title: Protease inhibitors partially overcome the interferon nonresponse phenotype in patients with chronic hepatitis C.
abstract: The outcome of triple therapy with protease inhibitors (PI) depends on the intrinsic response to interferon. Interferon-stimulated gene (ISG) expression differs by cell type in the liver and is a strong predictor of interferon responsiveness. Patients who respond well to interferon have low/absent ISG expression in hepatocytes but significant ISG expression in macrophages. Nonresponders (NRs) show the opposite pattern. We aimed to determine the association between cell-type-specific ISG staining and treatment outcome with PI-based triple therapy. Liver biopsy tissue from consecutive patients treated with boceprevir or telaprevir with peginterferon and ribavirin was stained for myxovirus A (MxA). Staining was scored 0-3 in macrophages (M-MxA) and hepatocytes (H-MxA), and IL28B genotyping was performed. Of 56 patients included 41 achieved SVR (73%) (sustained virological response), 2 (4%) relapsed, 10 (18%) were NRs, and 3 (5%) were lost to follow-up. Median M-MxA staining was stronger and H-MxA staining was weaker in patients who achieved SVR. MxA staining correlated with IL28B genotype and with the HCV RNA decline during lead-in phase. However, unlike with dual therapy, the negative predictive value (NPV) of absent or weak M-MxA staining was poor (42%), while the positive predictive value improved (93%). Although by multivariable logistic regression M-MxA staining was significantly associated with SVR (OR 4.35, 1.32-14.28, P = 0.012), the predictive ability was inadequate to withhold therapy. The interaction between macrophages and hepatocytes plays a critical role in interferon responsiveness; however, the addition of a PI at least partially overcomes the interferon nonresponse phenotype making the predictive ability of ISG staining less clinically useful.
authors.affiliation: Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: A
authors.initials: A
authors.lastname: Duarte-Rojo
authors.affiliation: Department of Pathology, University of Toronto, Toronto, ON, Canada.|University Health Network, Toronto, ON, Canada.
authors.forename: S E
authors.initials: SE
authors.lastname: Fischer
authors.affiliation: Department of Pathology, University of Toronto, Toronto, ON, Canada.|University Health Network, Toronto, ON, Canada.
authors.forename: O
authors.initials: O
authors.lastname: Adeyi
authors.affiliation: University Health Network, Toronto, ON, Canada.|Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Zita
authors.affiliation: Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Deneke
authors.affiliation: University Health Network, Toronto, ON, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Selzner
authors.affiliation: Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada.|Sandra Rotman Centre for Global Health, University of Toronto, Toronto, ON, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Division of Hepatology, Loyola University Health System, Maywood, IL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Malespin
authors.affiliation: Division of Hepatology, Loyola University Health System, Maywood, IL, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Cotler
authors.affiliation: University Health Network, Toronto, ON, Canada.
authors.forename: I D
authors.initials: ID
authors.lastname: McGilvray
authors.affiliation: University Health Network, Toronto, ON, Canada.|Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada.|Sandra Rotman Centre for Global Health, University of Toronto, Toronto, ON, Canada.
authors.forename: J J
authors.initials: JJ
authors.lastname: Feld
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D001706:Biopsy; D005260:Female; D020869:Gene Expression Profiling; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000627:therapeutic use*; D008099:Liver / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000627:therapeutic use; D011392:Proline / Q000031:analogs & derivatives / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000627:therapeutic use*; D012254:Ribavirin / Q000627:therapeutic use; D013194:Staining and Labeling
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D011480:Protease Inhibitors; D012254:Ribavirin; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline
keywords: boceprevir; interferon-lambda; interferon-stimulated genes; myxovirus A protein 1; peginterferon; telaprevir