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Inosine triphosphate pyrophosphohydrolase activity: more accurate predictor for ribavirin-induced anemia in hepatitis C infected patients than ITPA genotype

  • Nicole Chantal Peltenburg EMAIL logo , Jaap A. Bakker , Wim H.M. Vroemen , Robert J. de Knegt , Mathie P.G. Leers , Jörgen Bierau and Annelies Verbon
Published/Copyright: May 13, 2015
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 53 Issue 12

Abstract

Background:ITPA polymorphisms have been associated with protection against ribavirin-induced anemia in chronic hepatitis C (HCV) patients. Here we determined the association of inosine triphosphate pyrophosphohydrolase (inosine triphosphatase or ITPase) enzyme activity with ITPA genotype in predicting ribavirin-induced anemia.

Methods: In a cohort of 106 HCV patients, hemoglobin (Hb) values were evaluated after 4 weeks (T4) and at the time of lowest Hb value (Tnadir). ITPase activity was measured and ITPA genotype determined. Single-nucleotide polymorphisms (SNPs) tested were c.124+21A>C and c.94C>A. ITPase activity ≥1.11 mU/mol Hb was considered as normal.

Results: After 4 weeks of treatment, 78% of the patients with normal ITPase activity were anemic and 21% of the patients with low ITPase activity (p<0.001). Stratified by genotype, the percentages of anemic patients were: wt/wt 76%, wt/c.124+21A>C 46% (p=0.068), and wt/c.94C>A 29% (p=0.021). At Tnadir, virtually all patients with normal ITPase activity were anemic, compared to only 64% of the patients with low activity (p=0.02). Thirteen patients had wt/c.124+241A>C genotype. Within this group all five patients with normal ITPase activity and only four of eight with decreased activity developed anemia. Presence of HCV RNA did not influence ITPase activity.

Conclusions: This study is the first to report that ITPase activity predicts the development of anemia during ribavirin treatment. ITPase activity and ITPA genotype have high positive predictive values for development of ribavirin-induced anemia at any time during treatment, but ITPase activity predicts ribavirin-induced anemia more accurately.

Keywords: hepatitis C; inosine triphosphatase; inosine triphosphate pyrophosphohydrolase; ITPA; ITPase; ribavirin-induced anemia
Corresponding author: Nicole Chantal Peltenburg, Division of Infectious Diseases, Department of Internal Medicine, Erasmus MC, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands, Phone: +31 107040704, Fax: +31 107033875, E-mail: ; and Division Infectious Diseases, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
aPresent address: Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands

Acknowledgments

We want to thank Patricia J. Nelemans MD, PhD, Department of Epidemiology, Maastricht University Medical Centre, Maastricht, The Netherlands for her help with the statistical analysis.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Financial support: Roche Netherlands BV, (Grant / Award Number: 129014261).

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Lavanchy D. The global burden of hepatitis C. Liver Int 2009;29:74–81.10.1111/j.1478-3231.2008.01934.xSearch in Google Scholar

2. Yoshida H. Development of hepatocellular carcinoma from chronic hepatitis C. Nihon Rinsho 2011;69:309–13.Search in Google Scholar

3. Charlton M. Hepatitis C infection in liver transplantation. Am J Transplant 2001;1:197–203.10.1034/j.1600-6143.2001.001003197.xSearch in Google Scholar

4. Unknown. Hepatitis C information for health professionals. Atlanta2012 [updated 16 Aug 2012]; Available from: http://www.cdc.gov/hepatitis/HCV/HCVfaq.htm=section1. Accessed 19 March, 2012.Search in Google Scholar

5. Afdhal NH, McHutchison JG, Zeuzem S, Mangia A, Pawlotsky JM, Murray JS, et al. Hepatitis C pharmacogenetics: state of the art in 2010. Hepatology 2011;53:336–45.10.1002/hep.24052Search in Google Scholar

