Sunday, September 23, 2012

Test of IL28B Polymorphisms in Chronic Hepatitis C Patients Treated with PegIFN and Ribavirin Depends on HCV Genotypes

Test of IL28B Polymorphisms in Chronic Hepatitis C Patients Treated with PegIFN and Ribavirin Depends on HCV Genotypes: Results from a Meta-Analysis

Zhifang Jia1#, Yanhua Ding2#, Suyan Tian1, Junqi Niu3, Jing Jiang1*
1 Division of Clinical Epidemiology, First Hospital of Jilin University, Changchun, China, 2 Department of Phase I Clinical Trials of Medicine, First Hospital of Jilin University, Changchun, China, 3 Department of Hepatology, First Hospital of Jilin University, Changchun, China
Many studies have been published on the association between single nucleotide polymorphisms (SNP) near the IL28B gene and response to the combined treatments of pegylated-interferon (PegIFN) and ribavirin (RBV) in chronic HCV-infected patients, but without identical conclusions. The aim of this study was to assess impact of the IL28B polymorphisms on the effect of HCV standard treatment using meta-analysis based method.
Association studies between polymorphisms of rs12979860 or rs8099917 and response to PegIFN/RBV treatment in chronic HCV patients were retrieved from PubMed. Data of qualified studies on sustained virological response (SVR) in different genotypes were extracted and analyzed using meta-analysis method in Stata 10 software.
Thirty-four papers, containing 46 independent studies, were included in the analysis. In the HCV G1/4 patients without treatment history, individuals carrying rs12979860 CC genotype were more likely to achieve SVR (OR 3.97, 95%CI 3.29–4.80) compared to those carrying CT/TT genotypes. Similar results were observed in the HCV G1/4 patients with unsuccessful or unknown treatment history (OR 3.76, 95%CI 2.67–5.28) or in the patients co-infected with human immunodeficiency virus (OR 5.20, 95%CI 3.04–8.90). However, associations could not be observed in HCV G2/3 patients. For rs8099917, similar results were obtained for genotype TT compared to genotypes TG/GG, indicating that TT genotype was significantly associated with better treatment response in patients infected with genotype 1 or 4 HCV, but not genotype 2 or 3 HCV.
Polymorphisms of rs12979860 and rs8099917 near IL28B only associate with the treatment response to PegIFN/RBV in patients infected with HCV genotype 1 or 4 but not with genotype 2 or 3, irrespective of the previous treatment history or HIV co-infected status. Therefore, identification of IL28B genotypes is necessary only in patients infected with relatively difficult-to-treat genotype 1 or 4 HCV.

In the present study, we collected and summarized studies on associations between SNPs near IL28B gene (rs12979860 and rs8099917) and the treatment effect of PegIFN/RBV in chronic HCV patients. Roughly, a 3-fold significant increase of possibility to clear virus (SVR) was observed for rs12979860 CC genotype or rs8099917 TT genotype in patients infected with HCV genotype 1 or 4, irrespective of race, treatment history or the status of HIV co-infection. However, no relationship was found in patients infected with HCV genotype 2 or 3. A possible interpretation is that the effect of SNPs is attenuated by a better treatment response in patients with genotype 2 or 3 HCV as several studies have reported that rs12979860 CC or rs8099917 TT genotype was associated with faster early viral elimination in patients with genotype 2 or 3 HCV [17], [20], [21], [24] and the rate of SVR in treatment-naïve subjects infected with genotype 2 or 3 is 80.6%, much higher than 48.5% in patients with HCV genotype 1 or 4.
Rs12979860, located about 3 kb upstream to the IL28B coding region, resides in the putative promoter or the regulatory region of IL28B gene and may affect the gene expression as predicted by a bioinformatics tool, FastSNP (​input_SNPListAnalysis.jsp). The C allele has been reported to be linked to higher serum levels of IL28B, IL28A and IL29 levels, which are all involved in the induction of expression of IFN-responsive genes [47]. The CC genotype has also been reported to be associated with lower levels of intrahepatic interferon-stimulated gene (ISG) expression, which is linked to better IFN-based treatment response [48]. However, the exact mechanism underlying effects of the SNP on treatment response still remains to be clarified. Nonetheless, several facts are noteworthy. Frequencies of favorable CC genotype of rs12979860 vary in different races, but in the same direction as SVR rates to PegIFN/RBV treatment [49], [50]. And the frequencies of CC genotype increase from the lowest in patients failed to treatment, to intermediate in patients with treatment-induced clearance, and then to the highest in patients with spontaneous clearance [50], [51]. In our analysis, the SVR rate declines with the reduction of C allele (72.7% for CC, 41.6% for CT, 34.4% for TT, Table 2) when data from the Caucasian HCV G1/4 treatment-naïve patients were combined. Rs8099917 has been reported to be in strong linkage disequilibrium with rs12979860 [4], [14][18]. Similar associations with HCV treatment are observed and the predictive value could not be increased when determined simultaneously [38]. Therefore, rs8099917 may share similar mechanism as rs12979860 on the association with treatment response although the mechanism is still unclear and determination of the genotype of one SNP may be enough in clinical practice.
Limitations and cautions should be taken into account before making conclusions. Firstly, selection of patients could cause a bias. Several studies analyzed patients with compliance >80% in all patients [16], [17], [21], [24], [38] or >80% only in non-SVR patients [4], [19], [22]. Non-responders are more likely to discontinue therapy prematurely [3] and the frequencies of unfavorable genotypes tend to be higher in non-responders [50], [51]. Therefore, selection of patients according to the compliance may result in an underestimation of SNP effect on treatment response. Secondly, therapeutic effect could be influenced by multiple variables known or unknown. For example, baseline HCV RNA level has been recognized to be reversely correlated with treatment effect [4]. In this analysis, we could not adjust this factor because different studies applied different criteria to define high and low levels of HCV RNA [4], [15], [16], [23]. Therefore, the unified design should be considered in future studies to calculate the net contribution of IL28B to treatment response. Thirdly, a group of patients with unsuccessful or unknown treatment history in our review was meant to represent the actual complex clinical setting. The interpretation of results from this group should be cautious since the portions of patients with treatment history were different among different studies. However, the study carried out in patients all failed to previous treatment also supported the association concluded in our analysis [42], indicating the predictable values of SNP near the IL28B gene. Finally, several studies were excluded from our analysis due to no sufficient data to calculate the ORs stratified by races and HCV genotypes according to our criteria [50][54]. However, the same conclusion would be derived if these studies were included, only with the values of ORs slightly altered, since these studies also favor the results we get.
In summary, our findings suggest that SNPs of IL28B are useful baseline predictors for virological response in patients infected with genotype 1 or 4 HCV when treated with PegIFN/RBV, but not in patients with genotype 2 or 3 HCV. Therefore, determination of IL28B genotype may be necessary only in HCV genotype 1 or 4 patients. For those patients infected with difficult-to-treat genotype 1 or 4 HCV and also bearing rs12979860 non-CC genotype or rs8099917 non-TT genotype, it is urgent to develop more effective therapy strategies.

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