title: Temperature rise after peginterferon alfa-2a injection in patients with chronic hepatitis C is associated with virological response and is modulated by IL28B genotype.
abstract: OBJECTIVE
  Interferon treatment for chronic hepatitis C is associated with non-specific symptoms including fever. We aimed to determine the association of temperature changes with interferon antiviral activity.
  
  
  METHODS
  60 treatment-naïve patients with chronic hepatitis C (67% genotype 1/4/6, 33% genotype 2/3) were admitted to start peginterferon alfa-2a and ribavirin in a clinical trial. Temperature was measured at baseline and 3 times daily for the first 24h and the maximal increase from baseline during that time (ΔTmax) was determined. Serum HCV-RNA, interferon-gamma-inducible protein-10 (IP-10) and expression of interferon-stimulated genes (ISGs - CD274, ISG15, RSAD2, IRF7, CXCL10) in peripheral blood mononuclear cells (PBMCs) were measured at very early time points, and response kinetics calculated. The IL28B single nucleotide polymorphism, rs12979860, was genotyped.
  
  
  RESULTS
  Temperatures rose by 1.2±0.8°C, peaking after 12.5h. ΔTmax was strongly associated with 1st phase virological decline (r=0.59, p<0.0001) and was independent of gender, cirrhosis, viral genotype or baseline HCV-RNA. The association with 1st phase decline was seen in patients with rs12979860CC genotype (r = 0.65, p <0.0001) but not in CT/TT (r = 0.13, p = 0.53) and patients with CC genotype had a higher DTmax (1.4 ± 0.8 C vs. 0.8 ± 0.6 +C, p = 0.001). DTmax was associated with 6- and 24-h induction of serum IP-10 and of PBMC ISG expression, but only in patients with rs12979860CC [corrected].ΔTmax weakly predicted early virological response (AUC=0.68, CI 0.49-0.88).
  
  
  CONCLUSIONS
  Temperature rise following peginterferon injection is closely associated with virological response and is modulated by IL28B polymorphism, reflecting host interferon-responsiveness.
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.
authors.forename: Hwalih
authors.initials: H
authors.lastname: Han
authors.forename: Mazen
authors.initials: M
authors.lastname: Noureddin
authors.forename: Michael
authors.initials: M
authors.lastname: Witthaus
authors.forename: Yoon J
authors.initials: YJ
authors.lastname: Park
authors.forename: Jay H
authors.initials: JH
authors.lastname: Hoofnagle
authors.forename: T Jake
authors.initials: TJ
authors.lastname: Liang
authors.forename: Yaron
authors.initials: Y
authors.lastname: Rotman
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D001831:Body Temperature / Q000235:genetics / Q000502:physiology; D054357:Chemokine CXCL10 / Q000097:blood; D005260:Female; D005334:Fever / Q000235:genetics* / Q000503:physiopathology*; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins / Q000627:therapeutic use; D012189:Retrospective Studies; D012254:Ribavirin / Q000627:therapeutic use*; D016896:Treatment Outcome; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D054357:Chemokine CXCL10; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C100416:peginterferon alfa-2a
keywords: EVR; Fever; HCV; Hepatitis C; IFN; IL28B; IP-10; ISG; Interferon alfa; PGE2; PegIFN; RVR; SVR; Temperature; Treatment; early virological response; hepatitis C virus; interferon; interferon-gamma-inducible protein-10; interferon-stimulated gene; peginterferon alfa 2a; prostaglandin E2; rapid virological response; sustained virological response