Association of hepatitis C virus NS5B variants with resistance to new antiviral drugs among untreated patients

Castilho, Magda Cristina Bernardino; Martins, Angélica N.; Horbach, Ingrid Siciliano; Perez, Renata de Mello; Figueiredo, Fábio P.; Pinto, Paulo de Tarso Aparecida; Nabuco, Leticia Cancela; Lima, Dirce Bonfim de; Tanuri, Amílcar; Pôrto, Luís Cristóvão; Júnior, Orlando da Costa Ferreira

doi:10.1590/s0074-02762011000800011

Cited by 17 publications

(16 citation statements)

References 45 publications

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“…Instead, A333E was frequent in G2 and rare in G3, while it could not be analyzed in G1. These results are in agreement with the frequency found in other countries [40]. The presence of these amino acid substitutions might be related to the relative susceptibility to IFN/RBV of G2 and G3 compared to G1.…”

Section: Discussionsupporting

confidence: 92%

Prevalence of amino acid mutations in hepatitis C virus core and NS5B regions among Venezuelan viral isolates and comparison with worldwide isolates

Jaspe

Sulbarán

et al. 2012

Virol J

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BackgroundRecent reports show that R70Q and L/C91M amino acid substitutions in the core from different hepatitis C virus (HCV) genotypes have been associated with variable responses to interferon (IFN) and ribavirin (RBV) therapy, as well to an increase of hepatocellular carcinoma (HCC) risk, liver steatosis and insulin resistance (IR). Mutations in NS5B have also been associated to IFN, RBV, nucleoside and non-nucleoside inhibitors drug resistance. The prevalence of these mutations was studied in HCV RNA samples from chronically HCV-infected drug-naïve patients.MethodsAfter amplification of core and NS5B region by nested-PCR, 12 substitutions were analyzed in 266 Venezuelan HCV isolates subtype 1a, 1b, 2a, 2c, 2b, 2j (a subtype frequently found in Venezuela) and 3a (n = 127 and n = 228 for core and NS5B respectively), and compared to isolates from other countries (n = 355 and n = 646 for core and NS5B respectively).ResultsR70Q and L/C91M core substitutions were present exclusively in HCV G1b. Both substitutions were more frequent in American isolates compared to Asian ones (69% versus 26%, p < 0.001 and 75% versus 45%, p < 0.001 respectively). In Venezuelan isolates NS5B D310N substitution was detected mainly in G3a (100%) and G1a (13%), this later with a significantly higher prevalence than in Brazilian isolates (p = 0.03). The NS5B mutations related to IFN/RBV treatment D244N was mainly found in G3a, and Q309R was present in all genotypes, except G2. Resistance to new NS5B inhibitors (C316N) was only detected in 18% of G1b, with a significantly lower prevalence than in Asian isolates, where this polymorphism was surprisingly frequent (p < 0.001).ConclusionsGenotypical, geographical and regional differences were found in the prevalence of substitutions in HCV core and NS5B proteins. The substitutions found in the Venezuelan G2j type were similar to that found in G2a and G2c isolates. Our results suggest a high prevalence of the R70Q and L/C91M mutations of core protein for G1b and D310N substitution of NS5B protein for the G3a. C316N polymorphism related with resistance to new NS5B inhibitors was only found in G1b. Some of these mutations could be associated with a worse prognosis of the disease in HCV infected patients.

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Section: Discussionsupporting

confidence: 92%

Prevalence of amino acid mutations in hepatitis C virus core and NS5B regions among Venezuelan viral isolates and comparison with worldwide isolates

Jaspe

Sulbarán

et al. 2012

Virol J

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“…The D244N, S326G, T329I, and D310N mutations were encountered as a minority variant in 10–12 patients (~60%). The Q309R mutation was encountered most frequently (in all patients) and even as a major haplotype in 4 patients, which is similar to previous observations 24 . However, when we analysed the presence of drug resistance populations in both compartments we noticed that the prevalence of the resistant variants was only somewhat higher in the liver as compared to plasma.…”

Section: Discussionsupporting

confidence: 91%

“…As non-nucleoside inhibitors bind more distantly to the active site of NS5B, resistance-associated variants often occur more frequently with these compounds 40 . Mutations that confer resistance to non-nucleoside inhibitors at position 316 in NS5B in vivo have been described in treatment-naïve patients at frequencies of 0.19–24% by Sanger sequencing analyses 24, 41–43 . We noticed this mutation in 16 out of 18 patients (~89%) either as dominant (50%) or minority haplotypes (39%).…”

Section: Discussionmentioning

confidence: 99%

Identification of HCV Resistant Variants against Direct Acting Antivirals in Plasma and Liver of Treatment Naïve Patients

