title: Naturally occurring mutations to HCV protease inhibitors in treatment-naïve patients.
abstract: BACKGROUND
  Protease inhibitors (PIs) to treat hepatitis C (HCV) virus infection have been approved and others are under development.
  
  
  RESULTS
  The aims of this study were to illustrate natural polymorphisms in the HCV protease and measure the frequency of PI resistance mutations in different HCV genotypes from PI-naïve patients.Direct sequencing of HCV NS3/4A protease was performed in 156 HCV patients naïve to PIs who were infected with genotype 1a (n = 31), 1b (n = 39), 2 (n = 30), 3 (n = 33) and 4 (n = 23).Amino acid (aa) substitutions associated with HCV PI resistance were found in 17/156 (10.8%) sequences. Mutations V36L, T54S, V55A/I, and Q80K/L were observed in 29% of patients with genotype 1a, and V55F, Q80L/N and M175L in 10% of patients with genotype 1b. The mutation V158M was found in 3% of patients with genotype 2, D168Q was present in 100% of patients with genotype 3 and D168E was observed in 13% of patients with genotype 4. In addition, multiple aa polymorphisms not associated with PI resistance were detected in patients with genotypes 1a, 1b and 4.
  
  
  CONCLUSIONS
  Although major PI resistance mutations were not detected, other resistance mutations conferring low level resistance to PIs together with a number of natural polymorphisms were observed in proteases of PI naïve HCV patients. A more extensive analysis is needed to better evaluate the impact of baseline resistance and compensatory mutations in the efficacy of HCV PI treatment.
authors.affiliation: Molecular Virology Unit, Virology and Microbiology Department, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Paolucci
authors.forename: Loretta
authors.initials: L
authors.lastname: Fiorina
authors.forename: Antonio
authors.initials: A
authors.lastname: Piralla
authors.forename: Roberto
authors.initials: R
authors.lastname: Gulminetti
authors.forename: Stefano
authors.initials: S
authors.lastname: Novati
authors.forename: Giorgio
authors.initials: G
authors.lastname: Barbarini
authors.forename: Paolo
authors.initials: P
authors.lastname: Sacchi
authors.forename: Marta
authors.initials: M
authors.lastname: Gatti
authors.forename: Luca
authors.initials: L
authors.lastname: Dossena
authors.forename: Fausto
authors.initials: F
authors.lastname: Baldanti
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology*; D016000:Cluster Analysis; D024882:Drug Resistance, Viral; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification; D006526:Hepatitis C / Q000821:virology*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010802:Phylogeny; D011110:Polymorphism, Genetic; D011480:Protease Inhibitors / Q000494:pharmacology*; D017385:Sequence Homology; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases