Soluble Markers of Immune Activation Differentially Normalize and Selectively Associate with Improvement in AST, ALT, Albumin, and Transient Elastography During IFN-Free HCV Therapy

Lenche Kostadinova, Carey L. Shive, Elizabeth Zebrowski, Brianna Fuller, Kelsey Rife, Amy Hirsch, Anita Compan, Anita Moreland, Yngve Falck-Ytter, Daniel L. Popkin, Donald D. Anthony

Abstract


Background: During chronic hepatitis C virus (HCV) infection, Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) levels mark active liver inflammation and tissue damage, while albumin reflects synthetic liver function and nutritional status. Transient Elastography (TE) is a clinical measure of liver stiffness that facilitates evaluation of liver damage stage. While a portion of the TE score is attributable to liver fibrosis and relatively irreversible damage, another component of the TE score is attributable to liver inflammation or edema. Markers of inflammation during chronic HCV infection include soluble markers of immune activation, which are also associated with morbid outcome (including cardiovascular disease and liver-disease progression). Whether soluble markers of immune activation or changes in their level during HCV therapy relate to normalization of AST, ALT, Albumin, or TE score, is not clear.

Methods: We evaluated soluble markers of immune activation (plasma sCD14, IL-6, sCD163, autotaxin [ATX], and Mac2BP) and TE score, and their relationship in 20 HCV-infected patients before, during, and after HCV-directed IFN-free direct-acting antiviral (DAA) therapy. We evaluated normalization of parameters and the relationship between each over a 6-month window.

Results: Before therapy, serum AST levels positively correlated with plasma levels of sCD14, sCD163, and Mac2BP, while ALT levels positively correlated with Mac2BP. Serum albumin level negatively correlated with plasma IL-6 and ATX levels. IFN-free therapy uniformly resulted in sustained virological response at 12 and 24 weeks after therapy completion. After initiation of therapy AST and ALT normalized, while levels of ATX, Mac2BP, sCD163, and TE score partially normalized over 6 months. Additionally, change in AST level and APRI score correlated with change in sCD163, IL-6, and Mac2BP levels, and change in ALT correlated with change in IL-6 and Mac2BP levels. Improvement in TE score correlated with a decrease in the level of sCD14 at week 4, and almost statistically significant with decrease in sCD14 at weeks 20-24 after initiation of IFN-free HCV therapy.

Conclusions: Soluble markers of immune activation normalize or partially normalize at different rates after initiation of curative HCV DAA therapy, and TE scores improve, with wide variability in the degree of absolute improvement in liver stiffness from patient to patient. Decline magnitude of sCD14 was associated with improvement in TE score, while magnitude of improvement in AST correlated with reduction in sCD163 levels. These data provide support for a model where monocyte/Kupffer cell activation may account for a portion of the liver inflammation and edema, which is at least partially reversible following initiation of HCV DAA therapy.


Keywords


hepatitis C; cellular immunity; T cell; monocyte; inflammation

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References


1. Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH. Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med. 2000;132(4):296-305. PubMed PMID: 10681285.

2. Ansaldi F, Orsi A, Sticchi L, Bruzzone B, Icardi G. Hepatitis C virus in the new era: perspectives in epidemiology, prevention, diagnostics and predictors of response to therapy. World J Gastroenterol. 2014;20(29):9633-52. PubMed PMID: 25110404. Pubmed Central PMCID: PMC4123355. doi: 10.3748/wjg.v20.i29.9633

3. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908-43. PubMed PMID: 22424438. doi: 10.1016/j.jhep.2011.12.001

4. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Jr., Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347(13):975-82. PubMed PMID: 12324553. doi: 10.1056/NEJMoa020047

5. Hadziyannis SJ, Sette H, Jr., Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer H, Jr., Bernstein D, Rizzetto M, Zeuzem S, Pockros PJ, Lin A, Ackrill AM, Group PIS. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140(5):346-55. PubMed PMID: 14996676.

