Special Issue "Viral Resistance in HCV Infection"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: 31 October 2021.

Special Issue Editors

Dr. Francesca Ceccherini-Silberstein
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Guest Editor
Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
Interests: clinical virology; HIV infection; antiviral drugs and strategies; HIV-HBV-HCV drug-resistance; viral pathogenesis; viral tropism; viral evolution and dynamics; genotypic (by Sanger and NGS sequencing); structural and functional analysis of viral proteins
Dr. Federico Garcia
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Guest Editor
Microbiology Department, University Hospital San Cecilio, Granada, Spain
Interests: clinical virology; molecular epidemiology and resistance of HIV and hepatitis; sexually transmitted infections; Mycoplasma genitalium epidemiologya, pathogenesis and resistance to antibiotics; microbiome and metagenome analysis; infectious and non infectious diseases

Special Issue Information

Dear Colleagues,

The introduction of new multi-genotypic direct-acting antivirals (DAA) in clinical practice has revolutionized HCV treatment, permitting the achievement of >95% rates of sustained virological response in many patients. However, virological failures can occur particularly if the treatments are sub-optimal and/or with too short a duration. Failure is often associated with the development of resistance. The wide genetic variability in terms of different genotypes and subtypes, together with the natural presence and/or easy development of resistance during treatment, are intrinsic characteristics of HCV that may affect the treatment outcome and the chances of achieving a virological cure.

This issue will explore, in detail, aspects of HCV variability and resistance to new interferon-free DAA regimens.

Dr. Francesca Ceccherini-Silberstein
Dr. Federico Garcia
Guest Editors

Manuscript Submission Information

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Keywords

  • hepatitis C virus
  • resistance associated substitutions
  • direct acting antivirals
  • treatment
  • natural resistance
  • genotype
  • unusual subtypes
  • failure
  • rescue therapy
  • reinfection
  • coinfection
  • compartmentalization
  • epidemiology

Published Papers (5 papers)

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Editorial

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Editorial
SHARED: An International Collaboration to Unravel Hepatitis C Resistance
Viruses 2021, 13(8), 1580; https://doi.org/10.3390/v13081580 - 10 Aug 2021
Viewed by 525
Abstract
The advent of direct-acting antivirals (DAAs) has transformed the treatment landscape of hepatitis C [...] Full article
(This article belongs to the Special Issue Viral Resistance in HCV Infection)
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Research

