Mutações De Resistência A Inibidores De NS5B De Hepacivírus C Em Pacientes Cronicamente Infectados

Abstract

Hepacivirus C (HCV) is responsible for the infection of over 150 million individuals worldwide, with 71 million of these evolving to the chronic form of the infection. Lacking corrective activity on its NS5B RNA-dependent RNA polymerase (RdRp) polymerase, HCV has a high rate of nucleotide substitutions in the genome during replication, which may give the virus a variability of quasispecies and resistant variants. to treatments. Anti-HCV therapy was initially performed with interferon and ribavirin, which brought a high rate of side effects to patients. From 2015, the administration of Direct Action Antivirals (DAAs) was approved in Brazil, which are directed to specific stages of the replicative cycle. However, due to the high mutation rate, resistance-associated substitutions (RAS) have been described in the resistant variants. The present work aimed to analyze the genetic variability of HCV NS5B palm domain in chronically infected individuals. For this purpose, viral variants from serum samples from 53 chronically infected patients with genotypes 1a, 1b or 3a, residents of the northwestern region of São Paulo, submitted or not to interferon and ribavirin (INF + RBV) or DAAs based therapeutic protocols were analyzed. The sequences comprising the NS5B palm domain region of the viruses from each sample were aligned, edited and analyzed for the presence of RAS previously described for this NS5B region. Additionally, the sequences were used for phylogenetic reconstruction. Among the results, 67% of patients who had previously used INF + RBV did not respond to initial treatment and underwent AED retreatment, and of these 83.3% did not respond to treatment and 16.7% relapsed. Sequence analysis showed that RAS C316N / Y and Q309R were detected in the samples of 3 patients of genotype 1b, and the RAS C316Y was identified in the sample of one HCV 1a patient, but these patients responded to treatment with AADs. Phylogenetic analyzes showed that the 3 HCV 1b patients who presented the RAS were grouped in the same monophyletic branch, showing high similarity between the viral variants of these patients. Thus, it can be concluded that previous treatment with interferon and ribavirin may be a contributing factor to non-response to a second therapeutic protocol with AADs. In addition, the combination of RAS C316N and Q309R does not necessarily imply resistance to antiviral treatment, but the study of circulating viral variants in the region is important for determining the route of transmission.