Raj

Hundie

Schürch

et al. 2017

Sci Rep

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Current standard-of-care treatment of chronically infected hepatitis C virus (HCV) patients involves direct-acting antivirals (DAA). However, concerns exist regarding the emergence of drug -resistant variants and subsequent treatment failure. In this study, we investigate potential natural drug-resistance mutations in the NS5B gene of HCV genotype 1b from treatment-naïve patients. Population-based sequencing and 454 deep sequencing of NS5B gene were performed on plasma and liver samples obtained from 18 treatment- naïve patients. The quasispecies distribution in plasma and liver samples showed a remarkable overlap in each patient. Although unique sequences in plasma or liver were observed, in the majority of cases the most dominant sequences were shown to be identical in both compartments. Neither in plasma nor in the liver codon changes were detected at position 282 that cause resistance to nucleos(t)ide analogues. However, in 10 patients the V321I change conferring resistance to nucleos(t)ide NS5B polymerase inhibitors and in 16 patients the C316N/Y/H non-nucleoside inhibitors were found mainly in liver samples. In conclusion, 454-deep sequencing of liver and plasma compartments in treatment naïve patients provides insight into viral quasispecies and the pre-existence of some drug-resistant variants in the liver, which are not necessarily present in plasma.

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“…). Mutations in the NS5B region at amino acid positions 244, 282, 309, 310, 316, and 320 were previously associated with drug‐resistant HCV strains [Migliaccio et al, ; Howe et al, ; Castilho et al, ; Jaspe et al, ; Ali et al, ; Tong et al, ]. In our study, amino acid variations at positions 244, 309, and 310 were found in subtypes 6f, 6c, 6n, and 6i (Table and Fig.…”

Section: Resultssupporting

confidence: 74%

“…Thus, interferon-alpha (INF-a), ribavirin, and new antiviral agents such as HCV NS3/4A serine protease inhibitors, nucleoside inhibitors, and non-nucleoside inhibitors have been successful antiviral treatments [Ferenci and Reddy, 2011;Sofia et al, 2012;Varshney et al, 2012]. Because the NS5B region shows high genetic diversity among HCV genotypes, several amino acid mutations (such as D244N, S282T, Q309R, D310N, C316N, and L159F/L320F) in this region are associated with HCV resistance [Migliaccio et al, 2003;Howe et al, 2008;Castilho et al, 2011;Jaspe et al, 2012;Ali et al, 2014;Tong et al, 2014]. Thus, this region also has particular clinical significance.…”

Section: Introductionmentioning

confidence: 99%

Characterization of partial NS5B region among hepatitis C virus genotype 6 subtypes isolated from Thai blood donors

Chaiwong

Sistayanarain

2016

Journal of Medical Virology

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The hepatitis C virus (HCV) is an important cause of liver dysfunction which continues to spread in Thailand, particularly as genotype 6. The NS5B gene fragment is particularly variable and thus provides a valuable tracker for its spread. Therefore, the purpose of this study was to characterize the HCV genotype 6 based on partial NS5B region using Thai blood donor samples. Twenty-nine samples were genotyped as HCV 6 by nested PCR, nucleotide sequencing and amino acid sequence analysis. Amplified products were identified as HCV genotypes 6f, 6c, 6n, and 6i. There were amino acid variations of 4-18 residues in subtypes 6f, 6c, and 6n whereas subtype 6i was conserved when compared with their referent strains. In subtypes 6f, 6c, 6n, and 6i, the amino acid mutations at positions 244, 309, and 310 which are associated with HCV resistance were present. In summary, the sequences and phylogenetic analysis of NS5B of HCV used in our study yielded the genotypes 6f, 6c, 6n, and 6i. This finding indicates diversity of amino acids in NS5B of HCV. Characterizing the partial NS5B region among hepatitis C virus genotype 6 subtypes may predict efficacious anti-HCV therapy. J. Med. Virol. 88:1785-1790, 2016. © 2016 Wiley Periodicals, Inc.

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Association of hepatitis C virus NS5B variants with resistance to new antiviral drugs among untreated patients

Cited by 17 publications

References 45 publications

Prevalence of amino acid mutations in hepatitis C virus core and NS5B regions among Venezuelan viral isolates and comparison with worldwide isolates

Prevalence of amino acid mutations in hepatitis C virus core and NS5B regions among Venezuelan viral isolates and comparison with worldwide isolates

Identification of HCV Resistant Variants against Direct Acting Antivirals in Plasma and Liver of Treatment Naïve Patients

Characterization of partial NS5B region among hepatitis C virus genotype 6 subtypes isolated from Thai blood donors

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