Naturally occurring resistance mutations to inhibitors of HCV NS5A region and NS5B polymerase in DAA treatment-naïve patients

Paolucci, Stefania; Fiorina, L; Mariani, B; Gulminetti, Roberto; Novati, Stefano; Barbarini, Giorgio; Bruno, Raffaele; Baldanti, Fausto

doi:10.1186/1743-422x-10-355

Cited by 86 publications

(118 citation statements)

References 36 publications

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“…A requirement for unequivocal subtype 1 calling before treatment might also be endorsed for some interferon-free regimens which are currently being investigated in clinical trials restricted to HCV-1b-designated subjects only (ClinicalTrials.gov identifiers NCT01732796, NCT01728324, NCT01581 203, and NCT01767116). Second, the striking differences between subtypes 1a and 1b in genetic barriers to resistance to most DAAs (4,12,35), and the presence of naturally occurring resistance mutations in other HCV-1 subtypes (11), strongly suggest that a similar phenomenon is likely to occur with other genotypes, especially for genotypes 2, 4, and 6 because of their high subtype diversity (11 subtypes for G2, 17 for G4, and 24 for G6). Unfortunately, subtype-specific resistance data for other genotypes remain scarce (36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

High-Resolution Hepatitis C Virus Subtyping Using NS5B Deep Sequencing and Phylogeny, an Alternative to Current Methods

et al. 2015

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There are seven confirmed hepatitis C virus (HCV) genotypes, with whole-genome nucleotide sequences differing by Ͼ30%, and each can be further subdivided into related subtypes (67 confirmed), with nucleotide sequence divergence of between 15% and 30% (1).Genotype identification has long been used in clinical practice, because major genotypes have different response rates and require different doses and durations of pegylated interferon and ribavirin (PR) treatment. In contrast, until recently, subtype identification was mainly used in epidemiological studies. However, both in vitro studies and clinical trials with different classes of direct-acting antiviral (DAA) agents (NS3 protease, NS5A-, and nucleos[t]ide and nonnucleos[t]ide NS5B-polymerase inhibitors), given with PR or in interferon-free combinations, have shown lower response rates for HCV genotype 1a than for HCV genotype 1b (2-8). Moreover, at least for HCV genotype 1, both the frequency and the pattern of resistance to different DAA classes are subtype specific (9). A striking example is the NS3-Q80K polymorphism, naturally found in Ͼ30% of naive subtype 1a patients but in Ͻ1% of subtype 1b patients (10), which conveys 30%-to-40%-lower sustained-virologic-response (SVR) rates to the macrocyclic protease inhibitor simeprevir (2). Similarly, all subtype 1g sequences identified naturally carry a mutation conferring resistance to linear NS3 protease inhibitors (11).Subtype-specific differences in the genetic barrier to resistance appear to correlate to the RNA-dependent RNA polymerase mu-

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Section: Discussionmentioning

confidence: 99%

High-Resolution Hepatitis C Virus Subtyping Using NS5B Deep Sequencing and Phylogeny, an Alternative to Current Methods

et al. 2015

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“…When only RAVs relevant for the ongoing regimen were considered, their frequency was similar to that previously described [22,27,30].…”

Section: Discussionmentioning

confidence: 93%

Evolution of Resistance-Associated Variants of All-Oral Direct-Acting Antiviral Therapy of Hepatitis C in a Clinical Setting

Lai¹,

Milazzo²,

Bergna³

et al. 2017

J Antivir Antiretrovir

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Because of the high variability of Hepatitis C virus (HCV), it might be important to characterize in vivo the evolution of resistance-associated mutations (RAVs) to direct-acting antivirals (DAAs) in different genotypes.NS3-, NS5A-and NS5B-HCV substitutions were studied by next generation sequencing (NGS) on 74 HCVinfected patients who started a DAA regimen. RAVs with frequencies of 1% and 15% were analyzed.Globally, 43, 15, 12 and 4 patients were infected with subtype 1a, 1b, genotype 4 and subtype 3a, respectively. The majority of patients (64.8%) had cirrhosis, 70.3% were HIV-coinfected and 14.9% were DAA-experienced. Overall baseline prevalence of RAVs was 74.3%, 52.2%, 45.9% and 36.8% to any NS3, NS5B and NS5A inhibitors available at that time, respectively, and dropped to 39.2%, 26.1%, 22.8% and 16.2%, respectively, when only mutations associated with the ongoing regimen were considered. The highest proportion of mutations was detected in subtype 1a (81.4%, p=.026), particularly in NS3 region (76.9%, p<.001). Among the 7 failing patients, 57.1% had a baseline sequence showing substitutions as majority species. At the time of viral relapse two patients accumulated further RAVs that were missing even as minority variants at baseline.Although almost half of the patients showed natural substitutions at baseline, these substitutions did not induce resistance to DAAs. A limited role of NGS with a low cut-off was suggested by our study, as the detection of minor species seems not to predict the selection for resistant variants at the time of failure. The impact of pre-treatment RAVs on the achievement of sustained virologic response with DAA is limited.

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“…S3). Analysis of the NS5B RNA-dependent RNA polymerase amino acid sequence at 30 positions critical for interaction with or resistance to HCV polymerase inhibitors [11,12,13,14] showed presence of amino acid substitution C451T in all HCV-2l sequences, as in all HCV genotype 4, 6 and 7 sequences and most of the genotype 3 HCV, whereas subtypes 2 non-l HCV harbored the C451V substitution. The M414L substitution that confers resistance to HCV nonnucleoside inhibitors [15,16], already described in most of the genotype 4 HCV [17], was found in all HCV-2l sequences, whereas HCV of subtypes 2 non-l harbor amino acid substitution M414Q that was also associated with drug resistance in replicon assays [18].…”

Section: Resultsmentioning

confidence: 99%

Hepatitis C Virus of Subtype 2l in Marseille, Southeastern France

et al. 2015

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The rate of eradication of chronic hepatitis C considerably increases with direct-acting antiviral agents, particularly hepatitis C virus (HCV) polymerase inhibitors. While implementing full-length HCV NS5B polymerase sequencing in our clinical microbiology laboratory, we identified atypical HCV sequences, classified as subtype 2l, from 2 patients. HCV-2l NS5B polymerase sequences were detected from 5 and 14 additional patients by screening our laboratory hepatitis virus sequence database and the NCBI GenBank sequence database. Phylogenetic analyses show unambiguously that all HCV-2l sequences are clustered apart from HCV 2 non-l sequences, which compose a second cluster. Mean (±SD) nucleotide identity between near full-length NS5B fragments of subtype 2l was 93.4 ± 0.8% (range: 92.4-95.1). Of note, all HCV-2l sequences obtained in our laboratory and in other centers were from serum samples collected in France. Analysis of the HCV-2l NS5B polymerase amino acid sequences at 30 positions critical for interaction with or resistance to HCV polymerase inhibitors showed specific patterns.

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Naturally occurring resistance mutations to inhibitors of HCV NS5A region and NS5B polymerase in DAA treatment-naïve patients

Cited by 86 publications

References 36 publications

High-Resolution Hepatitis C Virus Subtyping Using NS5B Deep Sequencing and Phylogeny, an Alternative to Current Methods

High-Resolution Hepatitis C Virus Subtyping Using NS5B Deep Sequencing and Phylogeny, an Alternative to Current Methods

Evolution of Resistance-Associated Variants of All-Oral Direct-Acting Antiviral Therapy of Hepatitis C in a Clinical Setting

Hepatitis C Virus of Subtype 2l in Marseille, Southeastern France

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