The Effect Of DAAs on miRNA-122 And Insulin Resistance In Chronic HCV Patients
The Effect Of DAAs on miRNA-122 And Insulin Resistance In Chronic HCV Patients
The hepatitis C virus is a major cause of chronic liver diseases, including cirrhosis and
 hepatocellular carcinoma, and infects approximately 3 % of the world population (150-170
 million). It is estimated that approximately 80 % of patients with acute hepatitis C fail to
 eliminate the virus and become chronically infected Hepatitis C virus infection is strongly
 associated with the dysregulation of glucose homoeostasis such as insulin resistance and type
 2 diabetes. Despite these findings of insulin resistance development via direct effects on
 insulin signalling pathway, the complex relationship between intrahepatic Hepatitis C virus
 infection and extrahepatic insulin resistance remains elusive.

 One of the countries most affected by Hepatitis C virus is Egypt. The Egyptian Demographic
 and Health Surveys measured antibody prevalence among the adult population aged 15-59 years
 at 10.0% in 2015-substantially higher than global levels.

 Several micro ribonucleic acids have been determined to play a key role in regulating viral
 replication and pathogenesis during infection. micro ribonucleic acid-122 expression is
 enriched in the liver, accounting for approximately 70 % of the total micro ribonucleic acid
 population in normal adult hepatocytes. Moreover, a particularly intriguing function of micro
 ribonucleic acid-122 involves its role in the Hepatitis C virus replication cycle.

 Antagonism of micro ribonucleic acid-122 not only reduces viral replication but also reduces
 Hepatitis C virus propagation by decreasing the expression of enzymes involved in lipid
 metabolism, which can enhance Hepatitis C virus replication in cell culture models.
The hepatitis C virus (HCV) is an enveloped, single-stranded positive-sense Ribo-Nucleic Acid
 virus which is a major cause of chronic liver diseases, including cirrhosis and
 hepatocellular carcinoma (HCC), and infects approximately 3 % of the world population(150-170
 million).

 One of the countries most affected by HCV is Egypt. The Egyptian Demographic and Health
 Surveys measured antibody prevalence among the adult population aged 15-59 years at 14.7% in
 2009 and at 10.0% in 2015 To attend to this challenge, Egypt developed a national strategy
 for Hepatitis C Virus control and established HCV prevention and treatment programs using
 Direct Acting-Antivirals (DAAs).

 Egypt launched an ambitious national HCV treatment program aiming to treat over 250,000
 chronically infected individuals per year, with the goal of achieving a national chronic
 infection prevalence of <2% by 2025.

 Although the consequences of chronic HCV infection are generally associated with liver
 manifestations such as hepatic fibrosis, cirrhosis, steatosis (known as non-alcoholic fatty
 liver disease, NAFLD) and HCC, the liver-related mortality of 350,000 individuals annually is
 still underestimated due to the lack of consideration of extrahepatic effect including a
 growing evidence showing that HCV infection is strongly associated with the dysregulation of
 glucose homoeostasis such as insulin resistance (IR) and type 2 diabetes (T2D).

 HCV-related type 2 diabetes mellitus may arise from a complex interaction between IR,
 steatosis and inflammatory processes People infected with HCV are 4 times more likely to
 develop Type 2 Diabetes; and HCV-infected patients with uncontrolled glucose are at higher
 risk to develop advanced liver fibrosis, HCC, and exhibit decreased sustained virologic
 response (SVR) to traditional interferon treatment.

 HCV protein NS5A and the core protein directly inhibit microsomal triglyceride transfer
 protein (MTP) activity, thereby reducing very low-density lipoprotein (VLDL) assembly and
 inducing hepatic steatosis.

 Over time, accumulation of hepatic triglycerides leads to hepatic IR via decreased
 insulin-stimulated glycogen synthesis and enhanced hepatic gluconeogenesis; such conditions
 further cause peripheral IR in multiple organs through increased circulating insulin and free
 fatty acid levels.

 Regarding the molecular mechanisms of regulation of insulin signaling by HCV infection. HCV
 core protein has been found to increase serine rather than tyrosine phosphorylation of IRS-1
 ( insulin Receptor Substrate-1) in hepatocytes, resulting in its degradation and impaired
 downstream signaling Protien Kinase B signalling pathway.

 HCV core protein also stimulates Insulin Receptor Substrate-1 serine phosphorylation via
 increasing mTOR (mammalian Target Of Rapamycin)levels, resulting in decreased Protien Kinase
 B signaling.

 Reduced surface expression of glucose transporters GLUT1 and GLUT2 with consequential
 reduction in glucose uptake in HCV-infected hepatocytes has also been reported.

 Despite these findings of IR development via direct effects on insulin signaling pathways,
 the complex relationship between intrahepatic HCV infection and extrahepatic IR remains
 elusive.

 Several miRNAs have been determined to play a key role in regulating viral replication and
 pathogenesis during HCV infection.

 Host miRNAs can be activated by viral integration in the host genome; viral miRNAs can target
 host mRNAs, , or host miRNAs can target viral mRNAs.

 miR-122 expression is enriched in the liver, accounting for approximately 70 % of the total
 miRNA population in normal adult hepatocytes with approximately 66,000 copies per cell.

 miR-122 has a role in the HCV replication cycle, where it binds to two target sites (S1 and
 S2) in the highly conserved 5' untranslated region of the HCV genome, thus forming a complex
 of HCV oligomeric miR-122 that protects the HCV genome from nucleolytic degradation as well
 as from the host innate immune response.

 Many metabolic processes are potentially targeted by miR-122, including protein metabolism,
 carbohydrate metabolism, lipid metabolism and phospholipid metabolism. Signaling pathway
 ontology revealed several IR-related pathways [eg insulin/Insulin Growth Factor/Protien
 Kinase B signaling, Phosphoinositide 3-Kinase signaling, apoptosis, Epidermal Growth Factor
 receptor signaling,G protien-coupled receptors signaling pathway.

 Antagonism of miRNA-122 not only reduces viral replication but also reduces HCV propagation
 by decreasing the expression of enzymes involved in lipid metabolism, which can enhance HCV
 replication in cell culture models.

 miR-122 represents an interesting therapeutic target for the treatment of liver disease
 including viral hepatitis, fibrosis, steatosis and HCC. Experimental studies have elegantly
 demonstrated that a miR-122 inhibitor efficiently reduces viral load in chronically infected
 HCV patients without detectable resistance.
Inclusion Criteria:

 -  Chronic HCV patients eligible for treatment with Direct Acting Antivirals.

 -  Chronic HCV patients 3 months after starting of treatment

 Exclusion Criteria:

 -  Cirrhosis

 -  Diabetes Mellitus

 -  Hemochromatosis

 -  HBV

 -  HIV

 -  Hepatocellular carcinoma (HCC)

 -  Chemotherapy

 -  Organ transplantation