title: [Significance of hepatitis C virus baseline polymorphism during the antiviral therapy].
abstract: The treatment of chronic hepatitis C has developed significantly during the last 25 years. In patients with genotype 1 infection 40-50% sustained virologic response could be achieved using pegylated interferon and ribavirin dual combination, which could be increased significantly with the introduction of direct acting antivirals. Three major groups of direct acting antivirals are known, which directly inhibit different phases of viral life cycle, by inhibiting the function of several non-structural proteins (NS3/4A protease, NS5A protein and NS5B polymerase). Due to the rapid replication rate of hepatitis C virus and the error-prone NS5B polymerase activity, mutant virions are generated, which might have reduced susceptibility to direct acting antiviral therapy. Since these resistance associated variants might exist before the antiviral therapy, they are still able to replicate during the direct acting antiviral treatment. Due to this selection pressure, the resistant virus will replace the wild type. This was especially detected during monotherapy, therefore, the first generation of direct acting antivirals have been combined with pegylated interferon and ribavirin, while recently interferon-free combinations are being developed including 2 or 3 direct acting antivirals. Using the first generation protease inhibitors boceprevir and telaprevir, it could have been seen, that the rate of resistance associated variants is higher and the therapeutic outcome is worse in patients with hepatitis C virus genotype 1a, than in 1b. Similar phenomenon was seen with the second generation of NS3/4A protease inhibitors as well as with NS5A or NS5B polymerase. This is due to the lower genetic barrier to resistance, ie. usually fewer mutations are enough for the emergence of resistance in genotype 1a. The selection of resistance associated variants is one of the most important challenges during the interferon-free therapy.
authors.affiliation: Belgyógyászati Intézet, Gasztroenterológiai Tanszék, Debreceni Egyetem, Általános Orvostudományi Kar Debrecen, Nagyerdei krt. 98., 4032.
authors.forename: István
authors.initials: I
authors.lastname: Tornai
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003521:Cyclopropanes; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy*; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage; D006801:Humans; D007372:Interferons / Q000008:administration & dosage; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000008:administration & dosage; D019384:Nucleic Acid Synthesis Inhibitors / Q000627:therapeutic use*; D009842:Oligopeptides / Q000008:administration & dosage; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012254:Ribavirin / Q000008:administration & dosage; D000069616:Simeprevir; D013449:Sulfonamides / Q000008:administration & dosage; D019562:Viral Load / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D006575:Heterocyclic Compounds, 3-Ring; D007372:Interferons; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D019384:Nucleic Acid Synthesis Inhibitors; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D012254:Ribavirin; D000069616:Simeprevir; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C585405:paritaprevir
keywords: direct acting antiviral agents; direkt ható antivirális szerek; genotype 1a and 1b; genotípus 1a és 1b; hepatitis C virus; hepatitis C-vírus; resistance; rezisztencia