Role of ITPA and SLC28A2 genes in the prediction of anaemia associated with protease inhibitor plus ribavirin and peginterferon in hepatitis C treatment

J Clin Virol. 2015 Jul:68:56-60. doi: 10.1016/j.jcv.2015.05.010. Epub 2015 May 14.

Abstract

Background: Anaemia is a common side-effect of ribavirin (RBV) use that overwhelms management of hepatitis C when protease inhibitors are added.

Aim: To assess the pharmacogenomic impact of candidate genes SLC28A2, SLC28A3 and ITPA on anaemia in patients receiving triple therapy.

Methods: Patients (n=161) with chronic hepatitis C genotype 1 treated with telaprevir (n=95) or boceprevir (n=66) were included. Using RT-PCR we genotyped ITPA (rs1127354, rs7270101) and SLC28A3 (rs56350726, rs10868138) and SLC28A2 (rs11854484). Clinically significant anaemia (CSA) was diagnosed when at least one of the following criteria was observed: (a) haemoglobin <8.5g/dL during treatment; (b) blood transfusion required; (c) erythropoietin administered.

Results: CSA occurred in 44% (69/157) of patients and was associated with SLC28A2 rs11854484 [CC/CT genotypes: 33% (26/78) vs. TT genotype: 56% (36/64); p=0.006]. Further, the needed for blood transfusion was related to genotype [CC: 0% (0/18) vs. CT: 13% (8/61) vs. TT: 27% (17/64); p=0.016]. Similarly, ITPA rs1127354 genotypes [AA/AC: 19% (3/16) vs. CC: 45% (61/135; p=0.060] were linked to CSA. In multivariate analysis, SLC28A2 rs11854484 TT genotype (OR:2.33;95%CI:1.10-4.95; p=0.027), female sex (OR:2.54;95% CI:1.13-5.71;p=0.024) and Hb drop at week 4) OR: 1.36; 95CI%: 1.11-1.67; p=0.003) were independently associated with CSA. Similarly, ITPA rs1127354 genotypes [AA/AC: 16% (3/19) vs. CC: 63% (85/134); p=0.0001] and ITPA rs6051702 genotypes [CC/CA: 46% (26/57) vs. CC: 65% (60/93); p=0.023] were related to Hb drop of >3g/dL at week 4.

Conclusions: In patients receiving first generation protease inhibitors, genotype SLC28A2 rs11854484 predicts CSA, and helps to identify a subgroup of patients with better tolerance of triple therapy.

Keywords: Adverse event; Anaemia; Boceprevir; Hepatitis C; ITPA; Lead-in-phase; Pharmacogenomics; Polymorphism; SLC28; Telaprevir.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Anemia / chemically induced*
  • Anemia / epidemiology
  • Anemia / genetics
  • Antiviral Agents / adverse effects*
  • Antiviral Agents / therapeutic use
  • Drug Therapy, Combination / adverse effects
  • Drug Therapy, Combination / methods
  • Female
  • Genetic Predisposition to Disease
  • Hepatitis C, Chronic / complications
  • Hepatitis C, Chronic / drug therapy*
  • Humans
  • Incidence
  • Male
  • Membrane Transport Proteins / genetics*
  • Middle Aged
  • Oligopeptides / adverse effects
  • Oligopeptides / therapeutic use
  • Proline / adverse effects
  • Proline / analogs & derivatives
  • Proline / therapeutic use
  • Prospective Studies
  • Protease Inhibitors / adverse effects*
  • Protease Inhibitors / therapeutic use
  • Pyrophosphatases / genetics*
  • Ribavirin / adverse effects*
  • Ribavirin / therapeutic use
  • Risk Assessment
  • Young Adult

Substances

  • Antiviral Agents
  • Membrane Transport Proteins
  • Oligopeptides
  • Protease Inhibitors
  • cif nucleoside transporter
  • Ribavirin
  • telaprevir
  • 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
  • Proline
  • Pyrophosphatases
  • ITPA protein, human