Značaj genskih polimorfizama IL28B u predikciji stabilnog virusološkog odgovora pacijanta sa hroničnim C hepatitisom

Abstract

UVOD: IL28B polimorfizmi se smatraju važnim prognostičkim faktorom za ishod terapije pacijenata sa hroničnim C hepatitisom koji se leče standardnom, dvojnom terapijom PEG-IFN/RBV. CILJ: Ovo istraživanje ima za cilj da ispita uticaj pojednačnih polimorfizama (eng. Single nucleotide polymorphisms, SNP): rs8099917, rs12979860 i rs12980275 i njihovih kombinacija (IL28B profili) na SVR, kao i uticaj virusoloških faktora i faktora od strane domaćina. METODOLOGIJA: Istraživanje je obuhvatilo 136 pacijenata sa hroničnim C hepatitisom genotip 1 koji su lečeni po protokolu - pegilovani-interferon α2a/α2b i ribavirin tokom 48 nedelja. Za ispitivanje polimorfizama korišćen je SSP-PCR (eng. Sequence specific primer - PCR) metod. REZULTATI: SVR je postiglo 58.8% pacijenata. Genotipovi TTrs8099917, CCrs12979860 i AArs12980275 su označeni kao “povoljni” zbog značajno veće prevalence u grupi pacijenata koja je odgovorila na primenjenu terapiju. S druge strane, genotipovi GGrs8099917 i TTrs12979860 su označeni kao “nepovoljni” jer su bili povezani sa izostankom odgovora na terapiju. Prisustvo CCrs12979860 ili AArs12980275 povećava verovatnoću za SVR 3 odnosno 1.5 puta. IL28B profil koji u sebi sadrži makar jedan povoljan genotip TTrs8099917 ili CCrs12979860 ili AArs12980275, se pokazao kao nezavisni prediktor odgovora na primenjenu terapiju, a potom i mlađe životno doba i niži stepen nekroinflamatorne aktivnosti jetre. Među pacijentima koji su postigli SVR, 87.5% je imalo neki od ovih IL28B profila. Najjaču PPV ima CCrs12979860 (81.8%), dok su najjaču NPV pokazali TTrs12979860 i GGrs8099917, 65.5%, odnosno 61.6%. Niža serumska aktivnost AST u korelaciji je sa TTrs8099917, dok je niži nivo virusne replikacije pre početka terapije u korelaciji sa GGrs8099917. ZAKLJUČAK: Rezultati ovog ispitivanju su potvrdili da sva tri ispitivana polimorfizma imaju važnu ulogu u predikciji SVR. Od ispitivanih parametara kao nezavisni prediktor ishoda terapije, pokazao se IL28B profil koji u sebu sadrži makar jedan povoljan genotip od tri ispitivana polimorfizma.

BACKGROUND: The three single nucleotide polymorphisms (SNPs) near IL28B gene were shown to be highly predictive of sustained virological response (SVR) in patients with chronic hepatitis C virus (HCV) infection. AIM: This study attempted to demonstrate the role of single and combined IL28B polymorphisms (rs8099917, rs12979860 and rs12980275) and other host and viral factors in predicting response to treatment, in Caucasian patients infected with HCV genotype 1. METHODOLOGY: The study comprised 136 patients with chronic hepatitis C infection genotype 1 who were treated with pegilated-interferon α2a/α2b and ribavirin for 48 weeks. SNPs were identified using SSP-PCR (Sequence specific primer - PCR). RESULTS: 58.8% achieved SVR. Genotypes TTrs8099917, CCrs12979860 and AArs12980275 were associated with favorable response to treatment, while GGrs8099917 and TTrs12979860 were identified as predictors of treatment failure. Patients carrying genotypes CCrs12979860 or AArs12980275 were 3 and 1.5 times more likely to achieve SVR, respectively. The presence of IL28B profiles (combinations of genotypes from all 3 SNPs), that included at least one of the favorable genotypes, was identified as the most important factor associated with SVR, followed by younger age and lower grade of histological activity. Of all patients who achieved SVR, 87.5% was carrying one of these IL28B profiles. The strongest PPV of single SNPs for achieving SVR was observed for CCrs12979860 (81.8%). The presence of TTrs12979860 showed the strongest NPV of 65.5%, followed by GGrs8099917 61.6%. The correlation of SNPs with other host and viral factors revealed association of TTrs8099917 and lower AST levels as well as lower baseline viral load and GGrs8099917. CONCLUSION: Results of this study confirm that all investigated IL28B polymorphisms are associated with treatment response and that presence of any of the favorable IL28B genotypes can be considered independent pretreatment determinant of the effectiveness of therapy.