To investigate the association between inosine triphosphatase (ITPase) activity and the degree of anaemia occurring during direct-acting antiviral (DAA)/ribavirin (RBV)-based therapy in patients with cirrhosis.
Methods
In a multicentre, prospective study 227 patients with HCV-related cirrhosis treated with DAA and RBV were enrolled. All patients were screened for the rs1127354 and rs7270101 ITPA single nucleotide polymorphisms using direct sequencing.
Results
150 (66.1%) patients had normal (100%) ITPase activity, 48 (21.1%) had moderate (60%) activity and 29 (12.8%) minimal (≤30%) activity. The ITPase activity significantly influenced the haemoglobin concentration: at day 15 it was -1.248 (sd ±0.978) in the 150 patients with an ITPase activity of 100% and -0.616 (±0.862) in the 77 patients with an ITPase activity less than 100% (P <0.000), and at day 30 it was -1.941 ±1.218 versus -1.11 ±1.218 (P <0.000). The 63 patients with a severe (at least 3/dl) haemoglobin decline, compared to those without, more frequently had an ITPase activity of 100% (82.1% versus 62.8%; P=0.021), were older (mean age ±sd: 66.7 ±8.2 versus 61.4 ±9.7 years; P=0.004) and were treated with a higher ribavirin dose (13.7 ±2.1 versus 12.8 ±2.5 mg/ kg/day; P=0.008). At multivariate logistic regression analysis, the ITPase activity of 100% (OR: 2.83; 95% CI: 1.12, 7.10), male gender (OR: 3.22; 95% CI: 1.35, 7.66), body mass index (OR: 1.17; 95% CI: 1.03, 1.34) and dose of ribavirin (OR: 1.22; 95% CI: 1.06, 1.47) were independent predictors of a severe decline in haemoglobin (P<0.0001).
Conclusions
This study suggests that the polymorphisms in the ITPA gene influence the severity of anaemia during the first month of a DAA/RBV-based treatment in HCV-related cirrhosis.
References
1.
GowerE., EstesC., BlachS., Razavi-ShearerK., RazaviH.Global epidemiology and genotype distribution of the hepatitis C virus infection.J Hepatol2014; 61Suppl 1: S45–S57.
2.
CoppolaN., ZampinoR., BelliniG.Association between a polymorphism in cannabinoid receptor 2 and severe necroinflammation in patients with chronic hepatitis C.Clin Gastroenterol Hepatol2014; 12: 334–340.
3.
CoppolaN., PisapiaR., TonzielloG.Virological pattern in plasma, peripheral blood mononuclear cells and liver tissue and clinical outcome in chronic hepatitis B and C virus coinfection.Antivir Ther2008; 13: 307–318.
4.
MillerM.H., AgarwalK., AustinA.Review article: 2014 UK consensus guidelines–hepatitis C management and direct-acting anti-viral therapy.Aliment Pharmacol Ther2014; 39: 1363–1375.
5.
VezaliE., AghemoA., ColomboM.A review of the treatment of chronic hepatitis C virus infection in cirrhosis.ClinTher2010; 32: 2117–2138.
6.
BorgiaG., ReynaudL., GentileI.Pernicious anemia during IFN-alpha treatment for chronic hepatitis C.J Interferon Cytokine Res2003; 23: 11–12.
7.
European Association for Study of Liver.EASL Recommendations on Treatment of Hepatitis C 2015.J Hepatol2015; 63: 199–236.
8.
McHutchisonJ.G., MannsM., PatelK.Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C.Gastroenterology2002; 123: 1061–1069.
9.
FellayJ., ThompsonA.J., GeD.ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C.Nature2010; 464: 405–408.
10.
Di MarcoV., CalvarusoV., GrimaudoS.Role of IL-28B and inosine triphosphatase polymorphisms in efficacy and safety of peg-interferon and ribavirin in chronic hepatitis C compensated cirrhosis with and without oesophageal varices.J Viral Hepat2013; 20: 113–121.
11.
ScherzerT.M., StättermayerA.F., StauberR.Effect of gender and ITPA polymorphisms on ribavirin-induced anemia in chronic hepatitis C patients.J Hepatol2013; 59: 964–971.
12.
D'AvolioA., De NicolòA., CusatoJ.Association of ITPA polymorphismsr s6051702/rs1127354 instead of rs7270101/rs1127354 as predictor of ribavirin-associated anemia in chronic hepatitis C treated patients.Antiviral Res2013; 100: 114–119.
13.
ClarkP.J., AghemoA., DegasperiE.Inosine triphosphatase deficiency helps predict anaemia, anaemia management and response in chronic hepatitis C therapy.J Viral Hepat2013; 20: 858–866.
14.
ChayamaK., HayesC.N., AbeH.IL28B but not ITPA polymorphism is predictive of response to pegylated interferon, ribavirin, and telaprevir triple therapy in patients with genotype 1 hepatitis C.J Infect Dis2011; 204: 84–93.
15.
