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7.1
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Viruses
Special Issues
Viral Resistance in HCV Infection
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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: closed (31 October 2021) | Viewed by 23043

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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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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 (10 papers)

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Editorial

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11 pages, 625 KiB  
Editorial
SHARED: An International Collaboration to Unravel Hepatitis C Resistance
by Anita Y.M. Howe, Francesca Ceccherini-Silberstein, Julia Dietz, Stephanie Popping, Jason Grebely, Chaturaka Rodrigo, Johan Lennerstrand, Mark W. Douglas, Milosz Parczewsk, P. Richard Harrigan, Jean-Michel Pawlotsky, Federico Garcia and SHARED Collaborators
Viruses 2021, 13(8), 1580; https://doi.org/10.3390/v13081580 - 10 Aug 2021
Cited by 6 | Viewed by 3301
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

Jump to: Editorial, Review, Other

13 pages, 2512 KiB  
Article
The Effect of Treatment-Induced Viral Eradication on Cytokine and Growth Factor Expression in Chronic Hepatitis C
by Leona Radmanić, Kristian Bodulić, Petra Šimičić, Adriana Vince and Snježana Židovec Lepej
Viruses 2022, 14(8), 1613; https://doi.org/10.3390/v14081613 - 24 Jul 2022
Cited by 4 | Viewed by 1307
Abstract
In this study, we evaluated the effect of hepatitis C virus eradication using direct-acting antivirals (DAA) on the serum cytokine and growth factor profiles of chronic hepatitis C patients (CHC). Serum concentrations of 12 cytokines and 13 growth factors were measured in 56 [...] Read more.
In this study, we evaluated the effect of hepatitis C virus eradication using direct-acting antivirals (DAA) on the serum cytokine and growth factor profiles of chronic hepatitis C patients (CHC). Serum concentrations of 12 cytokines and 13 growth factors were measured in 56 patients with CHC before, during the DAA treatment and after sustained virological response using bead-based flow cytometry. Cytokine and growth factor levels were also measured in 15 healthy individuals. The majority of the selected cytokines and growth factors exhibited similar concentrations before, during and after successful DAA treatment, the exceptions being IL-10, EGF, HGF and VEGF. Significantly lower concentrations of IL-10, IL-13, IL-4, IL-4, IL-9, TNF- α and higher levels of Ang-2, HGF and SCF were observed in patients with CHC before and after DAA treatment compared with healthy individuals. Patients with severe fibrosis stages exhibited higher levels of Ang-2 and lower levels of EGF, PDGF-AA and VEGF. Furthermore, IL-4, IL-5 and SCF were characterized as potential biomarkers of DAA treatment using random forest. Additionally, logistic regression characterized EGF as a potential biomarker of severe CHC. Our results suggest inhibition of pro-inflammatory processes and promotion of liver regeneration in CHC patients during DAA treatment. Full article
(This article belongs to the Special Issue Viral Resistance in HCV Infection)
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15 pages, 1017 KiB  
Article
The European Prevalence of Resistance Associated Substitutions among Direct Acting Antiviral Failures
by Stephanie Popping, Valeria Cento, Carole Seguin-Devaux, Charles A. B. Boucher, Adolfo de Salazar, Eva Heger, Orna Mor, Murat Sayan, Dominique Salmon-Ceron, Nina Weis, Henrik B. Krarup, Robert J. de Knegt, Oana Săndulescu, Vladimir Chulanov, David A. M. C. van de Vijver, Federico García and Francesca Ceccherini-Silberstein
Viruses 2022, 14(1), 16; https://doi.org/10.3390/v14010016 - 22 Dec 2021
Cited by 3 | Viewed by 3069
Abstract
Background: Approximately 71 million people are still in need of direct-acting antiviral agents (DAAs). To achieve the World Health Organization Hepatitis C elimination goals, insight into the prevalence and influence of resistance associated substitutions (RAS) is of importance. Collaboration is key since DAA [...] Read more.
Background: Approximately 71 million people are still in need of direct-acting antiviral agents (DAAs). To achieve the World Health Organization Hepatitis C elimination goals, insight into the prevalence and influence of resistance associated substitutions (RAS) is of importance. Collaboration is key since DAA failure is rare and real-life data are scattered. We have established a European collaboration, HepCare, to perform in-depth analysis regarding RAS prevalence, patterns, and multiclass occurrence. Methods: Data were extracted from the HepCare cohort of patients who previously failed DAA therapy. Geno—and subtypes were provided by submitters and mostly based on in-house assays. They were reassessed using the Comet HCV subtyping tool. We considered RAS to be relevant if they were associated with DAA failure in vivo previously reported in literature. Results: We analyzed 938 patients who failed DAA therapy from ten different European countries. There were 239 genotypes (GT) 1a, 380 GT1b, 19 GT2c, 205 GT3a, 14 GT4a, and 68 GT4d infections. Several unusual subtypes (n = 15) (GT1b/g/l, GT3b, GT4k/n/r/t) were present. RAS appeared in over 80% of failures and over a quarter had three or more RAS. Multiclass RAS varied over target region and genotype between 0–48%. RAS patterns such as the Q30R + L31M and Q30R + Y93H in GT1a, the L31V + Y93H and L31V + Y93H for GT1b, and A30K + L31M and A30K/V + Y93H for GT3a all occurred with a prevalence below 5%. Conclusion: RAS occur frequently after DAA failures and follow a specific genotype and drug related pattern. Interpretation of the influence of RAS on retreatment is challenging due to various patterns, patients’ characteristics, and previous treatment history. Moving towards HCV elimination, an ongoing resistance surveillance is essential to track the presence of RAS, RAS patterns and gather data for a re-treatment algorithm. Full article
(This article belongs to the Special Issue Viral Resistance in HCV Infection)
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12 pages, 1411 KiB  
Article
Drug Resistance Profile and Clinical Features for Hepatitis C Patients Experiencing DAA Failure in Taiwan