6. Lam BP, Jeffers T, Younoszai Z, Fazel Y, Younossi ZM. The changing landscape of hepatitis C virus therapy: focus on interferon-free treatment. Therap Adv Gastroenterol. 2015;8(5):298-312. PubMed PMID: 26327920. Pubmed Central PMCID: PMC4530432. doi: 10.1177/1756283X15587481

7. Simmons B, Saleem J, Heath K, Cooke GS, Hill A. Long-Term Treatment Outcomes of Patients Infected With Hepatitis C Virus: A Systematic Review and Meta-analysis of the Survival Benefit of Achieving a Sustained Virological Response. Clin Infect Dis. 2015;61(5):730-40. PubMed PMID: 25987643. Pubmed Central PMCID: PMC4530725. doi: 10.1093/cid/civ396

8. Backus LI, Belperio PS, Shahoumian TA, Mole LA. Direct-Acting Antiviral Sustained Virologic Response: Impact on Mortality in Patients without Advanced Liver Disease. Hepatology. 2018. PubMed PMID: 29377196. doi: 10.1002/hep.29811

9. Grandhe S, Frenette CT. Occurrence and Recurrence of Hepatocellular Carcinoma After Successful Direct-Acting Antiviral Therapy for Patients With Chronic Hepatitis C Virus Infection. Gastroenterol Hepatol (N Y). 2017;13(7):421-5. PubMed PMID: 28867970. Pubmed Central PMCID: PMC5572972.

10. Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, Christidis C, Ziol M, Poulet B, Kazemi F, Beaugrand M, Palau R. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003;29(12):1705-13. PubMed PMID: 14698338.

11. Talwalkar JA, Kurtz DM, Schoenleber SJ, West CP, Montori VM. Ultrasound-based transient elastography for the detection of hepatic fibrosis: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2007;5(10):1214-20. PubMed PMID: 17916549. doi: 10.1016/j.cgh.2007.07.020

12. Singh S, Facciorusso A, Loomba R, Falck-Ytter YT. Magnitude and Kinetics of Decrease in Liver Stiffness After Antiviral Therapy in Patients With Chronic Hepatitis C: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018;16(1):27-38 e4. PubMed PMID: 28479504. Pubmed Central PMCID: PMC5671365. doi: 10.1016/j.cgh.2017.04.038

13. Facciorusso A, Del Prete V, Turco A, Buccino RV, Nacchiero MC, Muscatiello N. Long-term liver stiffness assessment in hepatitis C virus patients undergoing antiviral therapy: Results from a 5-year cohort study. J Gastroenterol Hepatol. 2017. PubMed PMID: 28976021. doi: 10.1111/jgh.14008

14. Arima Y, Kawabe N, Hashimoto S, Harata M, Nitta Y, Murao M, Nakano T, Shimazaki H, Kobayashi K, Ichino N, Osakabe K, Nishikawa T, Okumura A, Ishikawa T, Yoshioka K. Reduction of liver stiffness by interferon treatment in the patients with chronic hepatitis C. Hepatol Res. 2010;40(4):383-92. PubMed PMID: 20236358. doi: 10.1111/j.1872-034X.2009.00618.x

15. Chekuri S, Nickerson J, Bichoupan K, Sefcik R, Doobay K, Chang S, DelBello D, Harty A, Dieterich DT, Perumalswami PV, Branch AD. Liver Stiffness Decreases Rapidly in Response to Successful Hepatitis C Treatment and Then Plateaus. PLoS One. 2016;11(7):e0159413. PubMed PMID: 27442255. Pubmed Central PMCID: PMC4956253. doi: 10.1371/journal.pone.0159413

16. Negash AA, Ramos HJ, Crochet N, Lau DT, Doehle B, Papic N, Delker DA, Jo J, Bertoletti A, Hagedorn CH, Gale M, Jr. IL-1beta production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease. PLoS Pathog. 2013;9(4):e1003330. PubMed PMID: 23633957. Pubmed Central PMCID: PMC3635973. doi: 10.1371/journal.ppat.1003330

17. Szabo G, Mandrekar P, Dolganiuc A. Innate immune response and hepatic inflammation. Semin Liver Dis. 2007;27(4):339-50. PubMed PMID: 17979071. doi: 10.1055/s-2007-991511

18. Ahlenstiel G, Titerence RH, Koh C, Edlich B, Feld JJ, Rotman Y, Ghany MG, Hoofnagle JH, Liang TJ, Heller T, Rehermann B. Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner. Gastroenterology. 2010;138(1):325-35 e1-2. PubMed PMID: 19747917. Pubmed Central PMCID: PMC2862622. doi: 10.1053/j.gastro.2009.08.066

