Effect of IL28B genotype on early viral kinetics during interferon-free treatment of patients with chronic hepatitis C

Gastroenterology. 2012 Apr;142(4):790-5. doi: 10.1053/j.gastro.2011.12.057. Epub 2012 Jan 13.

Abstract

Background & aims: 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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / therapeutic use*
  • Australia
  • Cyclopropanes
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Double-Blind Method
  • Drug Therapy, Combination
  • Genotype
  • Hepacivirus / drug effects*
  • Hepacivirus / genetics
  • Hepacivirus / growth & development
  • Hepatitis C, Chronic / diagnosis
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / genetics
  • Hepatitis C, Chronic / immunology
  • Humans
  • Interferons
  • Interleukins / genetics*
  • Isoindoles
  • Kinetics
  • Lactams / therapeutic use*
  • Lactams, Macrocyclic
  • Models, Biological
  • Models, Statistical
  • New Zealand
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Proline / analogs & derivatives
  • RNA, Viral / blood
  • Sulfonamides / therapeutic use*
  • Treatment Outcome
  • Viral Load
  • Virus Replication / drug effects

Substances

  • 2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine
  • Antiviral Agents
  • Cyclopropanes
  • interferon-lambda, human
  • Interleukins
  • Isoindoles
  • Lactams
  • Lactams, Macrocyclic
  • RNA, Viral
  • Sulfonamides
  • Deoxycytidine
  • Interferons
  • danoprevir
  • Proline