Hepatitis C virus drug resistance associated substitutions and their clinical relevance: Update 2018

Sorbo, M.C.; Cento, Valeria; Maio, V.C. Di; Howe, Anita Y.M.; García, Féderico; Perno, Carlo Federico; Ceccherini‐Silberstein, Francesca

doi:10.1016/j.drup.2018.01.004

Cited by 173 publications

(235 citation statements)

References 133 publications

Supporting

Mentioning

219

Contrasting

Unclassified

Order By: Relevance

“…Most previous studies focused on the characterization of RASs for genotype 1 . While this study used genotype 1‐6 infectious culture systems for resistance profiling of grazoprevir and paritaprevir, selected RASs were in general comparable to those previously selected in replicons and in patients …”

Section: Discussionmentioning

confidence: 95%

“…In vitro testing is required for characterization of RASs. In constrast to enzyme and replicon assays, infectious HCV culture systems allow investigation of the complete genome and viral life cycle, and results obtained in such systems reflect in vivo data …”

Section: Discussionmentioning

confidence: 99%

“…The main DAA targets are the HCV nonstructural protein (NS) 3 protease (NS3P), the NS5A protein, and the NS5B polymerase. To counteract the emergence of resistance, DAAs are administered in combinations, and protease inhibitors (PIs) are important components of several DAA‐based treatment regimens . The PI grazoprevir in combination with the NS5A inhibitor elbasvir, as well as the PI paritaprevir in combination with the NS5A inhibitor ombitasvir and the nonnucleosidic NS5B inhibitor dasabuvir, were approved for treatment of genotypes 1 and 4 .…”

mentioning

confidence: 99%

“…However, resistance to DAAs is emerging . Thus, a subset of DAA‐treated patients is experiencing treatment failure, associated with the selection of HCV resistance–associated substitutions (RASs) . Furthermore, in certain regions, specific RASs pre‐exist in up to 50% of individuals .…”

mentioning

confidence: 99%

See 3 more Smart Citations

Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

Jensen¹,

Fahnøe²,

Pham³

et al. 2019

Hepatology

View full text Add to dashboard Cite

Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance–associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as a RAS hotspot for genotype 1‐4, but not 5 and 6, escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156‐RASs were not maintained. For genotypes 1 and 2, persistence of 156‐RASs depended on genome‐wide substitution networks, co‐selected under continued PI treatment and identified by next‐generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156‐RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir, and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre‐existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156‐RASs, we observed genome‐wide selection of substitutions under treatment. Conclusion: Comprehensive PI resistance profiling for HCV genotypes 1‐6 revealed 156‐RASs as key determinants of high‐level resistance across clinically relevant PIs. We obtained in vitro proof of concept for persistence of highly fit genotype 1‐3 156‐variants, which might pose a threat to clinically relevant combination treatments.

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

Jensen¹,

Fahnøe²,

Pham³

et al. 2019

Hepatology

View full text Add to dashboard Cite

show abstract

“…The simple identification of subtype 4r, as discussed above, would provide sufficient information to reinforce treatment in patients infected with this subtype. However, HCV resistance testing can be used confidently in settings that have easy access to a reliable, quality‐controlled assay, as recently reported . Classically, three coding regions are analyzed, including NS3 protease, NS5A, and NS5B RNA polymerase, whereas in‐house databases or free‐access Internet tools are used for sequence interpretation.…”

Section: Discussionmentioning

confidence: 99%

Frequent Antiviral Treatment Failures in Patients Infected With Hepatitis C Virus Genotype 4, Subtype 4r

et al. 2019

View full text Add to dashboard Cite

show abstract

Mechanisms of Resistance to Antiviral Agents

Shafer,

Boivin,

Howe

et al. 2023

ClinMicroNow

View full text Add to dashboard Cite

Understanding the mechanisms of viral drug resistance is critical for clinical management of individuals receiving antiviral therapy, for developing new antiviral drugs, and for drug resistance surveillance. This chapter reviews the mechanisms of resistance to antiviral drugs used to treat infections by eight common viruses: herpes simplex, cytomegalovirus, varicella‐zoster virus, human immunodeficiency virus type 1, influenza A and B, hepatitis B, hepatitis C, and severe acute respiratory syndrome coronavirus 2. Drug‐resistant virus subpopulations may exist at low levels in clinical isolates or may arise only during drug exposure. The error‐prone polymerases in RNA viruses render the development of resistance more frequent than in DNA viruses. Drug‐resistant viruses are identified by in vitro passage experiments in which wild‐type viruses are cultured in increasing concentrations of an inhibitory drug and by ex vivo analysis of virus isolates obtained from individuals receiving antiviral therapy.

show abstract

Hepatitis C virus drug resistance associated substitutions and their clinical relevance: Update 2018

Cited by 173 publications

References 133 publications

Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

Frequent Antiviral Treatment Failures in Patients Infected With Hepatitis C Virus Genotype 4, Subtype 4r

Mechanisms of Resistance to Antiviral Agents

Contact Info

Product

Resources

About