title: Frequency of Natural Resistance within NS5a Replication Complex Domain in Hepatitis C Genotypes 1a, 1b: Possible Implication of Subtype-Specific Resistance Selection in Multiple Direct Acting Antivirals Drugs Combination Treatment.
abstract: Different HCV subtypes may naturally harbor different resistance selection to anti-NS5a inhibitors. 2761 sequences retrieved from the Los Alamos HCV database were analyzed in the NS5a domain 1, the target of NS5a inhibitors. The NS5a resistance-associated polymorphisms (RAPs) were more frequently detected in HCV G1b compared to G1a. The prevalence of polymorphisms associated with cross-resistance to compounds in clinical use (daclatasvir, DCV, ledipasvir, LDV, ombitasvir, and OMV) or scheduled to come into clinical use in the near future (IDX719, elbasvir, and ELV) was higher in G1b compared to G1a (37/1552 (2.4%) in 1b sequences and 15/1209 (1.2%) in 1a isolates, p = 0.040). Interestingly, on the basis of the genotype-specific resistance pattern, 95 (6.1%) G1b sequences had L31M RAP to DCV/IDX719, while 6 sequences of G1a (0.5%) harbored L31M RAP, conferring resistance to DCV/LDV/IDX719/ELV (p < 0.0001). Finally, 28 (2.3%) G1a and none of G1b isolates harbored M28V RAP to OMV (p < 0.0001). In conclusion, the pattern of subtype-specific resistance selection in the naturally occurring strains may guide the treatment option in association with direct acting antivirals (DAAs) targeting different regions, particularly in patients that are difficult to cure, such as those with advanced liver disease or individuals who have failed previous DAAs.
authors.affiliation: Infectious Diseases Department, Scientific Institute Ospedale San Raffaele, 20127 Milan, Italy. bagaglio.sabrina@hsr.it.|Vita-Salute University, 20132 Milan, Italy. bagaglio.sabrina@hsr.it.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bagaglio
authors.affiliation: Infectious Diseases Department, Scientific Institute Ospedale San Raffaele, 20127 Milan, Italy. andolinaandrea9@gmail.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Andolina
authors.affiliation: Infectious Diseases Department, Scientific Institute Ospedale San Raffaele, 20127 Milan, Italy. merli.marco@hsr.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Merli
authors.affiliation: Infectious Diseases Department, Scientific Institute Ospedale San Raffaele, 20127 Milan, Italy. uberti.caterina@hsr.it.
authors.forename: Caterina
authors.initials: C
authors.lastname: Uberti-Foppa
authors.affiliation: Infectious Diseases Department, Scientific Institute Ospedale San Raffaele, 20127 Milan, Italy. morsica.giulia@hsr.it.
authors.forename: Giulia
authors.initials: G
authors.lastname: Morsica
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: HCV genotypes; HCV natural resistance; NS5a inhibitors