Naturally occurring mutations associated with resistance to HCV NS5B polymerase and NS3 protease inhibitors in treatment-naïve patients with chronic hepatitis C

Abstract

BackgroundThe detection of baseline resistance mutations to new direct-acting antivirals (DAAs) in HCV chronically infected treatment-naïve patients could be important for their management and outcome prevision. In this study, we investigated the presence of mutations, which have been previously reported to be associated with resistance to DAAs in HCV polymerase (NS5B) and HCV protease (NS3) regions, in sera of treatment-naïve patients.FindingsHCV RNA from 152 naïve patients (84 % Italian and 16 % immigrants from various countries) infected with different HCV genotypes (21,1a; 21, 1b; 2, 2a; 60, 2c; 22, 3a; 25, 4d and 1, 4k) was evaluated for sequence analysis. Amplification and sequencing of fragments in the NS5B (nt 8256–8640) and NS3 (nt 3420–3960) regions of HCV genome were carried out for 152 and 28 patients, respectively. The polymorphism C316N/H in NS5B region, associated with resistance to sofosbuvir, was detected in 9 of the 21 (43 %) analysed sequences from genotype 1b-infected patients. Naturally occurring mutations V36L, and M175L in the NS3 protease region were observed in 100 % of patients infected with subtype 2c and 4.ConclusionA relevant proportion of treatment naïve genotype 1b infected patients evaluated in this study harboured N316 polymorphism and might poorly respond to sofosbuvir treatment. As sofosbuvir has been approved for treatment of HCV chronic infection in USA and Europe including Italy, pre-treatment testing for N316 polymorphism on genotype 1b naïve patients should be considered for this drug.

Resistance mutations of NS3 and NS5b in treatment-naïve patients infected with hepatitis C virus in Santa Catarina and Rio Grande do Sul states, Brazil

“…At last, several polymorphisms not associated with resistance to DAAs were observed in our study (Table 1), and previously reported by others (Constantino et al, 2015). Polymorphisms, prior to therapy, are part of the quasispecies population in infected individuals, and may not alter viral fitness (Peres-da-Silva et al, 2012;Paolucci et al, 2013;Nishiya et al, 2014).…”

“…The L320F mutation was present in only one sample (1.59%) of genotype 1a. L320F is known to confer low resistance to sofosbuvir and sofosbuvir associated with mericitabine (Paolucci et al, 2013), which are associated to treatment failure in clinical trials (Constantino et al, 2015). In a previous study, L320F single mutation had no significant impact on the 50% effective concentration (EC50) and EC90 values for mericitabine (£2.7 fold) (Tong et al, 2014).…”

Internal Disequilibria and Phenotypic Diversification during Replication of Hepatitis C Virus in a Noncoevolving Cellular Environment

“…Despite average sustained response rates approaching 98% with new treatments based on direct-acting antiviral (DAA) combinations, several limitations for the prevention and control of HCV-associated diseases remain, even for human populations with access to treatment. There is an increasing frequency of circulating inhibitor-resistant mutants, a fraction of patients do not respond to the new treatments, DAAs may evoke hepatocarcinoma recurrence, and no preventive or therapeutic vaccines are available (21)(22)(23)(24)(25)(26)(27)(28). Studies on HCV dynamics in infected patients are relevant to establish relationships between population complexity and clinical parameters (reviewed in references 3 and 18).…”

Pipeline for specific subtype amplification and drug resistance detection in hepatitis C virus

“…Our approach should also broaden its application given the increasing evidence of the presence of RAS in treatment-naïve patients [15–17]. Finally, an analogous pipeline of sequence-based oligonucleotide design and deep-sequencing scrutiny of prominent mutations can be applied to emergent viral diseases associated with highly variable RNA viruses.…”