NS5A Sequence Heterogeneity and Mechanisms of Daclatasvir Resistance in Hepatitis C Virus Genotype 4 Infection
| Autor: | Philip D. Yin, Nannan Zhou, Dennis Hernandez, K. Sims, Xiaoyan Yang, Fiona McPhee, Joseph Ueland, Fei Yu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Pyrrolidines Hepacivirus viruses Viral Nonstructural Proteins medicine.disease_cause NS5A Global Health polymorphism 0302 clinical medicine Polymorphism (computer science) Genotype Immunology and Allergy Phylogeny Genetics education.field_of_study biology Imidazoles virus diseases Valine Hepatitis C Infectious Diseases Viruses HCV 030211 gastroenterology & hepatology medicine.drug Gene Expression Regulation Viral Daclatasvir Hepatitis C virus Population resistance 03 medical and health sciences Major Articles and Brief Reports Drug Resistance Viral medicine Humans daclatasvir education Polymorphism Genetic biology.organism_classification medicine.disease Virology digestive system diseases 030104 developmental biology Amino Acid Substitution Carbamates |
| Zdroj: | The Journal of Infectious Diseases |
| ISSN: | 1537-6613 0022-1899 |
| Popis: | Background. Daclatasvir is an NS5A inhibitor approved for treatment of infection due to hepatitis C virus (HCV) genotypes (GTs) 1–4. To support daclatasvir use in HCV genotype 4 infection, we examined a diverse genotype 4–infected population for HCV genotype 4 subtype prevalence, NS5A polymorphisms at residues associated with daclatasvir resistance (positions 28, 30, 31, or 93), and their effects on daclatasvir activity in vitro and clinically. Methods. We performed phylogenetic analysis of genotype 4 NS5A sequences from 186 clinical trial patients and 43 sequences from the European HCV database, and susceptibility analyses of NS5A polymorphisms and patient-derived NS5A sequences by using genotype 4 NS5A hybrid genotype 2a replicons. Results. The clinical trial patients represented 14 genotype 4 subtypes; most prevalent were genotype 4a (55%) and genotype 4d (27%). Daclatasvir 50% effective concentrations for 10 patient-derived NS5A sequences representing diverse phylogenetic clusters were ≤0.080 nM. Most baseline sequences had ≥1 NS5A polymorphism at residues associated with daclatasvir resistance; however, only 3 patients (1.6%) had polymorphisms conferring ≥1000-fold daclatasvir resistance in vitro. Among 46 patients enrolled in daclatasvir trials, all 20 with baseline resistance polymorphisms achieved a sustained virologic response. Conclusions. Circulating genotype 4 subtypes are genetically diverse. Polymorphisms conferring high-level daclatasvir resistance in vitro are uncommon before therapy, and clinical data suggest that genotype 4 subtype and baseline polymorphisms have minimal impact on responses to daclatasvir-containing regimens. |
| Databáze: | OpenAIRE |
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