title: Effect of IL28B genotype on early viral kinetics during interferon-free treatment of patients with chronic hepatitis C.
abstract: OBJECTIVE
  Although interleukin 28B (interferon, lambda 3) (IL28B) genotype affects the response of patients with chronic hepatitis C to peginterferon and ribavirin, little is known regarding its effect on response to direct-acting antivirals in interferon-free combinations. We analyzed the effects of IL28B genotype on the viral kinetic (VK) response to an interferon-free combination of the nucleoside polymerase inhibitor mericitabine (RG7128) and the hepatitis C virus (HCV) protease inhibitor danoprevir.
  
  
  METHODS
  We performed a double-blind, dose-escalation study of patients with chronic HCV genotype 1 infection who were interferon treatment naive or had not responded to previous therapy with peginterferon and ribavirin. Patients were sequentially assigned to 1 of 7 cohorts then randomly assigned to groups that received up to 13 days of treatment with mericitabine (500 or 1000 mg, twice daily) plus danoprevir (100 or 200 mg, every 8 hours, or 600 or 900 mg, twice daily) or placebo. Eighty-three of 87 patients were genotyped for the IL28B single-nucleotide polymorphism rs12979860. VKs were analyzed only in patients who received 13 days of treatment, at optimal doses, using a biphasic model to describe first- and second-phase slopes of viral decay during therapy.
  
  
  RESULTS
  At day 14 (the end of interferon-free treatment), the mean reduction in the serum level of HCV RNA was slightly greater in patients with the CC polymorphism (5.01 log(10) IU/mL) than those without (4.59 log(10) IU/mL). Modeling revealed that patients with the CC polymorphism had slightly better early VKs, most apparent in the β-phase of viral decay. A mixed effect on the α-phase was observed, which was reduced in magnitude but prolonged in patients with CC, who also had better on-treatment response to peginterferon and ribavirin during follow up.
  
  
  CONCLUSIONS
  IL28B genotype appears to affect early VKs in patients with chronic hepatitis C receiving interferon-free treatment.
authors.affiliation: Roche, Nutley, New Jersey, USA. tom.chu@roche.com
authors.forename: Tom W
authors.initials: TW
authors.lastname: Chu
authors.forename: Rohit
authors.initials: R
authors.lastname: Kulkarni
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Roberts
authors.forename: Catherine
authors.initials: C
authors.lastname: Stedman
authors.forename: Peter W
authors.initials: PW
authors.lastname: Angus
authors.forename: Brett
authors.initials: B
authors.lastname: Ritchie
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Lu
authors.forename: David
authors.initials: D
authors.lastname: Ipe
authors.forename: Uri
authors.initials: U
authors.lastname: Lopatin
authors.forename: Soren
authors.initials: S
authors.lastname: Germer
authors.forename: Victor A
authors.initials: VA
authors.lastname: Iglesias
authors.forename: Robert
authors.initials: R
authors.lastname: Elston
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Shulman
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D001315:Australia; D003521:Cyclopropanes; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D054833:Isoindoles; D007700:Kinetics; D007769:Lactams / Q000627:therapeutic use*; D047029:Lactams, Macrocyclic; D008954:Models, Biological; D015233:Models, Statistical; D009520:New Zealand; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011392:Proline / Q000031:analogs & derivatives; D012367:RNA, Viral / Q000097:blood; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D003841:Deoxycytidine; D007372:Interferons; D007378:Interleukins; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D011392:Proline; D012367:RNA, Viral; D013449:Sulfonamides; C552098:2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C553752:danoprevir