"Studying the Role of some Interferon-Stimulated and Vitamin D Related Genes Polymorphism in Treatment Outcome of HCV”

Abstract

hronic Hepatitis C is the one of most common causes of chronic viral liver disease worldwide leading to significant morbidity and mortality due to liver disease and hepatocellular carcinoma of infected persons. Egypt has the highest incidence and prevalence of HCV infection worldwide. With more than 12 million infected individuals, CHC represents a major public health and economic burden in Egypt. The high genetic heterogeneity (6 different HCV genotypes and a significant number of subtypes) represents an important feature of viral strain, which affects duration and response to treatment. Hepatitis C virus G4 makes up 20% of HCV infections worldwide, but in general is relatively uncommon in the US and Europe. Genotype 4 is prevalent in Egypt, Africa and the Middle East. The standard of care for hepatitis C therapy has long been Peg-IFN and RBV until 2011, when new DAAs were widely approved. Although they represent a substantial advance in efficacy with better tolerability, but come at a high cost. While resource rich countries can afford to use these treatments as first line therapy, access to such expensive, may be limited in resource constrained countries. Hence, Peg-IFN and RBV, are still used as the standard of care. Although Peg-IFN/RBV is a somewhat less optimal therapeutic choice in a resource constrained setting owing to its lower SVR rates and intolerable side effects, it will continue in the near future. Current data on G4 CHC regarding treatment response and duration are limited and controversial. Consequently, there is an important unmet need to simplify treatment strategy for G4 using a roadmap based management that can provide a practical guide for decision making before starting the treatment. Thus, the current study was designed in an attempt to study the role of some SNPs in some immune related genes as well as other related serum biomarkers in predicting treatment outcomes for HCV G4 Egyptian population. In order to fulfil our aim, thepresent study was conducted on 200 subjects divided into the following two groups: (A) SVR group: consists of 91 CHC patients with negative serum HCV RNA levels after 6 months of treatment discontinuation. (B) NR group: consists of 109 CHC patients whom serum HCV RNA levels never reach a negative value after discontinuation of the treatment course. Results of the current study can be summarized as follows:

(1) Interleukin 28B rs12979860is the strongest predictor of Peg-IFN/ RBV response in CHC G4 population and in lower fibrosis grade models. (2) Baseline serum AFP levels and basic viral load levels are inversely related to the achievement of SVR in the overall CHC population, yet not in lower fibrosis grades patients. (3) Baseline serum 25-OH vitamin D levels is a direct independent predictor of treatment success with 12 ng/mL as a negative predictive value and 38 ng/mL as a positive predictive value. Additionally, it is an impressive predictor in F1, F2 and F3 fibrosis grades patients. (4) Polymorphisms at OASL rs1169279CT, VDR rs1544410TC as well as at ADAR rs1127309TC genes are not related to treatment outcomes for CHC G4 patients. (5) Single nucleotide polymorphisms at CYP2R1 rs10741657 and VDR rs2228570 genes are strong predictors of treatment outcome in various fibrosis grades model. Beside the latter (VDR rs2228570) gene being a valuable predictor in non-F4 patients. (6) Our all concluded predictors significantly increases the sensitivity and accuracy of the well-established IL28B rs12979860 in different fibrosis grades as well as in non-F4 patients. (7) As thepresent study predictive model significantly increase the predictive power of IL28B rs12979860, therefore they must then be used collectively for screening patients prior treatment decision. (8) Finally, presence of minor allele A at either CYP2R1 rs10741657 and VDR rs2228570 genes are complementary to IL28B rs12979860C/C genotype assuring SVR in naïve CHC G4 patients of different fibrosis grades panel.