title: Temporal dynamics of inflammatory cytokines/chemokines during sofosbuvir and ribavirin therapy for genotype 2 and 3 hepatitis C infection.
abstract: The analysis of inflammatory cytokines and chemokines produced during hepatitis C virus (HCV) infection has advanced our understanding of viral-host interactions and identified predictors of treatment response. Administration of interferons (IFNs) made it difficult to interpret biomarkers of immune activation during treatment. Direct-acting antiviral (DAA) regimens without IFN are now being used to treat HCV with excellent efficacy. To gain insight into HCV-host interactions occurring before, during, and after HCV treatment, we performed a case-control study that measured serial plasma levels of IFN-γ-inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1 beta (MIP-1β), and interleukin-18 (IL-18) in 131 patients with chronic HCV treated with sofosbuvir (SOF) plus ribavirin (RBV). A linear regression analysis using baseline factors identified strong positive associations between elevated alanine aminotransferase and pretreatment IP-10 and between the presence of cirrhosis and elevated pretreatment IL-18. Mean IP-10, MCP-1, MIP-1β, and IL-18 levels all decline on therapy, but display different dynamics late in treatment and after cessation of therapy. On treatment, IP-10 and MIP-1β levels were significantly higher in individuals who achieved sustained virological response (SVR). Logistic regression analyses examining treatment response in all patients demonstrated significant associations between higher baseline MIP-1β levels and smaller decreases in MIP-1β early in treatment and SVR. Higher early MIP-1β levels were also significantly associated with SVR in subsets of patients with cirrhosis and individuals with genotype 3 (GT3) infection, two factors associated with decreased responsiveness to treatment.
  
  
  CONCLUSIONS
  Changes in IP-10 levels mirror HCV RNA, suggesting that IP-10 is an indicator of innate immune viral recognition. MIP-1β levels remain elevated in GT2/3 patients who achieved SVR, suggesting differential immune activation in those who respond to SOF/RBV therapy and a potential role in predicting treatment responses.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA.
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Carlin
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA.
authors.forename: Paula
authors.initials: P
authors.lastname: Aristizabal
authors.affiliation: Gilead Sciences, Foster City, CA.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Song
authors.affiliation: Gilead Sciences, Foster City, CA.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Gilead Sciences, Foster City, CA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Paulson
authors.affiliation: Gilead Sciences, Foster City, CA.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Stamm
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Schooley
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA.
authors.forename: David L
authors.initials: DL
authors.lastname: Wyles
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood*; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012254:Ribavirin / Q000627:therapeutic use*; D000069474:Sofosbuvir / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D000998:Antiviral Agents; D018925:Chemokines; D016207:Cytokines; D012254:Ribavirin; D000069474:Sofosbuvir