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  • Substitutions V L F V and Q H


    Substitutions V36L, F43V and Q80H were identified in the present study. RAS V36L is associated with resistance to boceprevir [18]. In 2015, Brazilian clinical practice guidelines on the management of hepatitis C no longer included combined therapies with boceprevir or telaprevir as a treatment option. RAS V36L was identified in one subtype 1a patient from group 2. A 12-week therapy with simeprevir was initiated. V36L was not related with less susceptibility to this drug and SVR was achieved post-treatment. Analysis of mutations associated with resistance among patients infected with HCV subtype 1b indicated the presence of RAS F43V in a DAA treatment-naïve patient. To our knowledge, this is the first report of this mutation in vivo. Resistance profile for PIs was described in vitro and pointed out F43 locus as associated with resistance to simeprevir [18]. RAS Q80H, which can reduce susceptibility to simeprevir, was identified in one patient from group 2 infected with subtype 1b. Treatment with boceprevir was selected for this patient and Q80H did not influenced treatment response since SVR was achieved after treatment. No Brazilian data have described this mutation among treatment-naive patients.
    Authors' contribution
    Disclosure of interest
    Acknowledgements We appreciated the contributions of Ana Carolina Galha, Selma XSL Pinheiro and Islene Azevedo for technical assistances. In addition, we wish to thank Adilson José de Almeida (in memoriam), Moyra M Portilho, Vanessa A Marques and Letícia P Scalioni, for data analysis during the set up of this project.
    Introduction Hepatitis C is a liver disease caused by Hepatitis C Virus (HCV). It was first discovered in 1970 and was given remarkable interest as an unidentified third type of virus other than Hepatitis A and B. In 1989, HCV was identified and its CHIR-124 mg cloned [1]. Research efforts in the field of HCV has been continuously progressing due to the large number of reported worldwide HCV infections (∼3% of the world's population, 150–200 million people, with specially high prevalence in Asia and North of Africa) [2], [3]. The fact that over 85% of HCV patients will probably develop chronic hepatitis and that 20% of the chronic infections will progress to liver cirrhosis and Hepatocellular Carcinoma (HCC) [4], [5] represented a strong motivation to conduct extensive research in this field. HCV is a member of the Flaviviridae family with a single positive-strand RNA encoding a poly-protein that undergoes proteolytic cleavage to 10 polypeptides, each with a distinct function. The structural proteins consist of a nucleocapside (C protein) which interacts with progeny viral genomes for virus assembly, in addition to two envelope glycoproteins (E1, E2) both of which are targets of the host antibody response and possibly ion channels (p7). The nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B form a complex with viral RNA to initiate viral replication in a cytoplasmic membranous structure [6], [7], [8], [9], [10], [11], [12]. Unlike Hepatitis A and B, there is no vaccine for prevention of HCV infection. The current recommended therapy for HCV infection relies only on antiviral drugs. Before 2011, the treatment of choice was a combination of Pegylated Interferon (IFN) alpha with the antiviral nucleoside analogue ribavirin [13], [14]. This therapy is effective in 50–80% of patients, depending on the HCV genotype. However, it is expensive and often associated with side effects that force discontinuation of the therapy [15], [16]. Recently, several inhibitors targeting the viral NS3 protease, NS5B or NS5A have been approved for the treatment of HCV [16], [17], [18]. This is in addition to several other proposed inhibitor compounds that are suggested via theoretical and molecular modeling studies on HCV [19], [20], [21], [22], [23]. Similar to RNA viruses, HCV has an error-prone RNA-dependent RNA polymerase (RdRp) that allowed an original HCV ancestor to evolve into seven genotypes and more than 80 subtypes of HCV, currently described according to the nucleotide variation found among different HCV isolates [24].