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Study of resistance mutations to the treatment with direct-acting antivirals in patients infected with Hepatitis C virus genotype 3

Abstract

Hepatitis C is a liver inflammation caused by Hepatitis C Virus (HCV), a positive single stranded RNA virus belonging to Flaviviridae family. According to the World Health Organization (WHO), approximately 185 million people are infected by HCV, with 350 thousand deaths related to this disease around world. In Brazil, the number is around 1.4 and 1.7 million people infected. There is no vaccine against HCV, and the latest treatment, based in the direct acting antivirals (DAA), has a high cost and the sustained virological response (SVR) varies according to the viral genotype. Recently, the use of second generation direct acting antivirals, Simeprevir, Sofosbuvir and Daclatasvir, was approved. The administration of these drugs led to an improvement of treatment response for all genotypes, however genotype 3 presented the lowest response when compared to the other genotypes. It is known that treatment resistance is greatly related to resistance mutations in the viral genome. It has been identified mutations that confer resistance to antiviral treatment for all DAAs that are used today. However, there are few data on genotype 3 specific mutations that can explain the lower SVR for this genotype. In Brazil, the clinical protocol and therapeutic guidelines of Health Ministry, published in July 2015, indicates the use of Sofosbuvir and Daclatasvir for treatment of genotype 3 infected patients. Genotype 3 is the second most prevalent in Brazil representing 30% of HCV infected patients, making studies on the factors involved in treatment resistance extremely important for the country public health. This project aims to investigate viral resistance mutations described in literature and investigate the existence of undescribed resistance mutations in patients infected by HCV genotype 3 who do not respond to treatment with Sofosbuvir and Daclatasvir. Also the replicative behavior of the new identified mutations will be evaluated in cell culture. (AU)

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