lopez-Talavera JC. Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection.Hepatology. 2010;52:822-832.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 192][Cited by in F6Publishing: 181][Article Influence: 12.9][Reference Citation Analysis (0)]
Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites.N Engl J Med. 2004;350:2265-2271.
[PubMed] [DOI][Cited in This Article: ]
Liu CH, Liu CJ, Lin CL, Liang CC, Hsu SJ, Yang SS, Hsu CS, Tseng TC, Wang CC, Lai MY. Pegylated interferon-alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus genotype 1 infection: a multicenter, randomized controlled trial.Clin Infect Dis. 2008;47:1260-1269.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 148][Cited by in F6Publishing: 159][Article Influence: 9.9][Reference Citation Analysis (0)]
Yan KK, Guirgis M, Dinh T, George J, Dev A, Lee A, Zekry A. Treatment responses in Asians and Caucasians with chronic hepatitis C infection.World J Gastroenterol. 2008;14:3416-3420.
[PubMed] [DOI][Cited in This Article: ]
Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.Nat Genet. 2009;41:1105-1109.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 1747][Cited by in F6Publishing: 1746][Article Influence: 116.4][Reference Citation Analysis (0)]
Mangia A, Minerva N, Bacca D, Cozzolongo R, Ricci GL, Carretta V, Vinelli F, Scotto G, Montalto G, Romano M. Individualized treatment duration for hepatitis C genotype 1 patients: A randomized controlled trial.Hepatology. 2008;47:43-50.
[PubMed] [DOI][Cited in This Article: ]
Thompson AJ, Muir AJ, Sulkowski MS, Ge D, Fellay J, Shianna KV, Urban T, Afdhal NH, Jacobson IM, Esteban R. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus.Gastroenterology. 2010;139:120-9.e18.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 513][Cited by in F6Publishing: 522][Article Influence: 37.3][Reference Citation Analysis (0)]
Jacobson IM, Catlett I, Marcellin P. Telaprevir substantially improved SVR rates across all IL28B genotypes in the ADVANCE trial [Abstract 1369].J Hepatol. 2011;54:S542-S543.
[PubMed] [DOI][Cited in This Article: ]
Pol S, Aerssens J, Zeuzem S, Andreone P, Lawitz EJ, Roberts S, Younossi Z, Foster GR, Focaccia R, Horban A. Limited impact of IL28B genotype on response rates in telaprevir-treated patients with prior treatment failure.J Hepatol. 2013;58:883-889.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 47][Cited by in F6Publishing: 48][Article Influence: 4.4][Reference Citation Analysis (0)]
Ruiz-Extremera A, Muñoz-Gámez JA, Salmerón-Ruiz MA, de Rueda PM, Quiles-Pérez R, Gila-Medina A, Casado J, Belén Martín A, Sanjuan-Nuñez L, Carazo A. Genetic variation in interleukin 28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCV-infected children.Hepatology. 2011;53:1830-1838.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 99][Cited by in F6Publishing: 107][Article Influence: 8.2][Reference Citation Analysis (0)]
Indolfi G, Mangone G, Bartolini E, Nebbia G, Calvo PL, Moriondo M, Tovo PA, de Martino M, Azzari C, Resti M. Comparative analysis of rs12979860 SNP of the IFNL3 gene in children with hepatitis C and ethnic matched controls using 1000 Genomes Project data.PLoS One. 2014;9:e85899.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 23][Cited by in F6Publishing: 20][Article Influence: 2.0][Reference Citation Analysis (0)]
Hierro L, Alvarez L, Lledìn MD, Andueza L, Gordo-Giralt R, Camarena C, de la Vega A, Munoz-Bartolo G, Frauca E, Dìaz C. IL28B gene polymorphisms in children with chronic hepatitis C.J Ped Gastroenterol Nutr. 2011;52:E22.
[PubMed] [DOI][Cited in This Article: ]
Mangia A, Thompson AJ, Santoro R, Piazzolla V, Copetti M, Minerva N, Petruzzellis D, Mottola L, Bacca D, McHutchison JG. Limited use of interleukin 28B in the setting of response-guided treatment with detailed on-treatment virological monitoring.Hepatology. 2011;54:772-780.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 46][Cited by in F6Publishing: 53][Article Influence: 4.1][Reference Citation Analysis (0)]
Liu CH, Liang CC, Liu CJ, Tseng TC, Lin CL, Yang SS, Su TH, Lin JW, Chen JH, Chen PJ. Interleukin 28B genetic polymorphisms play a minor role in identifying optimal treatment duration in HCV genotype 1 slow responders to pegylated interferon plus ribavirin.Antivir Ther. 2012;17:1059-1067.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 19][Cited by in F6Publishing: 20][Article Influence: 1.7][Reference Citation Analysis (0)]
European Paediatric Hepatitis C Virus Network. Three broad modalities in the natural history of vertically acquired hepatitis C virus infection.Clin Infect Dis. 2005;41:45-51.
[PubMed] [DOI][Cited in This Article: ]
Resti M, Jara P, Hierro L, Azzari C, Giacchino R, Zuin G, Zancan L, Pedditzi S, Bortolotti F. Clinical features and progression of perinatally acquired hepatitis C virus infection.J Med Virol. 2003;70:373-377.
[PubMed] [DOI][Cited in This Article: ]
