الفهرس 
AIM OF THE WORKOnly 14 pages are availabe for public view
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Abstract
HCV is a major factor of liver disease and one of the most important health issues worldwide. It has approximately 175 million Global Disease Burden which represent almost 3% of the whole population in the World (Munir et al., 2010). The prevalence of hepatitis C virus (HCV) in Egypt is over 14.7% of adult population. Egypt has the highest prevalence of hepatitis C in the world and consequently a high frequency of hepatocellular carcinoma (HCC) (Guerra et al., 2012).
Interferon has been the cornerstone of chronic HCV treatment for the past two decades. Pegylated interferon alpha (PEG-IFN) and ribavirin (RBV) has resulted in sustained virologic response (SVR) of up to 40–50% for genotype 1 and 4 and up to 70–80% in genotype 2 and 3 (Ghany et al., 2009).
Genetic analysis of the host may thus predict which patients are more likely to respond to treatment, taking into account that IL-28B genotype is only one of many factors that can influence response rates to PEG-IFN/RBV therapy in HCV infection (Bellanti et al., 2012). The rs12979860 SNP resides 3 kb upstream of the IL-28B gene, and variations at this position are associated with approximately 2-fold differences in spontaneous clearance and response to treatment. The C/C genotype is associated with better outcomes, and the T/T genotype, worse outcomes (Pagliaccetti & Robek, 2010).
Both host and viral factors are recognized to be important but do not adequately explain the observed variation in response to interferon based therapy for chronic HCV (Domagalski et al., 2013). The search for additional predictive factors for response is mandatory. Co-infection with other pathogens is, in some instances, an interfering factor against host genotype based prediction (El Awady et al., 2013).
Epstein-Barr virus (EBV) and Cytomegalovirus (CMV), members of the herpesvirus family, are common viruses that cause infectious mononucleosis (IM) characterized by fever, pharyngitis and lymphadenopathy. EBV/CMV infects at least 90% of the world’s population and can persist in a latent form after primary infection. Reactivation can occur years later, particularly under conditions of immunosuppression (Wang et al., 2010).
Regarding co-infection with CMV or EBV in chronic hepatitis C patients, there were many contradictory conclusions about the effect of these co-infection on HCV patients’ outcome.
Accordingly, the aim of this study was to explore whether co-infection with CMV and/or EBV could significantly affect the response to IFN on HCV patients and hence could be considered as significant predictor to interferon therapy in concordance with Interleukin-28B polymorphism.
105 adult Egyptian patients with chronic HCV infection - who received Pegylated interferon alpha and ribavirin (PEG-IFN/RBV) therapy - have been enrolled in this study. According to their response to treatment, they were categorized into two different groups: IFN responder patients (SVR) (n=38), 67 IFN nonresponder patients (NR).
Serum samples collected prior to start of therapy and after 12 weeks of therapy were assessed for detecting CMV and EBV antibodies by ELISA technique. Viral DNA was extracted from serum of each individual for molecular diagnosis of CMV-DNA and EBV-DNA. In addition, Genomic DNA was purified from peripheral blood for IL-28B SNP analysis. The role of EBV and CMV infection as well as IL-28B rs.12979860 SNP in determining virological response to anti-viral therapy were statistically analyzed.
Our results can be summarized in the following points:
1. Low median (3.32 ng/ml) baseline serum AFP levels were significantly related to SVR while higher median (6.39 ng/ml) baseline serum AFP levels were associated with NR patients (p-value= 0.01).
2. Regarding IL-28B rs.12979860 C/T polymorphism, CC genotype was significantly associated with SVR patients while TT genotype was significantly associated with lower SVR rates (p-value= 0.003).
3. As for CMV antibodies, CMV IgM was significantly increased in both groups (P-value< 0.01) at FUP but both groups showed the same pattern of CMV IgM rise (P-value= 0.28).
4. According to CMV IgG, there was no significant difference between both groups at baseline or FUP (p value=0.97) but pattern of change of CMV IgG from baseline to FUP between two groups was significantly difference (p-value= 0.04).
5. As for CMV viremia, it was increased from 6 patients at baseline to 20 patients at FUP without any significant difference between the two groups.
6. Regarding EBV antibodies, higher baseline levels of anti-VCA IgM was associated with NR (p-value= 0.01) and a comparable increase was noted among SVR and NR patients after 12 weeks of therapy.
7. Anti-VCA IgG did not show such significance at baseline or FUP for SVR and NR.
8. EBNA-1 IgG demonstrated a significant decline within SVR patients at week 12 (p value 0.02). while both groups showed the same pattern of EBNA-1 IgG decline from week 0 to week 12.
9. Regarding active EBV infection, it was represented in 61% at baseline which sorted into (55% in SVR and 63% among NR) and dropped to 55% after 12 weeks of IFN therapy (53% in SVR and 57% within NR) with no significant difference between two groups at baseline or FUP.
10. There were no correlations between qualitative or quantitative values of CMV and EBV markers with IL-28B polymorphism at baseline or FUP except anti-VCA IgG. Anti-VCA IgG titre was significantly increased at FUP among HCV patients with CC genotype (p-value= 0.003).
11. CMV/EBV co-infection in HCV patients was not correlated with patients’ outcome.
12. There was no correlation between CMV/EBV co-infection in HCV patients and IL-28B polymorphism.
13. Univariate and multivariate regression analysis for failure of achieving SVR among HCV patients showed that IL-28B polymorphism was the only parameter that showed a statistical significance (p-value= 0.01).
Conclusion
Baseline anti-VCA IgM could be a possible predictor of failure to achieve SVR in HCV patients while EBNA-1 IgG could be a marker for early virological response (EVR). Interleukin-28B polymorphism can predict response to PEG-IFN/RBV therapy. However, no correlation was found between CMV co-infection and HCV patients’ outcome. In addition, no correlation was observed between IL-28B polymorphism and co-infection with EBV or CMV.
Recommendations:
1. Further studies should focus on the effect of anti-VCA IgM and EBNA-1 IgG on the hepatitis C patients’ outcome.
2. It is also suggested to carry out further large-scale studies to evaluate Anti-VCA IgM and EBNA-1 IgG as predictor to interferon response of hepatitis C patients