title: Characterization of HCV NS3 Protease Variants in HCV/HIV-Coinfected Patients by Ultra-Deep Sequence Analysis: Relationship with Hepatic Fibrosis.
abstract: BACKGROUND
  Treatment of HCV/HIV coinfection is now largely based on utilization of direct acting agents. Pretreatment viral resistant-associated variants (RAVs) and host liver condition may affect the sustained virological response. In this study, we explored relative prevalence of protease resistance-associated mutations, the evolution of those RAVs after 12 weeks of pegylated interferon alfa exposure, and the role hepatic fibrosis might have on RAV display.
  
  
  METHODS
  Thirty nonresponder HCV/HIV-coinfected subjects were evaluated before and after 12 weeks of PegIFN treatment. Ultra-deep sequence analysis of NS3 RAVs was performed. Hepatic fibrosis was determined by sensitive computer-assisted histomorphometry determination.
  
  
  RESULTS
  At baseline, protease inhibitor RAVs were present in 73.3% of patients and expanded to 83.3% of patients after 12 weeks of PegIFN exposure. Q80K showed the highest prevalence before and after treatment at 46.7% and 56.7%, respectively. The presence of Q80K is positively correlated with percent collagen content of the liver tissue.
  
  
  CONCLUSIONS
  Key RAVs for HCV protease inhibitors are present in a major portion of the HCV/HIV-coinfected population before therapy. Some variants get selected after exposure. Correlation of Q80K with collagen content of the liver suggests that compartmentalization within the liver may contribute to persistence of mutations less fit than wildtype.
authors.affiliation: *Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH; †Department of Environmental Health, University of Cincinnati, Cincinnati, OH; and ‡Department of Pathology, Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA.
authors.forename: Enass A
authors.initials: EA
authors.lastname: Abdel-Hameed
authors.forename: Susan D
authors.initials: SD
authors.lastname: Rouster
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Goodman
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Sherman
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage*; D060085:Coinfection / Q000821:virology; D024882:Drug Resistance, Viral; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections / Q000150:complications; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy* / Q000821:virology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008103:Liver Cirrhosis / Q000453:epidemiology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; 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
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases