Variability and resistance mutations in the hepatitis C virus NS3 protease in patients not treated with protease inhibitors

Abstract

The goal of treatment of chronic hepatitis C is to achieve a sustained virological response, which is defined as exhibiting undetectable hepatitis C virus (HCV) RNA levels in serum following therapy for at least six months. However, the current treatment is only effective in 50% of patients infected with HCV genotype 1, the most prevalent genotype in Brazil. Inhibitors of the serine protease non-structural protein 3 (NS3) have therefore been developed to improve the responses of HCV-infected patients. However, the emergence of drug-resistant variants has been the major obstacle to therapeutic success. The goal of this study was to evaluate the presence of resistance mutations and genetic polymorphisms in the NS3 genomic region of HCV from 37 patients infected with HCV genotype 1 had not been treated with protease inhibitors. Plasma viral RNA was used to amplify and sequence the HCV NS3 gene. The results indicate that the catalytic triad is conserved. A large number of substitutions were observed in codons 153, 40 and 91; the resistant variants T54A, T54S, V55A, R155K and A156T were also detected. This study shows that resistance mutations and genetic polymorphisms are present in the NS3 region of HCV in patients who have not been treated with protease inhibitors, data that are important in determining the efficiency of this new class of drugs in Brazil.

Pre-Existing HCV Variants Resistant to DAAs and Their Sensitivity to PegIFN/RBV in Chinese HCV Genotype 1b Patients

“…The prevalence of HCV NS3/4A PIs resistance mutations was 8.00%, which was similar to the prevalence of 10.7% reported in an Italian study [24]. Zeminian et al reported that 18.9% of substitutions were involved in the resistance to PIs in Brazilian patients, which was higher than in the present study [25]. R117H and S174F, which were possibly resistant to first-generation PIs, made up the majority of the detected resistance mutations in this study.…”

Baseline Hepatitis C Virus (HCV) NS3 Polymorphisms and Their Impact on Treatment Response in Clinical Studies of the HCV NS3 Protease Inhibitor Faldaprevir

“…Several groups have reported the detection of HCV variants with natural NS3/4A polymorphisms that are associated with protease inhibitor resistance in PR treatment-naive and/or protease inhibitor-naive patients, in particular polymorphisms at NS3 codon 80 (12)(13)(14)(15)(16)(17)(18)(19)(20). It is not clear how these baseline polymorphisms impact response to treatment.…”

Characterization of clinical predictors of naturally occurring NS3/NS4A protease polymorphism in genotype 1 hepatitis C virus mono and HIV co‐infected patients

“…In addition, the absence in our data of Q80 K mutation that confers reduced susceptibly to some second wave PIs in genotype 1a samples is in line with other Brazilian studies, suggesting low prevalence of this substitution in this country. 5,6 It correlates with the highest proportion of genotype 1a subclade IC circulating in Brazil, once variability at position 80 is frequently associated with genotype subclade IA (North-American clade) and uncommon in subclades IB and IC. 16 Increased bilirubin level and hypoalbuminemia were independently associated with NS3 amino acid substitution in our study.…”

“…Some HCV strains may emerge in a dominant profile under selective drug pressure . Brazilian cross‐sectional studies have reported prevalence of 4.1‐18.9% of HCV infected patients harboring virus with NS3 resistance mutations in baseline …”

“…4 Brazilian cross-sectional studies have reported prevalence of 4.1-18.9% of HCV infected patients harboring virus with NS3 resistance mutations in baseline. 5,6 It is known that spontaneously occurring resistance may impair the rate of success of macrocyclic NS3/NS4A protease inhibitors (PIs), such as simeprevir/peginterferon/ribavirin and simeprevir/ sofosbuvir based regimens, especially in HCV genotype 1a infected cirrhotic patients. 3 Other factors may also contribute to the emergency of amino acid substitutions in HCV genome, including therapy with some particular DAA combinations, and length of infection.…”