by Chun-Ming Hong, You-Yu Lin, Chun-Jen Liu, Ya-Yun Lai, Shiou-Hwei Yeh, Hung-Chih Yang, Jia-Horng Kao, Shih-Jer Hsu, Yi-Hsiang Huang, Sheng-Shun Yang, Hsing-Tao Kuo, Pin-Nan Cheng, Ming-Lung Yu and Pei-Jer Chen
Viruses 2021, 13(11), 2294; https://doi.org/10.3390/v13112294 - 17 Nov 2021
Cited by 5 | Viewed by 2103
Abstract
About 4% of the population in Taiwan are seropositive for anti-HCV Ab and 70% with HCV RNA. To address this high chronic hepatitis C disease load, Taiwan National Health Insurance started reimbursing genotype-specific DAAs in 2017 and pangenotype DAAs in mid-2018. With a [...] Read more.
About 4% of the population in Taiwan are seropositive for anti-HCV Ab and 70% with HCV RNA. To address this high chronic hepatitis C disease load, Taiwan National Health Insurance started reimbursing genotype-specific DAAs in 2017 and pangenotype DAAs in mid-2018. With a 97% SVR12 rate, there were still 2–3% of patients that failed to clear HCV. To understand the causes of DAA failure in Taiwan, we conducted a multi-center, clinical, and virologic study. A total of 147 DAA-failure patients were recruited, and we searched HCV NS3/4A, NS5A and NS5B for known resistance-associated substitutions (RASs) by population sequencing, and conducted whole genome sequencing (WGS) for those without known RASs. A total of 107 patients received genotype-specific DAAs while 40 had pangenotype DAAs. Clinically, the important cause of failure is poor adherence. Virologically, common RASs in genotype-specific DAAs were NS5A-L31, NS5A-Y93, and NS5B-C316, while common RASs in pangenotype DAAs were NS5A-L31, NS5A-A/Q/R30, and NS5A-Y93. Additionally, new amino acid changes were found by WGS. Finally, we identified 12 cases with inconsistent baseline and post-treatment HCV genotypes, which is suggestive of re-infection rather than treatment failure. Our study described the drug resistance profile for DAA failure in Taiwan, showing differences from other countries. Full article
(This article belongs to the Special Issue Viral Resistance in HCV Infection)
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18 pages, 1992 KiB  
Article
Validation of a Genotype-Independent Hepatitis C Virus Near-Whole Genome Sequencing Assay
by Hope R. Lapointe, Weiyan Dong, Winnie W. Y. Dong, Don Kirkby, Conan Woods, Art F. Y. Poon, Anita Y. M. Howe, P. Richard Harrigan and Chanson J. Brumme
Viruses 2021, 13(9), 1721; https://doi.org/10.3390/v13091721 - 30 Aug 2021
Cited by 1 | Viewed by 2840
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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12 pages, 1123 KiB  
Article
Compartmentalization of Resistance-Associated Substitutions in HIV/HCV-Infected Patients: Possible Correlation with Infecting HCV Genotype
by Giulia Morsica, Riccardo Vercesi, Hamid Hasson, Emanuela Messina, Caterina Uberti-Foppa and Sabrina Bagaglio
Viruses 2021, 13(8), 1486; https://doi.org/10.3390/v13081486 - 29 Jul 2021
Viewed by 1290
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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12 pages, 775 KiB  
Article
Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b
by Mohammad Alkhatib, Velia Chiara Di Maio, Valentina De Murtas, Ennio Polilli, Martina Milana, Elisabetta Teti, Gianluca Fiorentino, Vincenza Calvaruso, Silvia Barbaliscia, Ada Bertoli, Rossana Scutari, Luca Carioti, Valeria Cento, Maria Mercedes Santoro, Alessandro Orro, Ivana Maida, Ilaria Lenci, Loredana Sarmati, Antonio Craxì, Caterina Pasquazzi, Giustino Parruti, Sergio Babudieri, Luciano Milanesi, Massimo Andreoni, Mario Angelico, Carlo Federico Perno, Francesca Ceccherini-Silberstein, Valentina Svicher, Romina Salpini and on behalf of HIRMA (Hepatocarcinoma Innovative Research MArkers) and Fondazione Vironet C (HCV Virology Italian Resistanceadd Show full author list remove Hide full author list
Viruses 2021, 13(5), 743; https://doi.org/10.3390/v13050743 - 23 Apr 2021
Cited by 1 | Viewed by 1822
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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16 pages, 2509 KiB  
Review
The Role of RASs /RVs in the Current Management of HCV
by Konstantinos Malandris, Georgios Kalopitas, Eleni Theocharidou and Georgios Germanidis
Viruses 2021, 13(10), 2096; https://doi.org/10.3390/v13102096 - 18 Oct 2021
Cited by 16 | Viewed by 2077
Abstract
The approval of combination therapies with direct-acting antiviral (DAA) regimens has led to significant progress in the field of hepatitis C virus (HCV) treatment. Although most patients treated with these agents achieve a virological cure, resistance to DAAs is a major issue. The [...] Read more.
The approval of combination therapies with direct-acting antiviral (DAA) regimens has led to significant progress in the field of hepatitis C virus (HCV) treatment. Although most patients treated with these agents achieve a virological cure, resistance to DAAs is a major issue. The rapid emergence of resistance-associated substitutions (RASs), in particular in the context of incomplete drug pressure, has an impact on sustained virological response (SVR) rates. Several RASs in NS3, NS5A and NS5B have been linked with reduced susceptibility to DAAs. RAS vary based on HCV characteristics and the different drug classes. DAA-resistant HCV variant haplotypes (RVs) are dominant in cases of virological failure. Viruses with resistance to NS3-4A protease inhibitors are only detected in the peripheral blood in a time frame ranging from weeks to months following completion of treatment, whereas NS5A inhibitor-resistant viruses may persist for years. Novel agents have been developed that demonstrate promising results in DAA-experienced patients. The recent approval of broad-spectrum drug combinations with a high genetic barrier to resistance and antiviral potency may overcome the problem of resistance. Full article
(This article belongs to the Special Issue Viral Resistance in HCV Infection)
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16 pages, 324 KiB  
Review
Virological Factors Associated with Failure to the Latest Generation of Direct Acting Agents (DAA) and Re-Treatment Strategy: A Narrative Review
by Lorenzo Onorato, Mariantonietta Pisaturo, Mario Starace, Carmine Minichini, Alessandra Di Fraia, Roberta Astorri and Nicola Coppola
Viruses 2021, 13(3), 432; https://doi.org/10.3390/v13030432 - 08 Mar 2021
Cited by 3 | Viewed by 1790
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)

