الفهرس 
Life cycle of HCVOnly 14 pages are availabe for public view
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Abstract
Hepatitis C virus (HCV) is a global problem and endemic in Egypt. chronic infection of HCV is associated with liver cirrhosis, hepatocellular carcinoma (HCC), liver failure, and death [4]. Genotype 4 (G 4) has a high prevalence in North Africa and Middle East and represents >90 % of hepatitis C patients in Egypt [3]. Ribavirin (RBV) still has a critical role in the treatment regimen of HCV due to the improved sustained virological response [6]. This study was conducted to investigate the effect of single nucleotide polymorphisms (SNPs) of genes involved in ribavirin (RBV) transport (SLC28A2 gene, ABCB1 gene and ABCB11 gene) on the clinical outcomes and pharmacokinetics of ribavirin in HCV- 4 Egyptian patients. Patients were recruited from the outpatient clinic of Tropical Medicine Department, Liver institute, Kafrelsheikh, Egypt. Patients were selected from April 2017 to August 2018. This study was a prospective, observational, pharmacogenetic, pharmacokinetic and single center study included 100 male Egyptian patients infected with HCV genotype 4, treated with sofosbuvir (SOF)/daclatasvir (DCV) and ribavirin (RBV). Patients received treatment for 12 weeks with sofosbuvir 400 mg once daily, daclatasvir 60 mg once daily, and weight-based ribavirin (1200 mg/day for patients weighing ≥75 kg and 600-1000 mg/day for patients weighing <75 kg) given in two divided doses, provided that no dose modification of any drug up to week 4 of therapy. Patients were observed for any dropout or reported side effects. The SNP genotyping was performed by real-time PCR using high resolution melting analysis. Ribavirin plasma trough concentrations were measured at week 4 of therapy using a liquid chromatography/tandem mass spectrometry (LC-MS/MS). HCV viral loads were measured. In addition, ALT, AST, total bilirubin, albumin, serum creatinine, hemoglobin, leukocyte count, and platelet count were measured at baseline and after 4 weeks of therapy. Patients who had undetectable HCV RNA at the end of treatment and for at least 12 weeks after treatment completion were considered responders, i.e. they achieved sustained virological response (SVR). Patients were considered non-responders if they had detectable HCV RNA at the end of treatment or at follow-up. The results showed that ABCB1 2677 G>T SNP and ABCB11 1331 T>C SNP were statistically associated with RBV Ctrough levels after 4 weeks of therapy. The present study also revealed the significant association of ABCB11 1331 T>C SNP with clinical outcomes (SVR). However, the present study has not showed any statistically significant association of SLC28A2-146 A>T SNP with RBV plasma levels or response. In conclusion, RBV is a critical component in anti-HCV treatment regimen. SNP genotyping for ABCB1 and ABCB11 genes can help in better personalized medicine for maximizing response for ribavirin as explored by the significant association between polymorphism in ABCB1 and ABCB11 genes and ribavirin pharmacokinetics and the significant association of ABCB11 1331 T>C SNP with clinical response. Before starting ribavirin intervention, pharmacogenetic profile is recommended for maximizing response and minimizing toxicity for ribavirin. Recommendations of our study are to evaluate more genes and larger sample size to explain the effects of genetic variations on pharmacokinetics and clinical outcomes.