Published online Oct 28, 2016. doi: 10.3748/wjg.v22.i40.8910
Peer-review started: June 21, 2016
First decision: August 8, 2016
Revised: September 12, 2016
Accepted: September 28, 2016
Article in press: September 28, 2016
Published online: October 28, 2016
To evaluate the occurrence of resistant mutations in treatment-naïve hepatitis C virus (HCV) sequences deposited in the European hepatitis C virus database (euHCVdb).
The sequences were downloaded from the euHCVdb (https://euhcvdb.ibcp.fr/euHCVdb/). The search was performed for full-length NS3 protease, NS5A and NS5B polymerase sequences of HCV, separated by genotypes 1a, 1b, 2a, 2b and 3a, and resulted in 798 NS3, 708 NS5A and 535 NS5B sequences from HCV genotypes 1a, 1b, 2a, 2b and 3a, after the exclusion of sequences containing errors and/or gaps or incomplete sequences, and sequences from patients previously treated with direct antiviral agents (DAA). The sequence alignment was performed with MEGA 6.06 MAC and the resulting protein sequences were then analyzed using the BioEdit 7.2.5. for mutations associated with resistance. Only positions that have been described as being associated with failure in treatment in in vivo studies, and/or as conferring a more than 2-fold change in replication in comparison to the wildtype reference strain in in vitro phenotypic assays were included in the analysis.
The Q80K variant in the NS3 gene was the most prevalent mutation, being found in 44.66% of subtype 1a and 0.25% of subtype 1b. Other frequent mutations observed in more than 2% of the NS3 sequences were: I170V (3.21%) in genotype 1a, and Y56F (15.93%), V132I (23.28%) and I170V (65.20%) in genotype 1b. For the NS5A, 2.21% of the genotype 1a sequences have the P58S mutation, 5.95% of genotype 1b sequences have the R30Q mutation, 15.79% of subtypes 2a sequences have the Q30R mutation, 23.08% of subtype 2b sequences have a L31M mutation, and in subtype 3a sequences, 23.08% have the M31L resistant variants. For the NS5B, the V321L RAV was identified in 0.60% of genotype 1a and in 0.32% of genotype 1b sequences, and the N142T variant was observed in 0.32% of subtype 1b sequences. The C316Y, S556G, D559N RAV were identified in 0.33%, 7.82% and 0.32% of genotype 1b sequences, respectively, and were not observed in other genotypes.
HCV mutants resistant to DAAs are found in low frequency, nevertheless they could be selected and therapy could fail due resistance substitutions in HCV genome.
Core tip: Chronic hepatitis C virus (HCV) infection is a significant cause of morbidity and mortality. The main therapeutic targets are the NS3/4A protease, NS5B polymerase, and NS5A replication complex. Pre-existence of resistance associated variants to direct antiviral agents (DAA) reduces sustained virologic response rates. Despite the low frequency of mutations, this resistant population is likely to be selected in patients undergoing therapy with DAA. Even though HCV variants resistant to DAA targeting one viral protein remain susceptible to DAA targeting another viral protein, combination therapy could fail due to selection of HCV with resistance substitutions in multiple targets.