SuzukiF., SuzukiY., AkutaN.Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir.Hepatology2011; 53: 415–421.
16.
CoppolaN., ZampinoR., CirilloG.TM6SF2 E167K variant is associated with severe steatosis in chronic hepatitis C, regardless of PNPLA3 polymorphism.Liver Int2015; 35: 1959–1963.
17.
ZampinoR., PisaturoM.A., CirilloG.Hepatocellular carcinoma in chronic HBV-HCV co-infection is correlated to fibrosis and disease duration.Ann Hepatol2015; 14: 75–82.
18.
CoppolaN., GentileI., PasqualeG.Anti-HBc positivity was associated with histological cirrhosis in patients with chronic hepatitis C.Ann Hepatol2013; 13: 20–26.
19.
European Association for the Study of the Liver.EASL Clinical Practice Guidelines: management of hepatitis C virus infection.J Hepatol2011; 55: 245–264.
20.
FilippiniP., CoppolaN., PisapiaR.Virological and clinical aspects of HBV-HCV coinfection in HIV positive patients.J Med Virol2007; 79: 1679–1685.
21.
ZampinoR., AlessioL., MarroneA.Role of ITPA and IL28B variants in the management of chronic hepatitis C treatment.Infez Med2015; 23: 134–139.
22.
StickelF., HelblingB., HeimM.Critical review of the use of erythropoietin in the treatment of anaemia during therapy for chronic hepatitis C.J Viral Hepat2012; 19: 77–87.
CoppolaN., PisaturoM., SagnelliC., SagnelliE., AngelilloI.F.Peg-interferon plus ribavirin with or without boceprevir or telaprevir for HCV genotype 1: a meta-analysis on the role of response predictors.PLoS One2014; 9: e94542.
25.
CheungM.C., WalkerA.J., HudsonB.E.Outcomes after successful direct acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis.J Hepatol2016; pii: S0168-8278(16)30314-2.
26.
YounossiZ.M., StepanovaM., HenryL.Adherence to treatment of chronic hepatitis C: from interferon containing regimens to interferon and ribavirin free regimens.Medicine (Baltimore)2016; 95: e4151.
27.
De FranceschiL., FattovichG., TurriniF.Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage.Hepatology2000; 31: 997–1004.
ArenasM., DuleyJ., SumiS., SandersonJ., MarinakiA.The ITPA c.94C>A and g.IVS2+21A>C sequence variants contribute to missplicing of the ITPA gene.Biochim Biophys Acta2007; 1772: 96–102.
30.
HitomiY., CirulliE.T., FellayJ.Inosine triphosphate protects against ribavirin-induced adenosine triphosphate loss by adenylosuccinate synthase function.Gastroenterology2011; 140: 1314–1321.
31.
JimmersonL.C., UrbanT.J., TruesdaleA.Variant ITPA phenotypes are associated with increased ribavirin triphosphate levels.J Clin Pharmacol2016; 57: 118–124.
32.
ThompsonA.J., SantoroR., PiazzollaV.Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV2/3 but do not decrease dose reductions of RBV or increase SVR.Hepatology2011; 53: 389–395.
33.
ThompsonA.J., FellayJ., PatelK.Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia and decrease the need for ribavirin dose reduction.Gastroenterology2010; 139: 1181–1189.
34.
OchiH., MaekawaT., AbeH.ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy–a genome-wide study of Japanese HCV virus patients.Gastroenterology2010; 139: 1190–1197.
35.
KurosakiM., TanakaY., NishidaN.Model incorporating the ITPA genotype identifies patients at high risk of anemia and treatment failure with pegylated-interferon plus ribavirin therapy for chronic hepatitis C.J Med Virol2013; 85: 449–458.
36.
AghemoA., GrassiE., RumiM.G.Limited utility of ITPA deficiency to predict early anemia in HCV patients with advanced fibrosis receiving telaprevir.PLoS One2014; 9: e95881.
37.
AmpueroJ., Del CampoJ.A., RojasL.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 Virol2015; 68: 56–60.
38.
MorioK., ImamuraM., KawakamiY.Effects of ITPA polymorphism on decrease of hemoglobin during simeprevir, peg-interferon, and ribavirin combination treatment for chronic hepatitis C.Hepatol Res2016; 46: 1256–1263.
39.
AASLD/IDSA HCV Guidance Panel.Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus.Hepatology2015; 62: 932–954.
40.
OgawaE., FurusyoN., NomuraH.Effectiveness and safety of sofosbuvir plus ribavirin for HCV genotype 2 patients 65 and over with or without cirrhosis.Antiviral Res2016; 136: 37–44.
41.
MorioK., ImamuraM., KawakamiY.ITPA polymorphism effects on decrease of hemoglobin during sofosbuvir and ribavirin combination treatment for chronic hepatitis C.J Gastroenterol2017; 52: 746–753.
42.
AmpueroJ., Romero-GómezM.Pharmacogenetics of ribavirin-induced anemia in hepatitis C.Pharmacogenomics2016; 17: 1587–1594.
