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

• Published in: International journal of antimicrobial agents Vol. 46; no. 2; pp. 219 - 224
• Main Authors: Sede, Mariano M., Laufer, Natalia L., Quarleri, Jorge
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2015
• Subjects: Adult; Amino Acid Substitution; antiretroviral agents; Antiviral Agents - therapeutic use; chronic hepatitis C; Coinfection - drug therapy; Coinfection - virology; cytotoxicity; Direct-acting antivirals; Drug Resistance, Viral; enzyme inhibitors; epitopes; Female; Gene Frequency; Genetic Variation; Genotype; HCV; Hepacivirus - classification; Hepacivirus - genetics; Hepacivirus - isolation & purification; Hepatitis C virus; Hepatitis C, Chronic - complications; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - virology; High-Throughput Nucleotide Sequencing; HIV Infections - complications; Human immunodeficiency virus; Humans; Infectious Disease; interferon-alpha; Interferons - therapeutic use; Longitudinal Studies; Male; Middle Aged; mixed infection; monitoring; Mutant Proteins - genetics; Mutation, Missense; NS3; NS5B; patients; Peg-IFN; proteinases; Resistance-associated variants (RAVs); Retrospective Studies; RNA; RNA, Viral - genetics; Sequence Analysis, DNA; T-lymphocytes; therapeutics; Treatment Failure; Viral Nonstructural Proteins - genetics; viruses; HCV; Peg-IFN; NS5B; Direct-acting antivirals; Resistance-associated variants (RAVs); NS3
• ISSN: 0924-8579; 1872-7913; 1872-7913
• DOI: 10.1016/j.ijantimicag.2015.04.011

•HCV genotype 1a protease and polymerase inhibitor resistance-associated variants (RAVs) were longitudinally studied among HIV co-infected patients.•HCV 1a quasispecies genetic diversity was measured by both pairwise nucleotide diversity (π) and Tajima's D statistic.•Several NS3 and NS5B RAVs with low frequencies (<5%) emerged randomly during follow-up.•The NS3 Q80R/K/L and NS5B A421V RAVs appeared as predominant variants in two patients.•Previous therapy and failure of peg-IFN+ribavirin did not influence the dynamics of NS3 or NS5B RAVs frequencies. 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.