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Article
Validation of a Genotype-Independent Hepatitis C Virus Near-Whole Genome Sequencing Assay
Viruses 2021, 13(9), 1721; https://doi.org/10.3390/v13091721 (registering DOI) - 30 Aug 2021
Viewed by 154
Abstract
Despite the effectiveness of direct-acting antiviral agents in treating hepatitis C virus (HCV), cases of treatment failure have been associated with the emergence of resistance-associated substitutions. To better guide clinical decision-making, we developed and validated a near-whole-genome HCV genotype-independent next-generation sequencing strategy. HCV [...] Read more.
Despite the effectiveness of direct-acting antiviral agents in treating hepatitis C virus (HCV), cases of treatment failure have been associated with the emergence of resistance-associated substitutions. To better guide clinical decision-making, we developed and validated a near-whole-genome HCV genotype-independent next-generation sequencing strategy. HCV genotype 1–6 samples from direct-acting antiviral agent treatment-naïve and -treated HCV-infected individuals were included. Viral RNA was extracted using a NucliSens easyMAG and amplified using nested reverse transcription-polymerase chain reaction. Libraries were prepared using Nextera XT and sequenced on the Illumina MiSeq sequencing platform. Data were processed by an in-house pipeline (MiCall). Nucleotide consensus sequences were aligned to reference strain sequences for resistance-associated substitution identification and compared to NS3, NS5a, and NS5b sequence data obtained from a validated in-house assay optimized for HCV genotype 1. Sequencing success rates (defined as achieving >100-fold read coverage) approaching 90% were observed for most genotypes in samples with a viral load >5 log10 IU/mL. This genotype-independent sequencing method resulted in >99.8% nucleotide concordance with the genotype 1-optimized method, and 100% agreement in genotype assignment with paired line probe assay-based genotypes. The assay demonstrated high intra-run repeatability and inter-run reproducibility at detecting substitutions above 2% prevalence. This study highlights the performance of a freely available laboratory and bioinformatic approach for reliable HCV genotyping and resistance-associated substitution detection regardless of genotype. Full article
(This article belongs to the Special Issue Viral Resistance in HCV Infection)
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Article
Compartmentalization of Resistance-Associated Substitutions in HIV/HCV-Infected Patients: Possible Correlation with Infecting HCV Genotype
Viruses 2021, 13(8), 1486; https://doi.org/10.3390/v13081486 - 29 Jul 2021
Viewed by 387
Abstract
Resistance-associated substitutions (RASs) may exist prior to treatment and contribute to the failure of treatment with direct-acting antivirals (DAAs). As the major site of HCV replication, naturally occurring variants with RASs may segregate into the liver. In the present study, we performed viral [...] Read more.
Resistance-associated substitutions (RASs) may exist prior to treatment and contribute to the failure of treatment with direct-acting antivirals (DAAs). As the major site of HCV replication, naturally occurring variants with RASs may segregate into the liver. In the present study, we performed viral population sequencing to retrospectively investigate the NS3 and NS5A RAS profiles in 34 HIV/HCV coinfected patients naïve to anti-HCV treatment who underwent diagnostic liver biopsy between 2000 and 2006 and had liver and plasma samples available. Sixteen were infected by HCV genotype (GT) 1a, 11 by GT3a, and 7 by GT4d. The analysis of the NS3 domain in GT1a showed a difference in strain between the liver and plasma in three cases, with a preponderance of specific RASs in the liver compartment. In GT4d samples, 6/7 coupled liver and plasma samples were concordant with no RASs. Sequence analysis of the NS5A domain showed the presence of RASs in the livers of 2/16 patients harboring GT1a but not in the corresponding plasma. In GT4d, NS5A RASs were detected in 7/7 liver tissues and 5/7 plasma samples. NS3 domain and NS5A domain were found to be conserved in plasma and livers of patients infected with GT3a. Thus, RASs within GT1a and GT4d more likely segregate into the liver and may explain the emergence of resistant strains during DAA treatment. Full article
(This article belongs to the Special Issue Viral Resistance in HCV Infection)
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Article
Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b
Viruses 2021, 13(5), 743; https://doi.org/10.3390/v13050743 - 23 Apr 2021
Viewed by 461
Abstract
HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain-1 interacts with cellular proteins inducing pro-oncogenic pathways. Thus, we explore genetic variations in NS5A domain-1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype-1b infected DAA-naïve cirrhotic [...] Read more.
HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain-1 interacts with cellular proteins inducing pro-oncogenic pathways. Thus, we explore genetic variations in NS5A domain-1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype-1b infected DAA-naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p < 0.001), M133I (20.6% vs. 3.9%, p < 0.001), and Q181E (11.8% vs. 0.6%, p < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3); p < 0.001). Focusing on HCC-group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4–6.2) log IU/mL vs. 5.3 (4.4–5.6) log IU/mL, p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell-cycle regulation (p53, p85-PIK3, and β-catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV-mediated oncogenesis. The role of theseNS5A domain-1 mutations in triggering pro-oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation. Full article
(This article belongs to the Special Issue Viral Resistance in HCV Infection)
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Review

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Review
Virological Factors Associated with Failure to the Latest Generation of Direct Acting Agents (DAA) and Re-Treatment Strategy: A Narrative Review
Viruses 2021, 13(3), 432; https://doi.org/10.3390/v13030432 - 08 Mar 2021
Cited by 1 | Viewed by 478
Abstract
The availability of all oral direct acting antiviral agents (DAAs) has revolutionized the management of HCV infections in recent years, allowing to achieve a sustained virological response (SVR) in more than 95% of cases, irrespective of hepatitis C Virus (HCV) genotype or staging [...] Read more.
The availability of all oral direct acting antiviral agents (DAAs) has revolutionized the management of HCV infections in recent years, allowing to achieve a sustained virological response (SVR) in more than 95% of cases, irrespective of hepatitis C Virus (HCV) genotype or staging of liver disease. Although rare, the failure to the latest-generation regimens (grazoprevir/elbasvir, sofosbuvir/velpatasvir, pibrentasvir/glecaprevir) represents a serious clinical problem, since the data available in the literature on the virological characteristics and management of these patients are few. The aim of the present narrative review was to provide an overview of the impact of baseline RASs in patients treated with the latest-generation DAAs and to analyze the efficacy of the available retreatment strategies in those who have failed these regimens. Full article
(This article belongs to the Special Issue Viral Resistance in HCV Infection)
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