19. Bility MT, Nio K, Li F, McGivern DR, Lemon SM, Feeney ER, Chung RT, Su L. Chronic hepatitis C infection-induced liver fibrogenesis is associated with M2 macrophage activation. Sci Rep. 2016;6:39520. PubMed PMID: 28000758. Pubmed Central PMCID: PMC5175173. doi: 10.1038/srep39520

20. Sandler NG, Koh C, Roque A, Eccleston JL, Siegel RB, Demino M, Kleiner DE, Deeks SG, Liang TJ, Heller T, Douek DC. Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. Gastroenterology. 2011;141(4):1220-30, 30 e1-3. PubMed PMID: 21726511. Pubmed Central PMCID: PMC3186837. doi: 10.1053/j.gastro.2011.06.063

21. Kazankov K, Barrera F, Moller HJ, Bibby BM, Vilstrup H, George J, Gronbaek H. Soluble CD163, a macrophage activation marker, is independently associated with fibrosis in patients with chronic viral hepatitis B and C. Hepatology. 2014;60(2):521-30. PubMed PMID: 24623375. doi: 10.1002/hep.27129

22. Kostadinova L, Shive CL, Judge C, Zebrowski E, Compan A, Rife K, Hirsch A, Falck-Ytter Y, Schlatzer DM, Li X, Chance MR, Rodriguez B, Popkin DL, Anthony DD. During Hepatitis C Virus (HCV) Infection and HCV-HIV Coinfection, an Elevated Plasma Level of Autotaxin Is Associated With Lysophosphatidic Acid and Markers of Immune Activation That Normalize During Interferon-Free HCV Therapy. J Infect Dis. 2016;214(9):1438-48. PubMed PMID: 27540113. doi: 10.1093/infdis/jiw372

23. Hiraoka A, Horiike N, Akbar SM, Michitaka K, Matsuyama T, Onji M. Expression of CD163 in the liver of patients with viral hepatitis. Pathol Res Pract. 2005;201(5):379-84. PubMed PMID: 16047947.

24. Sandahl TD, Gronbaek H, Moller HJ, Stoy S, Thomsen KL, Dige AK, Agnholt J, Hamilton-Dutoit S, Thiel S, Vilstrup H. Hepatic macrophage activation and the LPS pathway in patients with alcoholic hepatitis: a prospective cohort study. Am J Gastroenterol. 2014;109(11):1749-56. PubMed PMID: 25155228. doi: 10.1038/ajg.2014.262

25. Gronbaek H, Sandahl TD, Mortensen C, Vilstrup H, Moller HJ, Moller S. Soluble CD163, a marker of Kupffer cell activation, is related to portal hypertension in patients with liver cirrhosis. Aliment Pharmacol Ther. 2012;36(2):173-80. PubMed PMID: 22591184. doi: 10.1111/j.1365-2036.2012.05134.x

26. Kitchens RL, Thompson PA. Modulatory effects of sCD14 and LBP on LPS-host cell interactions. J Endotoxin Res. 2005;11(4):225-9. PubMed PMID: 16176659. doi: 10.1179/096805105X46565

27. Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science. 1990;249(4975):1431-3. PubMed PMID: 1698311.

28. Shive CL, Jiang W, Anthony DD, Lederman MM. Soluble CD14 is a nonspecific marker of monocyte activation. AIDS. 2015;29(10):1263-5. PubMed PMID: 26035325. Pubmed Central PMCID: PMC4452959. doi: 10.1097/QAD.0000000000000735

29. Yamazaki T, Joshita S, Umemura T, Usami Y, Sugiura A, Fujimori N, Shibata S, Ichikawa Y, Komatsu M, Matsumoto A, Igarashi K, Tanaka E. Association of Serum Autotaxin Levels with Liver Fibrosis in Patients with Chronic Hepatitis C. Sci Rep. 2017;7:46705. PubMed PMID: 28425454. Pubmed Central PMCID: PMC5397977. doi: 10.1038/srep46705

30. Mascia C, Vita S, Zuccala P, Marocco R, Tieghi T, Savinelli S, Rossi R, Iannetta M, Pozzetto I, Furlan C, Mengoni F, Mastroianni CM, Vullo V, Lichtner M. Changes in inflammatory biomarkers in HCV-infected patients undergoing direct acting antiviral-containing regimens with or without interferon. PLoS One. 2017;12(6):e0179400. PubMed PMID: 28636655. Pubmed Central PMCID: PMC5499435. doi: 10.1371/journal.pone.0179400