Other

8 pages, 407 KiB  
Brief Report
Genetic Subtypes and Natural Resistance Mutations in HCV Genotype 4 Infected Saudi Arabian Patients
by Mariantonietta Di Stefano, Mona H. Ismail, Thomas Leitner, Giuseppina Faleo, Saada A. Elmnan Adem, Mohamed O. M. E. Elamin, Obeidi Eltreifi, Marwan J. Alwazzeh, Jose R. Fiore and Teresa A. Santantonio
Viruses 2021, 13(9), 1832; https://doi.org/10.3390/v13091832 - 14 Sep 2021
Cited by 4 | Viewed by 2066
Abstract
This study aimed to characterize the HCV genetic subtypes variability and the presence of natural occurring resistance-associated substitutions (RASs) in Saudi Arabia patients. A total of 17 GT patients were analyzed. Sequence analysis of NS3, NS5A, and NS5B regions was performed by direct [...] Read more.
This study aimed to characterize the HCV genetic subtypes variability and the presence of natural occurring resistance-associated substitutions (RASs) in Saudi Arabia patients. A total of 17 GT patients were analyzed. Sequence analysis of NS3, NS5A, and NS5B regions was performed by direct sequencing, and phylogenetic analyses were used to determine genetic subtypes, RAS, and polymorphisms. Nine patients were infected by GT 4a, two with GT 4o and three with GT 4d. Two patients were infected with apparent recombinant virus (4a/4o/4a in NS3/NS5A/NS5B), and one patient was infected with a previously unknown, unclassifiable, virus of GT 4. Natural RASs were found in six patients (35%), including three infected by GT 4a, two by GT 4a/GT 4o/GT 4a, and one patient infected by an unknown, unclassifiable, virus of GT 4. In particular, NS3-RAS V170I was demonstrated in three patients, while NS5A-RASs (L28M, L30R, L28M + M31L) were detected in the remaining three patients. All patients were treated with sofosbuvir plus daclatasvir; three patients were lost to follow-up, whereas 14 patients completed the treatment. A sustained virological response (SVR) was obtained in all but one patient carrying NS3-RAS V170I who later relapsed. GT 4a is the most common subtype in this small cohort of Saudi Arabia patients infected with hepatitis C infection. Natural RASs were observed in about one-third of patients, but only one of them showed a treatment failure. Full article
(This article belongs to the Special Issue Viral Resistance in HCV Infection)
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