6. Soriano V, Poveda E, Vispo E, Labarga P, Rallón N, Barreiro P. Pharmacogenetics of hepatitis C. J Antimicrob Chemother 2012;67:523–9.10.1093/jac/dkr506Search in Google Scholar

7. Van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. J Am Med Ass 2012;308:2584–93.10.1001/jama.2012.144878Search in Google Scholar

8. Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al. Telaprevir and Peginterferon with or without ribavirin for chronic HCV infection. New Engl J Med 2009;360:1839–50.10.1056/NEJMoa0807650Search in Google Scholar

9. Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. New Engl J Med 2011;364:1195–206.10.1056/NEJMoa1010494Search in Google Scholar

10. Fried MW, Buti M, Dore GJ, Flisiak R, Ferenci P, Jacobson I, et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study. Hepatology 2013;58:1918–29.10.1002/hep.26641Search in Google Scholar

11. Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad F, Sheikh AM, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1,2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013;13:401–8.10.1016/S1473-3099(13)70033-1Search in Google Scholar

12. Rosen HR. Chronic hepatitis C infection. New Engl J Med 2011;364:2429–38.10.1056/NEJMcp1006613Search in Google Scholar PubMed

13. Fried MW, Schiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection. New Engl J Med 2002;347:975–82.10.1056/NEJMoa020047Search in Google Scholar PubMed

14. Pár A. Genetic polymorphisms as predictors of response to antiviral treatment in chronic hepatitis C virus infection. Orv Hetil 2011;152:876–81.10.1556/OH.2011.29113Search in Google Scholar PubMed

15. Tanaka Y. Interleukin28B and inosine triphosphatase help to personalize hepatitis C treatment. Digestion 2011;84(Suppl 1): 50–5.10.1159/000333214Search in Google Scholar PubMed

16. Schaefer EA Chung RT. The impact of human gene polymorphisms on HCV infection and disease outcome. Semin Liver Dis 2011;31:375–86.10.1055/s-0031-1297926Search in Google Scholar PubMed

17. Cariani E, Villa E, Rota C, Critelli R, Trenti T. Translating pharmacogenetics into clinical practice: interleukin (IL)28B and inosine triphosphatase (ITPA) polymophisms in hepatitis C virus (HCV) infection. Clin Chem Lab Med 2011;49:1247–56.10.1515/CCLM.2011.618Search in Google Scholar PubMed

18. Holmes JA, Desmond PV, Thompson AJ. Redefining baseline demographics: the role of genetic testing in hepatitis C virus infection. Clin Liver Dis 2011;15:497–513.10.1016/j.cld.2011.05.009Search in Google Scholar PubMed

19. Thompson AJ, Santoro R, Piazzolla V, Clark PJ, Naggie S, Tillmann HL, et al. 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. Hepatology 2011;53:389–95.10.1002/hep.24068Search in Google Scholar PubMed PubMed Central

20. Nishimura T, Osaki R, Shioya M, Imaeda H, Aomatsu T, Takeuchi T, et al. Polymorphism of the inosine triphosphate pyrophosphatase gene predicts ribavirin-induced anemia in chronic hepatitis C patients. Mol Med Report 2012;5:517–20.Search in Google Scholar

21. Lötsch J, Hofmann WP, Schlecker C, Zeuzem S, Geisslinger G, Ultsch A, et al. Single and combined IL28B, ITPA and SLC28A3 host genetic markers modulating response to anti-hepatitis C therapy. Pharmacogenomics 2011;12:1729–40.10.2217/pgs.11.99Search in Google Scholar PubMed

22. Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, Shianna KV, et al. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature 2010;464:405–8.10.1038/nature08825Search in Google Scholar PubMed

23. Azakami T, Hayes CN, Sezaki H, Kobayashi M, Akuta N, Suzuki F, et al. Common genetic polymorphism of ITPA gene affects ribavirin-induced anemia and effect of peg-interferon plus ribavirin therapy. J Med Virol 2011;83:1048–57.10.1002/jmv.22069Search in Google Scholar PubMed