31. Deterding K, Honer Zu Siederdissen C, Port K, Solbach P, Sollik L, Kirschner J, Mix C, Cornberg J, Worzala D, Mix H, Manns MP, Cornberg M, Wedemeyer H. Improvement of liver function parameters in advanced HCV-associated liver cirrhosis by IFN-free antiviral therapies. Aliment Pharmacol Ther. 2015;42(7):889-901. PubMed PMID: 26250762. doi: 10.1111/apt.13343

32. George SL, Bacon BR, Brunt EM, Mihindukulasuriya KL, Hoffmann J, Di Bisceglie AM. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients. Hepatology. 2009;49(3):729-38. PubMed PMID: 19072828. Pubmed Central PMCID: PMC2731713. doi: 10.1002/hep.22694

33. Charpentier C, Champenois K, Gervais A, Landman R, Joly V, Le Gac S, Larrouy L, Damond F, Brun-Vezinet F, Descamps D, Yazdanpanah Y. Predictive value of liver enzymes and inflammatory biomarkers for the severity of liver fibrosis stage in HIV/HCV co-infected patients. PLoS One. 2013;8(3):e59205. PubMed PMID: 23527135. Pubmed Central PMCID: PMC3602202. doi: 10.1371/journal.pone.0059205

34. Medrano LM, Garcia-Broncano P, Berenguer J, Gonzalez-Garcia J, Jimenez-Sousa MA, Guardiola JM, Crespo M, Quereda C, Sanz J, Canorea I, Carrero A, Hontanon V, Munoz-Fernandez MA, Resino S, Group GbS. Elevated liver stiffness is linked to increased biomarkers of inflammation and immune activation in HIV/hepatitis C virus-coinfected patients. AIDS. 2018;32(9):1095-105. PubMed PMID: 29438197. doi: 10.1097/QAD.0000000000001787

35. Malone DF, Falconer K, Weiland O, Sandberg JK. The dynamic relationship between innate immune biomarkers and interferon-based treatment effects and outcome in hepatitis C virus infection is altered by telaprevir. PLoS One. 2014;9(8):e105665. PubMed PMID: 25166593. Pubmed Central PMCID: PMC4148339. doi: 10.1371/journal.pone.0105665

36. Yamazaki T, Joshita S, Umemura T, Usami Y, Sugiura A, Fujimori N, Kimura T, Matsumoto A, Igarashi K, Ota M, Tanaka E. Changes in serum levels of autotaxin with direct-acting antiviral therapy in patients with chronic hepatitis C. PLoS One. 2018;13(4):e0195632. PubMed PMID: 29617443. Pubmed Central PMCID: 5884565. doi: 10.1371/journal.pone.0195632

37. Lidofsky A, Holmes JA, Feeney ER, Kruger AJ, Salloum S, Zheng H, Seguin IS, Altinbas A, Masia R, Corey KE, Gustafson JL, Schaefer EA, Hunt PW, Deeks S, Somsouk M, Chew KW, Chung RT, Alatrakchi N. Macrophage Activation Marker Soluble CD163 is a Dynamic Marker of Liver Fibrogenesis in HIV/HCV Coinfection. J Infect Dis. 2018. PubMed PMID: 29868909. doi: 10.1093/infdis/jiy331

38. Balagopal A, Philp FH, Astemborski J, Block TM, Mehta A, Long R, Kirk GD, Mehta SH, Cox AL, Thomas DL, Ray SC. Human immunodeficiency virus-related microbial translocation and progression of hepatitis C. Gastroenterology. 2008;135(1):226-33. PubMed PMID: 18457674. Pubmed Central PMCID: PMC2644903. doi: 10.1053/j.gastro.2008.03.022

39. McGovern BH, Golan Y, Lopez M, Pratt D, Lawton A, Moore G, Epstein M, Knox TA. The impact of cirrhosis on CD4+ T cell counts in HIV-seronegative patients. Clin Infect Dis. 2007;44(3):431-7. PubMed PMID: 17205454. doi: 10.1086/509580


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Copyright (c) 2018 Lenche Kostadinova, Carey L. Shive, Elizabeth Zebrowski, Brianna Fuller, Kelsey Rife, Amy Hirsch, Anita Compan, Anita Moreland, Yngve Falck-Ytter, Daniel L. Popkin, Donald D. Anthony

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