الفهرس 
Review of literatureOnly 14 pages are availabe for public view
 |  | from | 153 |  |  |
| | | from | 153 | | |
Abstract
6. Summary and Conclusion
Hepatitis C Virus (HCV) causes viral hepatitis infection that is a major global health issue. It is estimated that more than 80 million people are chronically infected worldwide, with 3–4 million new infections and 350 000 deaths, occurring each year as a result of complications related to HCV infection. HCV genotype ¬4 dominates the HCV epidemic in Egypt. The prevalence of HCV infection in Egypt among those aged 15-59 years HCV antibody represents 10.0% and HCV RNA 7.0%.
The combined therapy of pegylated interferon alpha and ribavirin (PEG-IFNα/RBV) was represented as the standard of care in chronic HCV. Unfortunately, this therapy is expensive and the prolonged PEG-IFNα/RBV therapy often associated with serious side effects. Drug resistance was the most serious side effect that reflects bad clinical outcome that led to increase the need to identify accurate predictors of treatment outcome to facilitate treatment decision making.
Many studies tried to investigate the common reasons that lead to the resistance for pegylated interferon alpha and ribavirin therapy. The majority studies were concentrated on HCV genotype 1, 2 and 3 and few studies concentrate on HCV genotype 4. Most of them discovered a great linkage between the genotypic variation among individuals and individuals’ response to therapy.
In 2009, genome-wide association studies have revealed that single nucleotide polymorphisms (SNPs) near the IL28B gene on chromosome 19 were strongly associated with viral response and therapy outcomes in HCV infected patients. Two of these SNPs are apparently highly prognostic to the favorable therapy response: rs12979860 and rs8099917. They were found to strongly predict therapy outcomes with CC (rs12979860) and TT (rs8099917) genotypes being highly prognostic of SVR.
Chemokines and cytokines are regulators of immunity and inflammation in HCV infection so they are attractive as potential markers for treatment outcome. Many are modulated via exogenous interferon and play vital roles in clearance of viruses. Interferon γ inducible protein 10 (IP-10) is a small cytokine that belongs to CXC chemokine family. It is 10 kDa protein, encoded by the CXCL10 gene IP-10 is secreted by several cells, including hepatocytes. Several studies have shown that the IP-10 may act as a prognostic marker for HCV treatment outcome. A strongly association between low pretreatment serum IP-10 levels and a favorable viral response through combined therapy in HCV infected patients with genotype 4.
The present study included fifty patients with HCV genotype 4 who received the combined therapy of PEG-IFNα/RBV. The patients included in this study were selected according to specified inclusion and exclusion criteria. We aimed to investigate the predictive power of SNPs rs12979860, rs8099917 of IL28B in association with serum IP-10 levels on treatment response to PEG-IFNα/RBV in hepatitis C patients.
Blood sample were withdrawn from each participant and subjected to; serum HCV viral load assessment, complete blood count analysis, serum liver transaminases level (serum ALT and AST), serum total bilirubin, albumin and creatinine measurements.
Genotyping of IL28B polymorphism was carried out by polymerase chain reaction (PCR), and restriction fragment length polymorphism (RFLP) to rs12979860 and rs8099917. Quantification of serum IP-10 carried out by using enzyme-linked immunosorbent assay (ELISA) kit.
In this study, the studied cases revealed 42% achieved sustained virological response (SVR) while 58% patients were with no viral response (NVR). The distribution of IL28B (C/T) rs12979860 genotypes and (T/G) rs8099917 genotypes among the HCV studied patients revealed that the heterozygous CT genotype 52% and the homozygous TT genotype 44% were the most frequently observed in rs12979860 and rs8099917, respectively. Followed by homozygous CC genotype then TT genotype for rs12979860 and heterozygous GT genotype then homozygous GG genotype for rs8099917. Regarding the favorable genotypes which show better response to therapy, it was found that homozygous CC genotype in rs12979860 and heterozygous TT genotype in rs8099917 were the most favorable genotypes as respectively, 66.7% and 81.0% patients achieved sustained virological response to (PEG-IFNα/RBV) therapy.
Baseline serum IP-10 levels were significantly lower in patients who achieved SVR than in NVR. where lower mean levels of baseline IP-10 was significantly correlated to SVR with a significantly lower value 331.7 pg/ml compared to 642.6 pg/ml in the NVR.
Combining both pretreatment IP-10 and IL28B SNPs might improve SVR prediction in favorable allele carriers of IL28B. Lower baseline IP-10 was significantly correlated to CC genotype in rs12979860 genotypes and TT genotype in rs8099917. Serum baseline IP-10 levels and IL28B genotypes can be considered as predictors of SVR.
Regarding the mean values of haematological parameters (TLC, platelets, Hemoglobin levels) with baseline IP-10 levels and IL28B SNPs genotypes in rs12979860, rs8099917; there was no statistical significant difference.
While among the biochemical parameters there was a significance difference observed between different IL28B rs12979860 genotypes with ALT and AST. In contrast, there was no significant difference in other parameters (albumin, bilirubin, creatinine). In IL28B rs8099917 genotypes there was a significant difference for liver function tests (ALT, AST, albumin and bilirubin) and exhibits no significant relation with creatinine. A significant relation (P<0.05) was observed between IP-10 levels and liver function tests (ALT, AST, albumin and bilirubin). In contrast, there was no significant relation with creatinine.
Conclusion:
We observed that synergistic pretreatment evaluation of IP-10 and IL28B SNPs genotypes improves the predictive performance of SVR. Thus, pretreatment IP-10 levels and IL28B genotypes could be used as a predictive tool for SVR to PEG-IFNα/RBV therapy in HCV genotype 4 infected Egyptian patients. Besides, CC genotype in IL28B rs12979860 and TT in IL28B rs8099917 were the most favorable genotype for therapy success. Also, a low baseline IP-10 level was favorable predictor for therapy.
Recommendation:
At the end of this study, we recommend before initiating antiviral therapy for HCV, it is preferred to pretreatment screening of IL28B SNPs variants in combination with measurement of IP-10 levels in order to minimize cost effective therapy and unnecessary side effects. Patients lacking IL28B C-allele(s) (rs12979860) or T- allele(s) (rs8099917) in combination with high IP-10 levels may require alteration of therapy type and/or duration. However, several new antiviral for hepatitis C become available and IFN-free therapeutic regimens developed. In this new scenario, a thorough re-evaluation of IL28B genotype as a tool for therapeutic decision making will be needed. The limited availability of new costly antiviral drugs in low-income countries with high percentages of HCV-positive patients will remain a relevant issue for many years. In this setting, dual therapy may still be an option, and IL28B genotype may have a role as a predictive factor for response.