24. Kurosaki M, Tanaka Y, Tanaka K, Suzuki Y, Hoshioka Y, Tamaki N, et al. Relationship between polymorphisms of the inosine triphosphatase gene and anaemia or outcome after treatment with pegylated interferon and ribavirin. Antivir Ther 2011;16:685–94.10.3851/IMP1796Search in Google Scholar PubMed

25. Sakamoto N, Tanaka Y, Nakagawa M, Yatsuhashi H, Nishiguchi S, Enomoto N, et al. ITPA gene variant protects against anemia induced by pegylated interferon-α and ribavirin therapy for Japanese patients with chronic hepatitis C. Hepatol Res 2010;40:1063–71.10.1111/j.1872-034X.2010.00741.xSearch in Google Scholar PubMed

26. Bakker JA, Bierau J, Drent M. Role for ITPA variants in the clinical course of pulmonary Langerhans’ cell histiocytosis? Eur Respir J 2010;36:684–6.10.1183/09031936.00026610Search in Google Scholar PubMed

27. Marinaki AM, Duley JA, Arenas M, Ansari A, Sumi S, Lewis CM, et al. Mutation in the ITPA gene predicts intolerance to azathioprine. Nucleos Nucleot Nucl 2004;23:1393–7.10.1081/NCN-200027639Search in Google Scholar PubMed

28. Stepchenkova EL, Tarakhovskaya ER, Spitler K, Frahm C, Menezes MR, Simone PD, et al. Functional study of the P32T ITPA variant associated with drug sensitivity in humans. J Mol Biol 2009;392:602–13.10.1016/j.jmb.2009.07.051Search in Google Scholar PubMed PubMed Central

29. Van Dieren JM, Hansen BE, Kuipers EJ, Nieuwenhuis EE, Van der Woude CJ. Meta-analysis: inosine triphosphate pyrophosphatase polymorphisms and thiopurine toxicity in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2007;26:643–52.10.1111/j.1365-2036.2007.03412.xSearch in Google Scholar PubMed

30. Van Dieren JM, Van Vuuren AJ, Kusters JG, Nieuwenhuis EE, Kuipers EJ, Van der Woude CJ. ITPA genotyping is not predictive for the development of side effects in AZA treated inflammatory bowel disease patients. Gut 2005;54:1664.Search in Google Scholar

31. Bruijne de J, Buster EH, Gelderblom HC, Brouwer JT, Knegt de RJ, Erpecum van KJ, et al. Treatment of chronic hepatitis C virus infection – Dutch national guidelines. Neth J Med 2008;66:311–22.Search in Google Scholar

32. WHO/UNICEF/UNU. Iron deficiency anaemia assessment, prevention and control: a guide for programme managers. Geneva: World Health Organization, 2001.Search in Google Scholar

33. Bierau J, Bakker JA, Lindhout M, Van Gennip AH. Determination of ITPase activity in erythrocyte lysates obtained for determination of TPMT activity. Nucleos Nucleot Nucl 2006;25:1129–32.10.1080/15257770600894253Search in Google Scholar PubMed

34. Shipkova M, Lorenz K, Oellerich M, Wieland E, Von Ahsen N. Measurement of erythrocyte inosine triphosphate pyrophosphohydrolase (ITPA) activity by HPLC and correlation of ITPA genotype-phenotype in a Caucasian population. Clin Chem 2006;52:240–7.10.1373/clinchem.2005.059501Search in Google Scholar PubMed

35. Bierau J, Bakker JA, Schippers JA, Grashorn JA, Lindhout M, Lowe SH, et al. Erythrocyte inosine triphosphatase activity is decreased in HIV-seropositive individuals. PLoS One 2012;7:e30175.10.1371/journal.pone.0030175Search in Google Scholar PubMed PubMed Central

