title: Previous failure of interferon-based therapy does not alter the frequency of HCV NS3 protease or NS5B polymerase inhibitor resistance-associated variants: longitudinal analysis in HCV/HIV co-infected patients.
abstract: Since 2011, treatment of chronic hepatitis C virus (HCV) includes direct-acting antivirals (DAAs) in addition to pegylated interferon-α (peg-IFN) and ribavirin (RBV). IFN-based treatment induces strong cytotoxic T-lymphocyte activity directed to the protease- and polymerase-derived epitopes. This enhanced immunological pressure could favour the emergence of viral epitope variants able to evade immune surveillance and, when resistance-associated variants (RAVs) are implicated, could also be co-selected as a hitchhiking effect. This study analysed the dynamics of the frequency of protease and polymerase inhibitor RAVs that could affect future HCV treatment in human immunodeficiency virus (HIV) co-infected patients on stable antiretroviral therapy with previous IFN-based treatment failure. HCV genotype 1a RNA was extracted from plasma samples of 18 patients prior to and during (24h and 4, 12, 24 and 48 weeks) therapy with peg-IFN+RBV. Next-generation sequencing was performed on HCV-RNA populations using NS3 and NS5B PCR-amplified coding regions. Two measures of genetic diversity were used to compare virus populations: average pairwise nucleotide diversity (π) and Tajima's D statistic. Several protease and polymerase RAVs were detected in all subjects at very low frequencies (<5%), and in most cases their presence was not constant during follow-up. Only samples from two patients for each region exhibited Q80R/K/L and A421V as highly predominant variants. No significant differences were observed among sampling times for either π or D values. In conclusion, previous therapy and failure of peg-IFN+RBV were not associated with an increase in DAA-targeting NS3 or NS5B RAVs that naturally exist in HIV co-infected subjects.
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
authors.forename: Mariano M
authors.initials: MM
authors.lastname: Sede
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
authors.forename: Natalia L
authors.initials: NL
authors.lastname: Laufer
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina. Electronic address: quarleri@fmed.uba.ar.
authors.forename: Jorge
authors.initials: J
authors.lastname: Quarleri
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000627:therapeutic use*; D060085:Coinfection / Q000188:drug therapy / Q000821:virology*; D024882:Drug Resistance, Viral; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections / Q000150:complications; D016174:Hepacivirus / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy / Q000821:virology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics; D020125:Mutation, Missense; D012367:RNA, Viral / Q000235:genetics; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D050505:Mutant Proteins; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Direct-acting antivirals; HCV; NS3; NS5B; Peg-IFN; Resistance-associated variants (RAVs)