Combined effects of different interleukin-28B gene variants on the outcome of dual combination therapy in chronic hepatitis C virus type 1 infection

Abstract

In patients with chronic hepatitis C virus (HCV) infection, several variants of the interleukin-28B (IL28B) gene have been shown to correlate significantly with a sustained virologic response (SVR). Recent evidence shows that determination of one single IL28B polymorphism, rs12979860, is sufficient for predicting treatment outcome. We examined whether the combined determination of the IL28B single-nucleotide polymorphisms (SNPs), rs12979860, rs8099917, rs12980275, and rs8103142, might improve the prediction of SVR in patients with HCV. In the study cohort, 54% of 942 patients with chronic HCV type 1 infection had SVR. The IL28B SNPs, rs12979860CC and rs8099917TT, correlated significantly with SVR (68% and 62%). The SNPs, rs12980275 and rs8103142, were in strong linkage disequilibrium with rs12979860 and were not included in further analysis. In homozygous carriers of the rs12979860 responder allele C, additional genotyping of the rs8099917 SNP had no effect on response prediction, whereas in carriers of the rs12979860 nonresponder allele, the rs8099917 SNP improved the response prediction. In heterozygous carriers of the rs12979860 nonresponder T allele, SVR rates were 55% in the presence of the rs8099917TT genotype and 40% in patients carrying the rs8099917 TG or GG genotype. Analysis of an independent confirmation cohort of 377 HCV type 1-infected patients verified the significant difference in SVR rates between the combined genotypes, rs12979860CT/rs8099917TT and rs12979860CT/rs8099917TG (38% versus 21%; P 5 0.018). Conclusion: Treatment outcome prediction could not be improved in homozygous carriers of the IL28B rs12979860 C responder allele by the additional determination of the rs8099917 SNP. There is evidence that a significant proportion of heterozygous carriers of the rs12979860 T nonresponder allele can profit with respect to SVR prediction by further determination of the rs8099917 SNP.

Impact of cohort size and host factors on combined analysis of interleukin 28B rs12979860 and rs8099917 in hepatitis C virus infection

“…3 Indeed, LPA levels in serum reported by Mazzocca et al were approximately 10 times higher than the previously reported LPA levels in plasma. 2,3 If their LPA values in serum were increased after sampling similarly in each sample, plasma LPA levels might be correlated with HCC burden as reported. To clarify this, we have newly measured plasma LPA levels in HCC patients,…”

“…Indeed, Italian patients have often been infected in the 1970-1980s through parenteral exposure, and as a consequence our cohort was older (mean age 55 years), more often cirrhotic (24%), and more often infected by HCV-1b (90%) than HCV patients from other geographical regions such as northern Europe. 2 Still, we cannot exclude that our relatively limited sample size might have prevented us seeing the differences observed by Fisher at al. ; however, this only strengthens the concept that the combined determination of the rs12979860 and rs8099917 genotype may hold a strong predictive power for an SVR mainly in large cohorts of patients, such as those enrolled in drug development studies, but might be less relevant at the individual level in clinical practice.…”

“…2 The authors genotyped 187 hepatitis C virus (HCV)-1 infected patients from an Italian cohort who received pegylated interferon and ribavirin. The overall genotype distribution of rs12979860 and rs8099917 and of the most prevalent combined genotypes rs12979860CC/rs8099917TT, rs12979860CT/rs8099917TT, and rs12979860CT/rs8099917TG were comparable to our cohort, as were the sustained virologic response (SVR) rates for the individual single nucleotide polymorphisms (SNPs).…”

“…First, because LPA is released from platelets, LPA has been measured in plasma but not in serum when evaluating its clinical significance. 2,3 Second, as we previously demonstrated, 4 LPA levels in plasma samples are markedly increased after sample preparation unless the temperature is kept under strict control, potentially because the synthetic enzyme autotaxin (ATX) and the substrate lysophosphatidyl choline coexist in plasma samples to abundantly produce LPA. LPA was once reported as a biomarker of ovarian cancer, 2 but contrary data were later demonstrated, in which a distinct sampling of plasma may explain this discrepancy.…”

HIV-HCV Co-Infection among Multitransfused Thalassemic Individuals-A Review

“…HCV genotype 3 is the major genotype (~86%) followed by genotype 1 among thalassemic individuals in this region. Standard therapy applied to HCV patients consists of a combination of pegylated interferon (Peg-IFN) alpha 2a or b and ribavirin (RBV) for 24-48 weeks depending upon HCV genotype, viremia as well as host factors such as IL28B genotype, age, sex, race and liver fibrosis status [10]. But the response rates in HIV/HCV co-infected thalassemic individuals were very poor (unpublished data).…”