36. Bierau J, Lindhout M, Bakker JA. Pharmacogenetic significance of inosine triphosphatase. Pharmacogenomics 2007;8:1221–8.10.2217/14622416.8.9.1221Search in Google Scholar PubMed

37. D’Avolio A, Ciancio A, Siccardi M, Smedile A, Baietto L, Simiele M, et al. Inosine triphosphatase polymorphisms and ribavirin pharmacokinetics as determinants of ribavirin-associate anemia in patients receiving standard anti-HCV treatment. Ther Drug Monit 2012;34:165–70.10.1097/FTD.0b013e31824bf778Search in Google Scholar PubMed

38. Ochi H, Maekawa T, Abe H, Hayashida Y, Nakano R, Kubo M, et al. ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy – a genome-wide study of Japanese HCV virus patients. Gastroenterology 2010;139:1190–7.10.1053/j.gastro.2010.06.071Search in Google Scholar PubMed

39. Suzuki F, Suzuki Y, Akuta N, Sezaki H, Hirakawa M, Kawamura Y, et al. Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir. Hepatology 2011;53:415–21.10.1002/hep.24058Search in Google Scholar PubMed

40. Thompson AJ, Fellay J, Patel K, Tillmann HL, Naggie S, Ge D, et al. Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia and decrease the need for ribavirin dose reduction. Gastroenterology 2010;139:1181–9.10.1053/j.gastro.2010.06.016Search in Google Scholar PubMed PubMed Central

41. Clark PJ, Aghemo A, Degasperi E, Galmozzi E, Vock DM, Patel K, et al. Inosine triphosphatase deficiency helps predict anaemia, anaemia management and response in chronic hepatitis C therapy. J Viral Hepat 2013;20:858–66.10.1111/jvh.12113Search in Google Scholar PubMed

42. Rembeck K, Waldenström J, Hellstrand K, Nilsson S, Nyström K, Martner A, et al. Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3. Hepatology 2014;59:2131–9.10.1002/hep.27009Search in Google Scholar PubMed

43. Bakker JA, Lindhout M, Habets DD, Van den Wijngaard A, Paulussen AD, Bierau J. The effect of ITPA polymorphisms on the enzyme kinetic properties of human erythrocyte inosine triphosphatase toward its substrates ITP and 6-Thio-ITP. Nucleos Nucleot Nucl 2011;30:839–49.10.1080/15257770.2011.606789Search in Google Scholar PubMed

44. Sumi S, Marinaki AM, Arenas M, Fairbanks L, Shobowale-Bakre M, Rees DC, et al. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum Genet 2002;111:360–7.10.1007/s00439-002-0798-zSearch in Google Scholar PubMed

45. Naggie S, Rallon NI, Benito JM, Morello J, Rodriguez-Novoa S, Clark PJ, et al. Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia in HIV/HCV-coinfected patients with all HCV genotypes. J Infect Dis 2012;205:376–83.10.1093/infdis/jir754Search in Google Scholar PubMed PubMed Central

46. Hitomi Y, Cirulli ET, Fellay J, McHutchison JG, Thompson AJ, Gumbs CE, et al. Inosine triphosphate protects against ribavirin-induced adenosine triphosphate loss by adenylosuccinate synthase function. Gastroenterology 2011;140:1314–21.10.1053/j.gastro.2010.12.038Search in Google Scholar PubMed

47. Maeda T, Sumi S, Ueta A, Ohkubo Y, Ito T, Marinaki AM, et al. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency in the Japanese population. Mol Genet Metab 2005;85:271–9.10.1016/j.ymgme.2005.03.011Search in Google Scholar PubMed

Article note

Previous presentation: Winner of oral presentation in category ‘Clinical’; April 2014; Dutch Association of Clinical Chemistry and Laboratory Medicines.

Received: 2015-1-17
Accepted: 2015-4-14
Published Online: 2015-5-13
Published in Print: 2015-11-1

©2015 by De Gruyter

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https://doi.org/10.1515/cclm-2015-0057
Keywords for this article
hepatitis C; inosine triphosphatase; inosine triphosphate pyrophosphohydrolase; ITPA; ITPase; ribavirin-induced anemia

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Biomarkers of inflammatory bowel disease: ready for prime time?
  4. Review
  5. Discriminant indices for distinguishing thalassemia and iron deficiency in patients with microcytic anemia: a meta-analysis
  6. Mini Reviews
  7. Cell-free DNA for diagnosing myocardial infarction: not ready for prime time
  8. The Laboratory Medicine and the care of patients infected by the Ebola virus. Experience in a reference hospital of Madrid, Spain
  9. Opinion Papers
  10. Theranos phenomenon − part 2
  11. Considerations in parathyroid hormone testing
  12. Quantity quotient reporting. Comparison of various models
  13. Genetics and Molecular Diagnostics
  14. Assessing quality and functionality of DNA isolated from FFPE tissues through external quality assessment in tissue banks
  15. Influence of storage conditions and extraction methods on the quantity and quality of circulating cell-free DNA (ccfDNA): the SPIDIA-DNAplas External Quality Assessment experience
  16. Non-invasive fetal ABO genotyping in maternal plasma using real-time PCR
  17. Screening non-deletion α-thalassaemia mutations in the HBA1 and HBA2 genes by high-resolution melting analysis
  18. General Clinical Chemistry and Laboratory Medicine
  19. European views on patients directly obtaining their laboratory test results
  20. Diagnostic performances of clinical laboratory tests using Triton X-100 to reduce the biohazard associated with routine testing of Ebola virus-infected patients
  21. Thrombin generation, D-dimer and protein S in uncomplicated pregnancy
  22. Multi-analyte analysis of non-vitamin K antagonist oral anticoagulants in human plasma using tandem mass spectrometry
  23. Second generation analysis of antinuclear antibody (ANA) by combination of screening and confirmatory testing
  24. Faecal leukocyte esterase activity is an alternative biomarker in inflammatory bowel disease
  25. Reference Values and Biological Variations
  26. Total folate and 5-methyltetrahydrofolate in the cerebrospinal fluid of children: correlation and reference values
  27. Effect of age and gender on reference intervals of red blood cell distribution width (RDW) and mean red cell volume (MCV)
  28. Infectious Diseases
  29. Inosine triphosphate pyrophosphohydrolase activity: more accurate predictor for ribavirin-induced anemia in hepatitis C infected patients than ITPA genotype
  30. The ratio of calprotectin to total protein as a diagnostic and prognostic marker for spontaneous bacterial peritonitis in patients with liver cirrhosis and ascites
  31. Letter to the Editors
  32. Misleading high-sensitivity troponin algorithm for NSTEMI in the ESC guidelines
  33. Adjustment of serum potassium for age and platelet count. A simple step forward towards personalized medicine
  34. The impact of Tween 20 on repeatability of amyloid β and tau measurements in cerebrospinal fluid
  35. Effect of storage time and temperature on the generation of reactive oxygen species in peripheral blood leukocytes
  36. Iohexol interference in the α2-globulin fraction of the serum protein capillary electrophoresis
  37. A functional variant in the γ-glutamyltransferase (GGT)1 gene is associated with airflow obstruction in smokers
  38. Comparison of measured venous carbon dioxide and calculated arterial bicarbonates according to the PaCO2 and PaO2 cut-off values of obesity hypoventilation syndrome
  39. Creatinine, Jaffe, and glucose: another inconvenient truth
  40. Analytical evaluation of a new liquid immunoturbidimetric assay for the determination of ferritin in serum
  41. Analytical assessment of the novel homocysteine liquid enzymatic assay on Beckman Coulter AU5800
  42. Immunoglobulin IgA, IgD, IgG, IgM and IgG subclass reference values in adults
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